1 LDL, HDL and endocrine-related cancer: From pathogenic 2 mechanisms to therapies 3 Giovanna Revillaa,b,*, Lídia Cedóa,c,*, Mireia Tondoa,*, José, Antonio Morala,d,e, 4 Ignacio Péreze, Rosa Corcoya,e,f, Francisco Blanco-Vacaa,b,c,†, Eugènia Matoa,f,† and 5 Joan Carles Escolà-Gila,b,c† 6 7 a Institut d’Investigacions Biomèdiques (IIB) Sant Pau, C/ Sant Quintí 77, 08041 8 Barcelona Spain. grevilla@santpau.cat; mfarras@santpau.cat; lcedo@santpau.cat; 9 mtondo@santpau.cat; amoral@santpau.cat; jperezg@santpau.cat; rcorcoy@santpau.cat; 10 fblancova@santpau.cat; emato@santpau.cat; jescola@santpau.cat 11 b 12 Departament de Bioquímica i Biologia Molecular, Universitat Autònoma de 13 Barcelona, C/ Antoni M. Claret 167, 08025 Barcelona, Spain 14 c 15 CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), C/ 16 Monforte de Lemos 3-5, 28029 Madrid, Spain 17 d 18 Department of General Surgery—Hospital de la Santa Creu i Sant Pau, C/ Sant Quintí 19 89, 08041 Barcelona, Spain. 20 e 21 Department de Medicina Universitat Autònoma de Barcelona, C/ Antoni M. Claret 22 167, 08025 Barcelona, Spain 23 f 24 CIBER de Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN), C/ Monforte 25 de Lemos 3-5, 28029 Madrid, Spain 26 27 *These authors contributed equally 28 † Senior authors 29 Corresponding authors: Joan Carles Escolà-Gil (jescola@santpau.cat), Francisco 30 Blanco-Vaca (fblancova@santpau.cat) or Eugènia Mato (emato@santpau.cat). Institut 31 d’Investigacions Biomèdiques (IIB) Sant Pau, C/ Sant Quintí 77, 08041 Barcelona 32 Spain. Telf : +34-935537588 1 33 Abstract: 34 35 Keywords: cancer; endocrine; cholesterol; HDL; LDL 36 2 37 1. Introduction 38 39 Cholesterol plays a critical role in cancer progression by enhancing cell proliferation, 40 migration, and invasion [1]. Endocrine-related cancers include those affecting the 41 hormone secreting tissues, such as the adrenal, pancreatic, thyroid, and reproductive 42 tissues, but also the main endocrine target tissues [4] such as the breast and prostate. 43 44 Intestinal cholesterol absorption is highly variable, but on average only 30% of serum 45 cholesterol in humans derive from the diet in humans [5,6]. All endocrine cells can 46 synthesize their own cholesterol, but circulating cholesterol is primarily synthesized in 47 the liver and is mainly transported to cells through low-density lipoproteins (LDL) [6]. 48 Indeed, circulating cholesterol balance is mainly determined by the hepatic synthetic 49 rate of cholesterol and th rate of excretion from the body, either as cholesterol or bile 50 [5,6]. 51 52 Intracellular cholesterol homeostasis is tightly regulated in most cell types 53 (MACROFAGOS NO) [7]. Acetyl-CoA is the major precursor of cholesterol synthesis, 54 producing hydroxyl methylglutaryl-CoA (HMG-CoA). The rate limiting step in the 55 cholesterol biosynthetic pathway is the reduction of HMG-CoA to mevalonate reaction 56 catalyzed by the enzyme HMG-CoA reductase (HMGCR). Alternatively, cells may 57 increase exogenous cholesterol uptake by upregulating the LDL receptor (LDLR) and 58 other lipoprotein receptors, such as LDLR-related protein 1 (LRP1) and scavenger 59 receptor type BI (SR-BI). A reduction of endoplasmic reticulum cholesterol levels 60 triggers the translocation of the transcriptional factor sterol regulatory element–binding 61 protein-2 (SREBP-2) to the nucleus, thereby iincresing expression of t HMGCR and and 62 LDLR expression, promoting both cholesterol biosynthesis and uptake [8]. Conversely, 63 intracellular cholesterol accumulation inactivates the SREBP-2 pathway. Excess of 64 intracellular unesterified cholesterol can be accumulated as cholesterol esters, mainly by 65 the action of acyl-coenzyme A: cholesterol acyltransferase (ACAT) 1 66 67 High-density lipoprotein (HDL) is the main lipoprotein cholesterol transporter to the 68 major steroidogenic organs. The adrenal and ovary preferentially take up cholesterol 69 from HDL via the SR-BI [9]. In contrast, the interaction between HDL and the 70 membrane ATP-binding cassette transporter (ABC) A1 has a key role in HDL-mediated 3 71 efflux of cellular unesterified cholesterol. Some functional oxysterols, such as 24- 72 hydroxycholesterol (HC), 25-HC, or 27-HC, are significant activators of liver X 73 receptors (LXRαβ ¡¿¿Y LRX ALFA’??) which can upregulate ABCA1, but also repress 74 LDLR pathway [10,11]. Furthermore, HDL, mainly through apolipoprotein (APO) A1 75 and paraoxonase (PON) 1, exhibit potent antioxidant and anti-inflammatory properties, 76 thus potentially antagonizing two main hallmarks of cancer progression (reviewed in 77 [12,13]). 78 79 In this article, we aimed to review the progress to date in the studyof e LDL and HDL 80 on intracellular cholesterol homeostasis impacting carcinogenic pathways in endocrine- 81 related cancers. For this analysis, PubMed was searched comprehensively with 82 combinations of the keyword breast, prostate, thyroid, pancreatic, ovarian, testicular, 83 and adrenal cancer and the rest of keywords related with intracellular cholesterol, LDL, 84 and HDL, as well as those with statins, ezetimibe, proprotein convertase subtilisin/kexin 85 9 (PCSK9), fibrates, niacin, cholesterol ester transfer protein (CETP) and cancer. 4 86 2. Breast cancer 87 88 Breast cancer was the third most common cancer worldwide in 2016. About 1.7 million 89 incident cases were estimated, increasing by 29% between 2006 and 2016. Moreover, 90 breast cancer was the fifth leading cause of cancer deaths , and the leading cause of 91 cancer death for women. Concretely, it is estimated that 1 in 20 women developed 92 breast cancer over their lifetime [14]. 93 94 Breast cancer is a complex disease which includes a variety of entities with differences 95 in clinical, morphological, and molecular attributes. Taking into account the expression 96 of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth 97 factor receptor 2 (HER2), breast cancers can be classified for predicting prognosis and 98 response to treatment [15]. The presence or absence of these biomarkers identifies the 99 three main sub-types of breast cancer: luminal (ER-positive), HER2-like (mainly ER- 100 negative and HER2-positive), and basal-like (mainly ER-negative, PR-negative, and 101 HER2-negative, also known as triple-negative) [16]. The two last sub-types are the most 102 aggressive [17]. 103 104 2.1. Cholesterol and breast cancer 105 Some studies have been published studying the relationship between total serum 106 cholesterol levels and risk of breast cancer, despite reporting divergent results. A large 107 prospective study performed in Korea found that high total cholesterol (≥ 240 mg/dL) 108 was positively associated with breast cancer in women compared with low cholesterol 109 levels (< 160 mg/dL) [18]. In contrast, total cholesterol was found inversely associated 110 with breast cancer risk in a French cohort [19], and other studies failed in finding 111 association [20–24]. These discrepancies may be due to differences in the impact of 112 cholesterol on the breast cancer sub-types, although this possibility needs further 113 research [25]. Moreover, dietary cholesterol intake was found positively associated with 114 the risk of postmenopausal breast cancer in a Canadian case-control study [26], results 115 that were corroborated by a meta-analysis, which reported that a cholesterol intake 116 greater than 370 mg/day increased the risk of breast cancer [27]. 117 The pathogenic role of cholesterol in breast cancer has also been investigated in 118 different experimental mouse models. In this sense, MMTV-PyMT mice fed a high- 119 fat/high-cholesterol (HFHC) diet showed accelerated and enhanced tumor progression 5 120 [28]. These mice are transgenic for the viral polyoma middle-T (PyMT) antigen under 121 the control of the murine mammary tumor virus (MMTV) promoter, that specifically 122 directs expression to the mammary epithelium, and are a model of luminal ER-positive 123 breast cancer [29]. Similarly, HFHC diet administration to immunodeficient mice 124 implanted orthotopically with the triple-negative breast cancer cells MDA-MB-231 125 induced angiogenesis and accelerated breast tumor growth [30]. The effects of 126 hypercholesterolemia on mammary tumor growth and metastasis were also explored in 127 APOE knockout mice, which exhibit marked dyslipidemia with elevated cholesterol 128 remnant lipoproteins. APOE knockout mice were fed HFHC diet and injected with non- 129 metastatic Met-1 and metastatic Mvt-1 mammary cancer cells obtained from PyMT 130 mice and c-Myc/VEGF tumor explants, respectively. Results showed that APOE 131 knockout mice displayed increased tumor growth only when the HFHC diet was 132 administered, not in standard chow diet, thereby indicating that high dietary fat and 133 cholesterol are necessary to promote tumorigenesis. Moreover, these mice exhibited a 134 greater number of pulmonary metastases [31]. Finally, two studies evaluated the effects 135 of a high-cholesterol diet, in order to specific address the effects of cholesterol, without 136 the interference of high saturated fat, in breast cancer development. PyMT mice 137 developed palpable tumors earlier when fed a high-cholesterol diet compared to those 138 fed a chow diet [32]. Similarly, high-cholesterol diet promoted breast tumor growth in 139 xenograft models of breast cancer, which presented lung metastases more frequently 140 [33]. Overall, these studies revealed that HFHC diet had deleterious effects in breast 141 cancer development, at least in part attributed to its high-cholesterol content. 142 143 2.2. LDL and breast cancer 144 145 LDL cholesterol (LDL-C) levels, at diagnosis of breast cancer, were found as a 146 prognostic factor of breast tumor progression in a prospective study in Portugal. In this 147 sense, patients with higher levels of LDL-C at diagnosis had larger tumors, with higher 148 differentiation and proliferative rate, and with more frequent HER2-like phenotype 149 [34]. A Mendelian randomization study showed that genetically raised LDL-C was 150 associated with higher risk of breast cancer, and specifically ER-positive breast cancer 151 [35]. However, no association was found between LDL-C and breast cancer risk in 152 another Mendelian randomization analysis [36], or in other meta-analyses and 6 153 prospective studies [21,37–40]. In contrast, two studies found that LDL-C or non-HDL- 154 cholesterol were inversely associated with the risk of breast cancer [20,41]. 155 156 The impact of LDL-C on breast cancer cells is divergent depending on their expression 157 of the main lipoprotein receptors. LDL-C promoted proliferation [42–44] and migration 158 [33,45], mainly in ER-negative cell lines, but not in ER-positive cells. LDL-C also 159 induced proliferation in the HER2-positive cell line BT-474 [33]. These differences may 160 be explained by the increased LDL-C internalization and esterification in HER2-like or 161 triple-negative cells, as they presented with increased expression of LDLR and 162 increased expression and activity of ACAT1 [43,46]. 163 164 A recent study reported that the treatment of mouse breast cancer 4T1 cells with LDL 165 increased the levels of reactive oxygen species (ROS), which in turn, induced cell 166 migration. These effects were counteracted by the addition of an inhibitor of xanthine 167 oxidase, an enzyme that generates ROS [47]. Similarly, mice that exhibited high LDL-C 168 levels due to a HFHC diet which were injected with these cells showed increased tumor 169 growth and metastasis compared to that fed with chow diet, and both were markedly 170 inhibited by xanthine oxidase inhibition, mainly through ERK signaling pathway 171 inhibition [47]. 172 173 Beyond LDL-C levels, the enhanced production of oxidized LDL (oxLDL) is a common 174 feature of both dyslipidemia and carcinogenesis. Patients with breast cancer showed 175 increased serum levels of oxLDL, and circulating levels of oxLDL were positively 176 associated with breast cancer risk [48]. The uptake of oxLDL is also increased in breast 177 cancer, as the lectin-like oxLDL receptor 1 (OLR1) is overexpressed in breast cancer 178 tissue [49], as well as in the breast cancer cell line HCC1143 compared to the NO SE 179 PORQUE DICES NORMAL, NO ES TUMORAL? mammary epithelial cell line 180 MCF10A [50]. In line with these results, upregulation of OLR1 in breast cancer cell 181 lines enhanced cell migration [50,51]. Moreover, ORL1 depletion or inhibition 182 significantly repressed the invasion and migration of breast cancer cells [50–52]. One of 183 the mechanisms by which oxLDL promotes breast carcinogenesis could be the 184 stimulation of miR-21 and the consequent activation of the PI3K/Akt pathway, as was 185 described in MCF10A cells treated with oxLDL [53]. Further oxLDL and OLR1 186 activate the inflammatory pathway through the nuclear factor κB (NF-κB), leading to 7 187 transformation [54]. Accordingly, forced overexpression of OLR1 resulted in 188 upregulation of NF-κB and target pro-oncogenes involved in apoptosis inhibition and 189 cell cycle regulation in both HCC1143 and MCF10A cells [50]. Moreover, TBC1D3, a 190 hominoid-specific oncogene, induced the expression of OLR1 in breast cancer cells, 191 regulated by NF-κB signaling [52]. Therefore, OLR1 may act as an oncogene by 192 activation of NF-κB target genes responsible for proliferation, migration, and apoptosis 193 inhibition [50]. 194 195 2.2. HDL and breast cancer 196 Controversy also exists about the association between HDL-cholesterol (HDL-C) levels 197 and breast cancer risk. Two different Mendelian randomization studies found that 198 genetically raised HDL-C increased the risk of breast cancer [35,36]. Conversely, a 199 prospective study found that HDL-C levels were inversely associated with breast cancer 200 risk [19]. In line with these findings, a retrospective study reported that low HDL-C 201 levels were significantly associated with worse overall survival in breast cancer patients 202 [55]. Other studies found the same association taking into account the menopausal 203 status; some found that low HDL-C among premenopausal women increased breast 204 cancer risk [37,56,57], whereas others found the same association only in 205 postmenopausal women [21,58]. Finally, some studies did not find association between 206 HDL-C and breast cancer risk [38,39,59] or survival [59]. Some in vitro analyses 207 supported the positive association of HDL-C in breast cancer risk, as HDL increased 208 proliferation in breast cancer cell lines [44,60], and stimulated migration through the 209 Akt and ERK1/2 signal transduction pathways [61]. In contrast, the protective role of 210 HDL in breast cancer can be attributed to some of their components, e.g. PON1 or 211 APOA1, which possess antioxidant and anti-inflammatory properties. PON1 activity 212 was found lower in patients with breast cancer compared to controls [62–64]. PON1 213 activity was found unchanged between metastatic and non-metastatic cancer patients 214 [62], but it was found lower in patients who needed neoadjuvant chemotherapy [64]. 215 Moreover, genetic polymorphisms in the antioxidant enzyme PON1 could influence 216 individual susceptibility to breast cancer. In the case of Q192R polymorphism, QQ 217 homozygotes had higher risk of the breast disease [63,65,66]. These effects could be 218 due to the differences in the activity of the Q and R alleles toward some substrates [67]. 219 However, other studies did not find association between Q192R genotypes and breast 220 cancer risk [68–71]. Concerning L55M polymorphism, carriers of at least one M allele 8 221 had increased risk for breast cancer [65,66,68–72], probably due to the lower levels of 222 mRNA and activity of the PON1-55M isoform compared to the 55L isoform [67]. 223 Therefore, L55M polymorphism could be considered as a molecular biomarker to 224 identify susceptible women to breast cancer. On the other hand, APOA1 levels were 225 found inversely associated with breast cancer risk [19,73,74]. However, human APOA1 226 transgenic mice with increased APOA1-containing HDL was not able to delay or reduce 227 breast tumor development in PyMT mice despite reducing oxLDL levels [75]. This 228 point could be related with the large cholesterol-containing HDL particles of PyMT 229 mice expressing human APOA1 [75]; they could constitute an extra cholesterol source 230 for the tumor. In contrast, APOA2 (which possesses proinflammatory actions and 231 decreased capacity to protect against LDL oxidation) overexpression increased breast 232 tumor burden in PyMT mice [76]. In vitro experiments have demonstrated that 233 overexpression of APOA1 in breast cancer cells increased the aggressive potential of 234 the ER-positive MCF-7 cells, while decreased the aggressiveness of the triple-negative 235 cell line MDA-MBA-231. In this way, overexpression of APOA1 decreased 236 proliferation and migration in MDA-MBA-231 cells, accompanied by increased ABCA1 237 levels and increased transfer of cholesterol to the plasma membrane. The opposite 238 effects were observed in MCF-7 cells, in which the transfer to the plasma membrane 239 seemed to be inefficient, thereby leading to intracellular accumulation of free- 240 cholesterol [77]. 241 242 Women with type 2 diabetes mellitus (T2DM) have an increased risk of developing 243 breast cancer [78,79]. This association between T2DM and breast cancer could be 244 attributed, at least in part, to the formation of functionally deficient HDL particles in 245 T2DM, which involves glycation and oxidation of APOs and other HDL-components of 246 HDL [80]. Accordingly, HDL from T2DM patients (and also glycated and oxidized 247 HDL particles produced in vitro) promoted cell proliferation, migration, and invasion of 248 breast cancer cells through the Akt/ERK pathway [81]. When breast cancer cells were 249 pre-treated with these modified HDLs and injected into mice, a promotion of pulmonary 250 and hepatic metastasis was found compared to cells pre-treated with normal HDL [82]. 251 Moreover, these pre-treated breast cancer cells also showed increased adhesion to 252 human umbilical vein endothelial cells (HUVEC) and extracellular matrix in vitro, 253 mainly due to elevated protein kinase C (PKC) activity and integrin secretion, which are 254 vital in promoting breast cancer cell metastasis [82]. Similarly, HDL isolated from 9 255 breast cancer patients complicated with T2DM promoted breast cancer cells adhesion to 256 HUVECs by activating PKC, which in turn stimulated the expression of intercellular 257 adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1), 258 compared to HDL isolated from healthy or breast cancer patients. Thus, HDL from 259 breast cancer and T2DM subjects can elevate the levels of ICAM-1 and VCAM-1 in 260 cells in circulation, but not within the tumor tissue, contributing to metastasis [83]. 261 262 2.4. Intracellular cholesterol metabolism and breast carcinogenesis 263 In order to supply the augmented need of cholesterol, proliferating breast cancer cells 264 can increase cholesterol uptake from the circulation. In this way, both LDLR and 265 SCARB1 expression, which codifies SR-BI, were found upregulated in breast cancer 266 tissue, which could (ATENCIÓN A INFERIR FUNCIONES A PARTIR DE DATOS 267 DE RNAm) increase the uptake of LDL-C and HDL-C from the bloodstream, 268 respectively [84,85]. As indicated above, tumors with higher LDLR (SI ES RNA VA 269 EN ITALICAS) expression were HER2-like and triple-negative, had higher histological 270 grades, Ki-67 expression, and tumor necrosis [46,86], and high LDLR expression was 271 associated with decreased recurrence-free survival, particularly in patients treated with 272 systemic therapies [87]. Similarly, high SR-BI expression was associated to tumor 273 aggressiveness and poor prognosis in breast cancer [46,86,88,89]. SR-BI expression 274 was upregulated concomitantly with the increase in the number and the size of the 275 tumors in PyMT mice fed a HFHC diet [28]. Moreover, in vitro knockdown of SR-BI in 276 breast cancer cells inhibited proliferation and migration, as well as decreased tumor 277 burden when injected to mice, effects that were associated with a reduction of Akt and 278 ERK1/2 activation [61]. 279 280 In contrast, loss of ABCA1 protein expression was found associated with a more 281 aggressive phenotype in human breast cancer patients [90], which was in accordance 282 with the notion that ABCA1 exerts antitumor effects by preventing the accumulation of 283 free cholesterol in cancer cells, inhibiting the release of tumor necrosis factor 284 progression [91]. However, in a recent report, the expression of ABCA1 in triple- 285 negative breast cancer was found higher than in non-cancerous mammary tissue, 286 whereas ABCG1 levels were not differentially expressed [92]. These discrepancies 287 could be explained by a study that found that ER-positive cells were more sensitive to 10 288 LXR induced G0/G1 arrest than ER-negative cells, but that LXR stimulation led to 289 higher induction of ABCA1 in ER-negative than in ER-positive cells [93]. 290 291 Apart from bloodstream uptake, cells can obtain cholesterol by de novo biosynthesis. 292 This pathway was found increased in cancer stem cells derived from ER-negative breast 293 cancers, which exhibit resistance to conventional therapy. Moreover, increased 294 cholesterol biosynthesis showed correlation with shorter relapse-free survival in a large 295 breast cancer cohort [94]. 296 297 Once inside the cell, cholesterol can be esterified or metabolized. One of the most 298 prevalent oxysterols is 27-HC, generated by sterol 27-hydroxylase CYP27A1, and 299 catabolized by oxysterol 7α-hydroxylase CYP7B1 [95]. 27-HC was increased in human 300 breast cancer tissue, concomitant with CYP7B1 downregulation, whereas CYP27A1 301 remained unchanged [96]. Furthermore, CYP7B1 gene (UP-REGULATION??) 302 expression was found to correlate with better survival [96], whereas CYP27A1 protein 303 expression was increased in higher grade tumors [32]. In vivo, 27-HC increased tumor 304 growth in murine or human cancer cell xenografts and in PyMT mice, in which 27-HC 305 also hastened metastasis to the lungs, an effect that implicated LXR activation [32,96]. 306 Moreover, 27-HC was found to stimulate the proliferation of ER-positive MCF-7 cells, 307 but not that of ER-negative cells, associated with increased protein levels of the E3 308 ubiquitin protein ligase mouse double minute 2 (MDM2) and decreased levels of the 309 tumor suppressor protein p53 [97]. It was also found to activate Myc (a critical 310 oncoprotein that can promote the proliferation, migration and invasion of cancer cells) 311 by increasing its protein stability [98]. 27-HC also induced angiogenesis by enhancing 312 the expression of vascular endothelial growth factor (VEGF) by the classical 313 ERα/VEGF signaling pathway in ER-positive breast cancer cells, or by promoting the 314 generation of ROS, which in turn activated the signal transducer and activator of 315 transcription (STAT)3/VEGF signaling in an ER independent manner [99]. Moreover, 316 27-HC induced epithelial-mesenchymal transition (EMT) by decreasing the expression 317 of E-cadherin and β-catenin [100], and by increasing the phosphorylation of STAT3, 318 that in turn promoted MMP9 expression [101]. Tumor associated macrophages (TAMs) 319 are the main source for local 27-HC production in breast tissues, and the 320 hypermethylation of the CYP7B1 promoter in breast cancer cells further attenuates de 321 degradation of 27-HC, resulting in its accumulation in tumor tissue [102]. The elevated 11 322 27-HC levels, a part from inducing cell proliferation and migration, increased the 323 secretion of chemokines such as CCL2, CCL3, and CCL4 from TAMs, which further 324 attract monocytes to tumor sites, and can be polarized to M2 type macrophages, which 325 woud further produce 27-HC [102]. 326 327 Collectively, these results indicate that targeting cholesterol uptake and conversion to 328 27-HC could be a good strategy for the treatment of breast cancer patients. A summary 329 of the main lipoprotein-mediated uptake and cholesterol-related downstream pathways 330 and their effects on oncogenic signaling pathways in breast cancer cells is shown in 331 Figure 1A. 12 332 3. Prostate cancer 333 Prostate cancer is the most commonly diagnosed cancer in men older than 50 years of 334 age and more than 98% have a glandular origin. Nevertheless, the anatomopathological 335 studies conducted in autopsies have also revealed their presence in men younger than 30 336 years of age, without previous symptomatology, suggesting that these tumors are able to 337 have a slow growth. In 2018, this disease represented the 7.1 % of all cancers diagnosed 338 in men, causing the 3.8% of all deaths, being in this sex the second most common cause 339 of cancer-related mortality in developed countries after lung cancer [103]. SIMPLISTA 340 The main biomarker for the prostate tumors screening is prostate-specific antigen (PSA) 341 serum level. PSA serum levels above 4.0 ng/mL represents a suspicion of neoplasia. 342 However, this marker alone is not enough for diagnosis of prostate cancer, because the 343 false-negative and also false-positive test results are frequent [104]. The degree of 344 malignancy of the tumor is determined by the Gleason Score, based on histological 345 analysis, thereby grading the prostate cancer from low-grade (score 6) to high-grade 346 cancers (8 to 10 score) [105]. 347 348 3.1. Cholesterol and prostate cancer 349 350 Some evidence indicates that high serum levels of cholesterol are associated with the 351 risk of developing aggressive prostate cancer, thus indicating that hypercholesterolemia 352 could be a critical factor for prostate cancer progression. A large prospective study 353 conducted in Korean adults, with a follow up to 14 years, showed that plasma 354 cholesterol levels were positively associated with the risk of prostate cancer, particularly 355 when individuals with total cholesterol levels ≥ 240 mg/dL) werecompared with those 356 with < 160 mg/dL [18]. In line with these findings, a prospective trial reported that men 357 with cholesterol levels < 200 mg/dL had a lower risk of high-grade prostate cancer 358 [106]. However, higher total cholesterol levels were associated with increased short- 359 term prostate cancer risk but an inverse risk association was observed with 20-year lag 360 time [107]. 361 Two meta-analysis did not find association of serum cholesterol levels with the risk of 362 prostate cancer [108] or with prostate cancer recurrence after radical prostatectomy 363 [109]. Similarly, the Swedish “Apolipoprotein MOrtality RISk” (AMORIS) prospective 364 study did not provide evidence for an association between serum total cholesterol and 365 prostate cancer risk [110].The REDUCE randomized trial conducted in men that 13 366 presented elevated PSA and a negative baseline biopsy, did not demonstrate that the 367 total cholesterol levels were related to either overall or low-grade prostate cancer risk. 368 However, the stratification of the patients with high total serum cholesterol showed 369 positive association with the increase risk of high-grade prostate cancer diagnosis [111]. 370 Overall, these findings do not convincingly support the association between high serum 371 cholesterol levels and prostate cancer risk. 372 373 Some epidemiological studies showed that Western diets with an excess of saturated fat 374 and cholesterol promoted prostate cancer development in association with increased 375 androgens levels [112,113]; however but the role of dietary cholesterol is unclear. 376 Several preclinical models have assessed the effects of dietary cholesterol in the 377 development of prostate cancer. A HFHC diet promoted tumor growth and intratumoral 378 levels of testosterone in xenograft mice bearing LNCaP, androgen-dependent human 379 prostate cancer cells. These results suggested that the diet-induced increase in tumor 380 androgen concentrations is due to de novo synthesis from exogenous cholesterol [114]. 381 Interestingly, intra-epithelial neoplasia was also enhanced by the HFHC diet in 382 C57BL/6:129Sv mice, but this increase was dependent on the accumulation of 383 cholesterol in the prostatic gland under LXRαβ deficient conditions [115]. It is 384 noteworthy that these dietary interventions used distinct high saturated fat diets and do 385 not allow to determine a direct, independent effect of the cholesterol content. 386 Therefore, the translation of these experimental results into humans could not be 387 anticipated [116]. Rather surprisingly, a large Canadian population-based case-control 388 study found an inverse association between dietary cholesterol intake and the risk of 389 prostate cancer [26]. Also, cholesterol intake was not associated with prostate cancer 390 risk in another case-control study conducted in Italy [117], suggesting that higher 391 cholesterol intake per se does not increase prostate cancer in humans. 392 393 3.2. LDL and prostate cancer 394 395 Few epidemiological studies investigated the association between LDL-C and malignant 396 prostate disease or with their aggressiveness, but results were contradictory. Several 397 studies did not support the association between LDL-C and the risk of aggressive 398 prostate cancer, as reported in a meta-analysis of 14 prospective studies that failed to 399 show association between risk of prostate cancer and blood levels of LDL-C [108]. 14 400 Furthermore, data from a French prospective study with a follow-up time of 11.5 years 401 did not show association between the prostate cancer risk and serum concentrations of 402 LDL-C or APOB100, HDL-C or APOA1 [19], similarly than a nested case-control 403 study conducted in U.S. with a follow-up of 2-years [118]. In contrast, another 404 prospective study from the Netherlands showed that LDL-C levels were associated with 405 an increased risk of prostate cancer, and also with its aggressive behavior [119]. 406 Interestingly, a large Mendelian randomization study found a weak evidence that 407 higher-C LDL levels increase aggressive prostate cancer risk [120]. These divergent 408 results may be explained by the heterogeneity in the approaches used and the large 409 differences on follow-up of these studies. 410 411 Other experimental approaches showed increased proliferative effect of LDL on 412 different cancer prostatic cell lines, compared with that of normal prostate cells. These 413 findings were concomitant with an upregulation of HMGCR, whereas ABCA1 was 414 downregulated [121]. The LDL-mediated effects on proliferation of prostate cancer 415 cells were induced by PTEN loss and activation of the Akt and ERK signaling 416 pathways, which in turn upregulate LDLR [122]. 417 418 Some studies pointed out to oxLDL, and its main receptor OLR1, in prostate cancer. In 419 this way, oxLDL levels were found to correlate with prostate cancer stage, and OLR1 420 expression correlated with lymph node metastasis [123]. oxLDL levels were increased 421 in benign prostatic hyperplasia, but not in prostate cancer patients of another small 422 cohort [124]. OLR1 was also overexpressed in prostate adenocarcinomas and 423 inassociation with high Gleason score [125]. In vitro, oxLDL stimulated proliferation, 424 migration, and invasion of prostate cancer cells, in part by promoting β-catenin, cMyc, 425 NF-κB, STAT1, and STAT3 signaling pathways [123]. OLR1 was also found 426 overexpressed in prostate cancer cell lines, and its activation by oxLDL promoted EMT 427 by increasing mesenchymal markers (vimentin, N-cadherin, snail, slug, MMP2, and 428 MMP9) and reducing epithelial markers (E-cadherin and plakoglobin) [125]. OLR1 429 silencing in prostate cancer cells exhibited lower tumorigenic potential in a xenograft 430 mouse model [125]. These data indicates that both oxLDL and OLR1 are major 431 determinants of accelerated prostate tumor progression and metastatis. 432 433 3.3. HDL and prostate cancer 15 434 435 A randomized, controlled trial in men with elevated PSA and a negative baseline biopsy 436 found that elevated serum HDL-C was associated with increased risk of both overall 437 and high-grade prostate cancer [111]. However, as occurred with LDL-C, some studies 438 did not support this association. A meta-analysis of 14 large prospective studies did not 439 find any association between HDL-C and high-grade prostate cancer [108]. Also, a large 440 Mendelian randomization trial reported above did not find evidence that genetically 441 predicted changes in HDL-C changed prostate cancer risk [120]. The lack of androgen- 442 dependent status data in some studies could explain the divergent results on the 443 association between HDL-C and prostate cancer risk [126]. 444 445 Since HDL also exhibited antioxidant properties, a recent report investigated the 446 potential of HDL or reconstituted APOA1-containing HDL on prostate cancer cell 447 proliferation induced by oxidative stress. Both native HDL and small APOA1- 448 containing HDL reduced ROS levels in prostate cancer cells, thus inhibiting ROS- 449 induced cell entry in the G2/M phase. Of note, these effects were independent of 450 androgen receptor activation or the modulation of the cell cholesterol content [127]. On 451 the other hand, HDL induced cell proliferation and migration of androgen-independent 452 prostate cancer cells through ERK1/2 and Akt, but these effects were not found in 453 androgen-dependent prostate cancer cells [128]. HDL also promoted migration and 454 invasion, concomitant with the increase of Ser727 phosphorylation of STAT3 via 455 ERK1/2 in androgen-independent prostate cancer cells, which was dependent on the 456 delivery of sphingosine-1-phosphate (S1P) [129]. SEGURO QUE S1P ES 457 PROCANCERIGENO EN ESTAS CIRCUNSTANCIAS?? These findings emphasize 458 the critical role of S1P in HDL-induced cell progression of androgen-independent 459 prostate cancer cells. 460 461 3.4. Intracellular cholesterol metabolism and prostate cancer 462 463 Cholesterol was found increased in the cytoplasmic fractions of prostate cancer tissue, 464 along with an upregulation of LDLR and the peripheral-type benzodiazepine receptor 465 involved in transferring cholesterol from the cytosol to the inner mitochondrial 466 membrane [130]. Cholesterol levels were also increased in the nucleus fraction, 467 concomitant with a high expression of Cyclin E, which could be enhancing cell division 16 468 [130]. The accumulation of cholesterol esters in lipid droplets was also found in high- 469 grade and metastatic human prostate cancer tissue, but not in normal prostate, benign 470 prostatic hyperplasia, prostatitis, or prostatic intraepithelial neoplasia [122]. As 471 commented above, PTEN loss activated PI3K/Akt signaling leading to accumulation of 472 cholesterol by increasing cholesterol uptake and, also, esterification in vitro [122]. 473 Importantly, the pharmacological inhibition of cholesterol esterification via ACAT1 474 significantly suppressed cancer proliferation, migration, invasion, and tumor growth in 475 xenograft mice [122], thereby indicating that cholesterol esters serve as a reservoir of 476 cholesterol for prostate cancer cell proliferation. However, dedifferentiated tumors and 477 those with lethal outcomes had lower expression of LDLR and ACAT1, but higher levels 478 of squalene monooxygenase, the second rate-limiting enzyme of cholesterol synthesis, 479 thus indicating a greater reliance on cholesterol synthesis than uptake in aggressive 480 prostate cancer [131]. Another report also found that cholesterol accumulation also 481 promoted EMT in prostate cancer cells via the ERK1/2 pathway; epidermal growth 482 factor receptor and adipocyte plasma membrane-associated protein accumulation in 483 lipid rafts [132]. These findings indicate that cholesterol biosynthesis and uptake during 484 cancer progression is extremely complex and remains to be clarified. 485 486 Noteworthy, androgen receptor has also been linked to cholesterol synthesis in prostate 487 cancer cells [133]. It is known that the androgen receptor binds an androgen-response 488 element within an intron of SCAP, upregulating SCAP expression and resulting in a 489 shift in the cellular equilibrium between SCAP and Insig, thereby promoting SREBP2 490 [134,135]. Thus, androgen receptor signalling may affect cholesterol synthesis [135]. In 491 line with these findings, an androgen responsive element can upregulate the enzyme 3β- 492 hydroxysterol Δ24- reductase (DHCR24) in androgen receptor-positive prostate cancer 493 cells, thereby promoting cholesterol accumulation. Furthermore, the amount of 494 DHCR24 protein and mRNA expression was higher in prostate cancer tissues than in 495 adjacent normal tissues [136]. 496 497 Importantly, HDL did not affect the cholesterol content ofprostate cancer cells and the 498 (lower response DE QUE TIPO?) of androgen-dependent cancer cells correlated with a 499 low level of ABCA1 [128]. It should be noted that androgens inhibit ABCA1 expression 500 in androgen-dependent prostate cancer cells, and this change enhanced growth rate 501 [128,137]. ¿¿¿NO SE ENTIENDEThese latter findings were not related with HDL??? 17 502 [133]. Taken together, these findings support a role of ABCA1 on prostate cancer 503 growth,but would seem independent of cell cholesterol content. Furthermore, an 504 analysis of clinical prostate samples for mRNA and prostate tissue biopsy cores for 505 protein expression found a higher SR-BI expression in high Gleason grade versus low 506 Gleason grade prostate cancer samples, but their consequences in HDL-C uptake or 507 oncogenic signaling remain to be clarified [138]. Overall, these findings emphasized the 508 critical role of ABCA1 and SR-BI on cell progression of prostate cancer cells, although 509 the role of ABCA1 is highly-dependent of androgen status. 510 511 Some metabolites of cholesterol such as 22(R)-hydroxycholesterol and 24(S)- 512 hydroxycholesterol are natural ligands of LXR and its activation inhibits prostate cancer 513 cell proliferation [139]. In the same way, LXR can prevent cholesterol accumulation in 514 the prostate and protect from abnormal cell proliferation when exposed to high dietary 515 cholesterol, mainly by downregulating LDLR and upregulating ABCA1 protein 516 expression [115]. A link was found between cholesterol accumulation and the 517 proliferative process through the oncogene and histone methyl transferase Enhancer of 518 Zeste Homolog 2 (EZH2) [115], which has been associated with aggressive human 519 prostate carcinomas [140]. Also, cholestane-3β, 5α, 6β-triol suppressed proliferation in 520 human prostate cancer cells and reduced the growth of tumor xenografts in nude mice 521 [141]. This treatment reduced the expression of Akt1, c-Myc, and Skp2 protein levels 522 whereas increased the cell cycle inhibitor p27(Kip) levels and the main proteins 523 associated with EMT. However, 27-HC stimulated the proliferation of prostatic cells 524 and induced the expression of PSA by increasing androgen receptor transcriptional 525 activity in prostate epithelial cells [142]. Also, 27-HC suppressed apoptosis induced by 526 docetaxel [142]. Consistently, CYP7B1, the main enzyme involved in 27-HC 527 catabolism, was highly expressed in high-grade prostatic intraepithelial neoplasia and 528 adenocarcinomas [143]. 529 530 Overall, these results indicate that targeting cholesterol uptake, synthesis and efflux and 531 their effects on intracellular cholesterol storage and conversion to 27-HC could be a 532 good strategy for the treatment of prostate cancer (summarized in Figure 1B). 18 533 4. Epithelial thyroid cancer 534 535 Thyroid cancer is a common endocrine malignancy whose incidence has increased in 536 the last past decades. This neoplasia corresponds the 2.1% of all cancer diagnoses 537 worldwide, affecting more women than men. Approximately 95% of thyroid cancer 538 cases have the origin in the follicular epithelium with an array of different histological 539 patterns and biological behavior [144,145]. Thyroid cancer is classified in two major 540 types. First, the well-differentiated thyroid carcinomas (DTC) which include the 541 papillary thyroid cancer (PTC), representing about 80 % of cases, is more common in 542 women, and can metastasized throughout lymph nodes in the neck or close to the 543 thyroid. This group also include the non-invasive follicular thyroid neoplasm with 544 papillary-like nuclear features (NIFTP); and the follicular thyroid cancer (FTC), that 545 represents about 5 to 10% of the diagnostic cases and can spread throughout lungs or 546 bones. The second group of tumors correspond to dedifferentiated thyroid cancer, that 547 include the poorly differentiated thyroid carcinoma (PDTC), formed by heterogeneous 548 tumors with a prevalence of 0.23% to 2.6%, and associated with high risk of cancer 549 recurrence including spread to lung and/or bones. This second group also include the 550 anaplastic thyroid carcinoma (ATC), represents 1% to 2% of thyroid cancers , an is the 551 tumor with the most aggressive behavior [4]. 552 553 4.1. Cholesterol and thyroid cancer 554 555 Only few studies have investigated the association between serum cholesterol levels and 556 thyroid cancer. A retrospective study investigated the lipoprotein profile of Chinese 557 patients with thyroid cancer. Serum cholesterol levels were lower in subjects with 558 thyroid cancer, mainly including patients with PTC and FTC [146]. This study also 559 reported significant differences between the metastatic and non-metastatic groups in 560 patients with PTC, but not in FTC patients [146]. Conversely, another retrospective 561 study from South Korea found that increased BMI was associated with the lymph node 562 metastases of patients with PTC, and other invasive features including large tumor size, 563 extra-thyroidal invasion, and multifocality, but these effects were independent of serum 564 cholesterol levels [147]. Another case-control study form Italy did not reveal significant 565 differences in serum cholesterol levels of DTC patients with suppressed thyrotropin 566 (TSH) due to levo-thyroxine therapy compared to that of the euthyroid subjects [148]. 19 567 568 4.2. LDL and thyroid cancer 569 570 As occurred with serum cholesterol, only few studies investigated the association 571 between LDL-C and thyroid cancer risk. In the Chinese retrospective study reported 572 above, LDL-C levels were also lower in the large cohort of women with thyroid cancer 573 and those showing metastasis in the PTC group [146]. In line with these findings, we 574 recently reported that patients bearing aggressive thyroid tumors presented an important 575 decrease in both systemic serum LDL-C levels and APOB100 levels along with an 576 upregulation of the LDLR expression in tumor tissue [149]. Noteworthy, LDL-C 577 promoted proliferation and migration in anaplastic thyroid cells, but these effects were 578 independent of changes in MAPK, PI3K, and mTOR signaling [149]. 579 580 4.3. HDL and thyroid cancer 581 582 The serum lipid profile of Chinese patients with thyroid cancer reported lower HDL-C 583 and APOA1 levels in women with thyroid cancer compared to the control group, and in 584 metastatic compared to non-metastatic patients with PTC [146]. However, we reported 585 that serum HDL-C levels were similar in patients with aggressive thyroid cancer 586 compared with those presenting a benign thyroid carcinoma [149]. 587 588 Since HDL-C may not be an accurate reflect of HDL function, a report evaluated one of 589 the main antioxidant and anti-inflammatory HDL component, PON1. A small case- 590 control study revealed that PON1 activity was significantly lower in patients with PTC 591 compared to the control group, although HDL-C, lipid hydroperoxide, and total free 592 sulfhydryl levels remained unchanged [150]. However, we did not found differences 593 neither in the APOA1 levels nor in PON1 and PAF-AH activities between patients with 594 the malignant thyroid tumors (PTC, PDTC, and FTC) and those patients with benign 595 thyroid tumors (Figure 2, panel A). Additional long-term and larger scale studies are 596 needed to clarify this issue. 597 It is noteworthy that we found that SCARB1 gene expression was upregulated in thyroid 598 carcinoma tissues of PTC and FTC compared to benign tumors, whereas ABCA1 and 599 ABCG1 expression remained unchanged (Figure 2, panel B). Furthermore, the 600 exogenous administration of HDL in anaplastic cells promoted cell proliferation along 20 601 with an upregulation of SCARB1 expression when compared with the effects of HDL on 602 thyroid follicular epithelial cells. HDL also enhanced cell migration in both cell lines 603 (Figure 2, panel C). These data rather suggest a differential effect of HDL in thyroid 604 tumorigenic cells; further, the role of SR-BI in thyroid carcinoma deserve further 605 investigation. 606 607 4.4. Intracellular cholesterol metabolism and thyroid cancer 608 609 Little is known about the regulation of intracellular cholesterol metabolism in the 610 thyroid carcinoma. As commented above, we found an upregulation of thyroid LDLR in 611 tumor tissues, whereas HMGCR and NR1H3, which codifies LXRα, were strongly 612 downregulated in malignant tumors, thus indicating a greater reliance on cholesterol 613 uptake in more aggressive thyroid tumors [149]. We also reported that the tumors with 614 worse prognosis showed higher levels of 27-HC which correlated with a of CYP7B1 615 downregulation. Importantly, the overexpression of CYP7B1 in anaplastic thyroid cell 616 lines arrested growth and reduced cellular migration, indicating that the accumulation of 617 27-HC (NO SERIA AL REVÉS??) in the thyroid cells may be promoting the 618 development and progression of epithelial thyroid cancer [149]. The identification of 619 positive ER (α/β) in thyroid tumor samples could partly explain the 27-HC-mediated 620 effects on cell proliferation [149]. 621 622 Taken together, these results indicate that targeting LDL-C uptake and the synthesis of 623 27-HC may be a therapeutic strategy for controlling epithelial thyroid cancer 624 (summarized in Figure 1C). 21 625 5. Pancreatic cancer 626 627 Pancreatic cancer is a malignancy of the digestive system that has ranked the 11th most 628 common cancer in the world [151]. The majority of cases occur in the exocrine 629 component that produces digestive enzymes. Pancreatic adenocarcinoma accounts for 630 85% of all pancreatic cancers [152]. Worldwide incidence of pancreatic cancer 631 correlates with increasing age and is more common in men than in women [103]. The 632 disease is classified form early to late stages (I to IV) but most of the patients are 633 asymptomatic until the disease develops to an advanced stage [153]. For this reason, 634 pancreatic cancer has a very poor prognosis, and most patients will eventually have 635 recurrence; only 25% of people survive 5 years after complete resection [154]. Because 636 of its poor prognosis, pancreatic cancer is the seventh leading cause of mortality from 637 all malignant tumors in Western Societies [103]. The lack of specific biomarkers for 638 early diagnosis may also help explain the high mortality of these patients. Modifiable 639 risk factors include smoking, alcohol, obesity, dietary factors, and exposure to toxic 640 substances. 641 642 5.1. Cholesterol and pancreatic cancer 643 644 Two large Mendelian randomization studies that investigated the causal relevance of 645 metabolic factors on pancreatic cancer did not found evidence for an association of 646 genetically predicted serum cholesterol and pancreatic adenocarcinoma [155,156]. 647 Furthermore, several large prospective studies reported null associations between serum 648 total cholesterol and the risk of pancreatic cancer [157–159]. Data analysis of some 649 large cohorts of Asian and Australia/New Zealand did not reveal any association 650 between total serum cholesterol and mortality from pancreatic cancer [160]. These 651 results were also confirmed in a large prospective cohort from UK [161]. However, two 652 prospective analyses of US population and seven cohorts from Norway, Austria, and 653 Sweden showed an inverse association between serum cholesterol levels and the risk of 654 pancreatic cancer [162,163]. Noteworthy, a meta-analysis that included eight large 655 studies from Asian and Europe revealed that serum cholesterol levels were not 656 significantly associated with the risk of pancreatic cancer [164]. However, this meta- 657 analysis showed a significant association of dietary cholesterol with the risk of 658 pancreatic cancer in 6 studies conducted in North America [164]. 22 659 660 The potential of dietary cholesterol was also analyzed in a meta-analysis of 19 studies 661 conducted in Europe, US, and Asia, but the association between dietary cholesterol and 662 pancreatic cancer risk was only significant in European studies [165]. However, in 663 another meta-analysis of 16 studies, mainly from Europe and North America, 664 demonstrated that cholesterol intake might increase the risk of pancreatic cancer, 665 particularly in US and Canada [166]. These effects were also observed in a case-control 666 study conducted in Japan [167]. Overall, these large studies found a general association 667 between cholesterol intake and pancreatic cancer, but the association varied between 668 geographical locations and their effects on serum cholesterol levels were rather limited 669 in most studies. Early studies in experimental modelsdemonstrated that N-nitrosobis- 670 induced pancreatic carcinogenesis in hamster was promoted by a cholesterol-containing 671 diet [168], whereas cholesterol-free diets did not affect pancreatic neoplastic lesions 672 [169]. 673 674 5.2. LDL and pancreatic cancer 675 676 The large Mendelian randomization studies reported above revealed that the main trait 677 associated with pancreatic adenocarcinoma was genetically predicted by body mass 678 index [155,156], but only one study found that genetically higher levels of LDL-C were 679 associated with pancreatic cancer, although LDL showed a BMI-mediated causal effect 680 [156]. Furthermore, a long-term detailed prospective Swedish cohort analysis did not 681 find evidence for an association between prostate cancer risk and LDL-C and neither 682 with the main LDLR ligand gene, APOB [170]. 683 684 OLR1 may also play a critical role in pancreatic cancer. A very recent study have 685 demonstrated that OLR1 expression was highly expressed in pancreatic cancer tissue 686 compared with that of adjacent normal tissue [171]. Furthermore, inhibition of OLR1 687 expression decreased the proliferation and metastasis of pancreatic cancer cells both in 688 vitro and in a xenograft mouse model. OLR1 promoted metastasis of pancreatic cancer 689 cells through increasing transcription of High mobility group AT-hook 2 (HMGA2) 690 through c-Myc [171]. It should be noted that human pancreatic adenocarcinoma cells 691 incubated with oxLDL and acetylated LDL, but not native LDL, enhanced their 692 cytokine production when they were cultured with human monocytes. Furthermore, 23 693 anti-CD36 antibody inhibited this stimulatory effect [172]. These findings establish a 694 potential role of modified LDL and their main receptors in pancreatic cancer 695 development. 696 697 5.3. HDL and pancreatic cancer 698 699 The analyses of two large Mendelian randomization studies did not provide any 700 evidence that genetically altered HDL-C were causally associated with an increased 701 pancreatic cancer risk [155,156]. Similar results were reported in a large Finnish 702 prospective analysis [157], and neither HDL-C was associated with pancreatic cancer 703 risk in the Alpha-Tocopherol, Beta-Carotene Study (ATBC) of Finnish male smokers 704 that investigated potentially modifiable factors for this cancer [173]. However, HDL-C 705 was found inversely associated with pancreatic cancer risk in other studies. In four 706 randomized controlled intervention studies of postmenopausal women from US, a 707 modest but significant inverse association of HDL-C with pancreatic cancer was found; 708 nevertheless, the inverse association dissapeared when women who lost significant 709 weight were excluded [174]. Interestingly, serum HDL-C levels were significantly 710 lower in pancreatic cancer postmenopausal women of a case-control study conducted in 711 Greece. [175]. 712 713 It is noteworthy that in several studies APOA1 levels was the main metabolic factor 714 inversely associated with pancreatic cancer, as occurred in a case-control study of 715 China, a prospective study of Sweden, and a retrospective study of Japan [170,176,177]. 716 In line with these findings, both APOA1 and the second quantitatively most important 717 HDL protein, APOA2, was found downregulated in proteomic serum analyses of 718 pancreatic adenocarcinoma patients [178–180]. The mechanism responsible for the link 719 between APOA1 and APOA2 and pancreatic cancer remains unclear. Reconstituted 720 APOA2-containing HDL increased lipid uptake and cell proliferation in human 721 pancreatic cancer cells and enhanced lipid uptake in xenograft tumors implanted in 722 mice, likely by upregulating SR-BI [181]. Furthermore, serum PON1 levels were 723 downregulated in a small case-control study conducted in patients with pancreatic 724 cancer [182]. 725 726 5.4. Intracellular cholesterol metabolism and pancreatic cancer 24 727 728 Beyond LDL-C levels, the use of a global transcriptomic microarray technology 729 revealed that invasive genetically-engineered murine pancreatic adenocarcinoma 730 samples showed a strongest upregulation of LDLR concomitant with an increased 731 cholesterol uptake [183]. The authors also demonstrated that pancreatic cancer cell 732 disruption of LDLR downregulated cholesterol uptake, impairing proliferative and 733 tumorigenic capacities and inhibiting the ERK-dependent survival pathway [183]. 734 Furthermore, elevated LDLR expression was correlated with an increased rate of relapse 735 in patients with pancreatic adenocarcinoma [183]. In line with these findings, an 736 independent study also showed that LDLR mRNA expression was associated with 737 decreased patient survival in pancreatic adenocarcinoma [184], thereby emphasizing the 738 significant contribution of LDL-C uptake to pancreatic cancer development. 739 740 The use of microarray technology also revealed that invasive genetically-engineered 741 murine pancreatic adenocarcinoma samples showed a strongest upregulation of critical 742 genes involved in de novo cholesterol synthesis, cholesterol storage and 743 oxysterol/steroid synthesis, particularly in HMGCR, 24-dehydrocholesterol reductase, 744 ACAT1, lipase A and 3-oxo-5α-steroid 4-dehydrogenase 1 genes [183]. Indeed, 745 increased levels of cholesterol were also observed in human pancreatic adenocarcinoma 746 cells [185]. Furthermore, these changes altered the ratio of cellular free/esterified 747 cholesterol [183]. In line with these findings, a significant accumulation of cholesteryl 748 esters mediated by ACAT1 was found in human pancreatic cancer specimens and cell 749 lines [186]. More importantly, expression of ACAT1, detected by 750 immunohistochemistry, showed a correlation with poor patient survival and, also, the 751 blockage of cholesterol esterification either by an ACAT1 inhibitor or by 752 downregulating ACAT1 expression suppressed tumor growth and metastasis in an 753 orthotopic mouse model of pancreatic cancer [186]. Similar results were found in a 754 xenograft mouse model of pancreatic adenocarcinoma treated with the ACAT1 inhibitor 755 avasimibe and the chemotherapy agent gemcitabine, in part by downregulating Akt 756 pathway [187]. Melittin, a Chinese traditional medicine for treating chronic 757 inflammation, immunological diseases, and cancer, also inhibited tumor growth in 758 pancreatic ductal adenocarcinoma xenograft mouse model by downregulating the main 759 genes involved in cholesterol biosynthesis, and also enhanced the antitumoral effects of 760 gemcitabine [188]. Other genes involved in cholesterol biosynthesis were associated 25 761 with radioresistance in pancreatic cancer cells [189]. Finally, caveolin-1, an active 762 component of caveolae affecting cholesterol signaling, plays a critical role in pancreas 763 cancer progression [190]. Caveolin-1 downregulation also resulted in a decrease 764 chemoresistant and metastatic phenotype of pancreatic cancer cells [191]. 765 766 Taken together, these findings indicate that targeting metabolic pathways involved in 767 cholesterol uptake, biosynthesis, and storage may be a successful strategy for the 768 treatment of patients with pancreatic adenocarcinoma (summarized in Figure 1D). 769 26 770 6. Ovarian cancer 771 772 Ovarian cancer has the highest mortality rate of all gynecological cancers worldwide 773 [103]. About 90% of ovarian cancers are epithelial tumors, including serous tumor, 774 endometrioid tumor, and mucinous cystadenocarcinoma [192]. The disease is often 775 asymptomatic or shows non-specific symptoms being, in many cases, diagnosed at 776 advanced stages [193]. More than one third of ovarian cancer patients present with 777 malignant ascites at diagnosis [194]. Usual treatments include optimal debulking 778 surgery followed by chemotherapy, mainly with platinum-based drugs [195]. Five-year 779 cause-specific survival for all epithelial ovarian cancers is 47%; however, advanced- 780 stage disease is a highly chemoresistant disease and the 5-year survival rate is only of 781 20% [192]. 782 783 6.1. Cholesterol and ovarian cancer 784 785 A recent meta-analysis which included 12 studies regarding association of ovarian 786 cancer risk with blood lipid level suggested that high cholesterol was associated with an 787 increased ovarian cancer risk [196]. The same association was observed in two 788 prospective studies that included cohorts from Austria, Norway, Sweden, and USA 789 [197,198]. 790 791 In contrast, reduced serum cholesterol levels were observed in ovarian cancer patients, 792 compared to healthy women in several case-control and prospective studies [199–202] 793 and in a recent meta-analysis which included 12 studies [203]. Compared with the 794 patients in stage I-II, the patients in stage III-IV had lower levels of cholesterol [199]. 795 Moreover, patients who were in complete remission of the cancer had higher cholesterol 796 compared to diagnosis, whereas patients who died from their ovarian cancer presented a 797 reduction in serum cholesterol [201]. The hypocholesterolemia observed in advanced 798 ovarian cancer patients could be due to increased cholesterol uptake by the tumor. 799 800 Concerning cholesterol intake, a meta-analysis that included 7 studies found 1% greater 801 risk of ovarian cancer per 50 mg/day increase in cholesterol intake [204]. A positive 802 association between ovarian cancer risk and higher consumption of dietary cholesterol 27 803 was also observed in a case-control study from Canada [205], and in the prospective 804 Nurses’ Health Study (NHS), although NHS2 study did not find this association [206]. 805 Another meta-analysis, as well as the European Prospective Investigation into Cancer 806 and Nutrition, and Netherlands Cohort Study failed to find an association between 807 cholesterol intake and ovarian cancer risk [207–209]. 808 809 6.2. LDL and ovarian cancer 810 811 A Mendelian randomization analysis of 22 406 women with invasive epithelial ovarian 812 cancer did not found any association between genetically variation ¿¿proxied?? in in 813 controlling circulating LDL-C and risk of epithelial ovarian cancer [210]. Similarly, the 814 AMORIS database did not find association between LDL or APOB levels and ovarian 815 cancer risk [40]. However, LDL was suggested as a predictor of clinical outcome in a 816 retrospective study from the U.S.A., since longer progression-free survival and overall 817 disease-specific survival was found in patients with normal LDL levels compared to 818 patients with elevated LDL [211]. On contrary, another retrospective study conducted in 819 China found that elevated preoperative LDL was associated with an improved 820 recurrence-free survival in women with ovarian cancer [212]. 821 822 Discrepancies were also found concerning LDL-C levels in different ovarian cancer 823 stages. Low LDL-C levels were observed in a small study conducted in Pakistan [200]. 824 In another case-control study from Israel, elevated LDL-C levels were observed in 825 early-stage ovarian and endometrial cancer patients compared to controls, but levels 826 dropped at advanced stages of the disease [213]. In contrast, no differences in LDL-C 827 levels were observed between low and high severity endothelial ovarian cancer patients 828 in a retrospective study conducted in China [214]. 829 830 When ovarian carcinoma cell lines CAOV3 and SKOV3 were treated with LDL, 831 proliferation rates remained unchanged [215]. However, concentrations of oxLDL as 832 small as 0.1 µg/mL stimulated proliferation in these cell lines, accompanied by an 833 induction of the expression of the cytokine cardiotrophin 1, which has anti-apoptotic 834 effects. These changes were counteracted when cells were treated with LXR agonists, 835 concomitantly to oxLDL [215]. Interestingly, increased levels of oxLDL were observed 28 836 in ovarian cancer patients compared to control subjects [48]. These results rather 837 indicate that oxLDL appears to have an important role in ovarian cancer development. 838 839 6.3. HDL and ovarian cancer 840 841 A large genome-wide analysis identified several loci involved in HDL transport 842 (including CETP, APOA1, and ABCG1) associated with epithelial ovarian cancer in 843 patients following first-line chemotherapy [216]. The role of HDL-C on ovarian cancer 844 was also supported by the results of a large meta-analysis that reported low HDL-C 845 levels in ovarian cancer patients [203]. And those of another meta-analysis that showed 846 an association between high HDL-C levels and lower ovarian cancer risk [196]. The 847 results of one of these studies also concluded that women with ovarian malignant 848 tumors had both significant lower APOA1 and HDL-C levels, particularly in the small 849 HDL3 fraction [217]. Other two retrospective studies also reported that low HDL-C 850 levels were strongly associated with severity of epithelial ovarian cancer [199,214]. In 851 line with these findings, HDL-C levels and PON1 activity were also lower in patients 852 with newly diagnosed epithelial ovarian cancer and this was associated with histological 853 grade of tumors and high lipid hydroperoxide levels [218]. 854 855 Importantly, a prospective study also revealed that serum LCAT activity, mainly 856 involved in the conversion of HDL3 to large HDL2, was lower in patients bearing 857 indolent ovarian tumors; noteworthy, this activity together with other two serum 858 biomarkers, were strongly associated with poor prognosis [219]. The use of 859 experimental models provided conclusive evidence of the anti-tumorigenic effects of 860 APOA1 in ovarian cancer since overexpression of human APOA1 increased HDL-C 861 levels, reduced tumor development, and increased survival in mice bearing ovarian 862 epithelial papillary serous adenocarcinoma cells [220]. Furthermore, human APOA1 863 incubation significantly inhibited proliferation of these adenocarcinoma cells [220]. 864 865 6.4. Intracellular cholesterol metabolism and ovarian cancer 866 The genome-wide analyses reported above identified that genetic inhibition of HMGCR 867 was significantly associated with lower odds of ovarian cancer [216]. In contrast, 868 microarray data analysis showed that SERBP2, HMGCR, and DHCR7 were strongly 869 repressed in ovarian carcinomas compared to normal and benign tissues [221]. Also, 29 870 patients with ovarian tumors expressing high levels of HMGCR had a significantly 871 favorable prognosis [222]. Other works also revealed potential divergent results in the 872 association of enzymes controlling the mevalonate pathway and ovarian cancer. Ovarian 873 cell carcinomas with functional mutations in AT-rich interactive domain-containing 874 protein 1A, showed a downregulation in several enzymes of mevalonate pathway, 875 including HMGCS and FDPS [223]. However, exposure to the ovarian 876 microenvironment upregulated the expression of many genes involved mevalonate 877 pathway in murine ovarian cancer cells, including HMGCR, HMGCS, and FDPS [224]. 878 879 It should be noted that intracellular cholesterol levels were elevated in high grade serous 880 ovarian cancer cells and malignant ascites.This feature modulated the sensitivity of 881 ovarian cancer cells to chemoresitance [225,226]. Furthermore, platinum-resistant 882 ovarian cancer cells also showed LDLR upregulation and this was associated with 883 worse survival in ovarian cancer patients [226]. In line with these findings, LDLR was 884 also upregulated in the microarray data analyses of ovarian carcinomas [221], thus 885 indicating a greater reliance on cholesterol uptake in in the ovarian tumor cells. 886 Cholesterol esters were also found to be increased in human ovarian carcinoma cell 887 lines along with an upregulation of ACAT1 [227]. ACAT1 inhibition reduced cell 888 proliferation, invasion, and viability in these ovarian cancer cells, mainly by increasing 889 both caspase 3/7 activities and p53, and by reducing ROS production [227]. 890 891 Gene expression and immunohystochemical analyses revealed that high expression of 892 ABCA1 in primary tumors was strongly associated with reduced survival in two cohorts 893 of serous ovarian cancer patients [228]. ABCA1 downregulation also inhibited ovarian 894 cancer cell growth and migration in vitro [228]. EN OTROS TUMORES AUMENTAR 895 ABCA1 ERA POSITIVO, LO QUE CUADRABA CON UNA MENOR TENDENCIA 896 A ACUMULAR COLESTEROL. EN OVARIO ES LO CONTRARIO ¿PORQUÉ? 897 Importantly, a very recent report found that ovarian cancer cells injected in mice, 898 stimulated ABCA1-mediated cholesterol efflux in tumor associated macrophages, 899 depleting lipid rafts and increasing IL-4 signaling, thereby inducing PI3K activity and 900 mTOR-mediated Akt phosphorylation [229]. Ovarian cancer cells might, thus, uptake 901 cholesterol from HDL effluxed on tumor-associated macrophages and these cells were 902 reprogrammed toward a tumor-promoting phenotype via STAT6 [229]. In contrat, 903 higher APOA1 mRNA levels in prechemotherapy serous ovarian cancer effusions were 30 904 associated with longer overall survival [230]. However, the potential of APOA1 to 905 regulate cholesterol efflux in the tumor microenvironment deserve further investigation. 906 907 908 As occurred with breast cancer patients, high expression of CYP27A1 was associated 909 with a significant decrease in overall survival in early stage ovarian cancer patients, 910 while high expression of CYP7B1 was associated with lower overall survival [231]. 911 Furthermore, exogenous 27-HC appeared to impact the peritoneal spread of 912 tumors.tumors failed to thrive in mice lacking CYP27A1 and orthotopically grafted 913 with ovarian cancer cells [231]. Finally, 25-HC also induced proliferative effects in 914 ovarian cancer cells by modulating ERα and Cyclin D1 protein levels [232]. 915 916 ¿¿Overall, these results indicate that targeting cholesterol uptake and efflux, 917 intracellular cholesterol storage and conversion to HC could be a good strategy for the 918 treatment of ovarian cancer patients (summarized in Figure 1E).?? 31 919 7. Adrenal and testicular cancer 920 921 Adrenal and testicular cells require large amounts of cholesterol for the optimal steroid 922 hormone production. These major steroidogenic organs synthesize cholesterol de novo 923 under the influence of the tropic hormone, while the adrenal preferentially use 924 cholesterol from LDL and HDL thought LDLR and SR-BI, respectively [233]. 925 926 The two major types of adrenal cortex tumors are the benign adrenocortical adenoma , 927 which is extremely common, and the rare and malignant adrenocortical carcinoma 928 [234]. Only 15% of adrenocortical adenomas are "functional", thereby producing 929 glucocorticoids, mineralocorticoids, and sex steroids. Sometimes, these tumors are 930 termed incidentalomas because they are found by accident. However, adrenocortical 931 ¿carcinomas? are mainly functional. Functional tumors result in endocrine disorders 932 such as Cushing's syndrome, hyperaldosteronism, female virilization, or male 933 feminization. Although functional adrenal incidentalomas were early associated with 934 high LDL-C [235], several later studies found no association with lipoprotein 935 cholesterol changes [236,237]. 936 937 Both human LDL- and HDL-C were used for steroid production by primary 938 adrenocortical cells obtained from adenomas [238]. These findings were also found in 939 adrenocortical carcinoma cells, mainly by the action of LDLR and SR-BI [239,240]. In 940 the latter report, the tumor tissue of the female patient expressed high levels of LDLR 941 and a severe reduction in LDL-C and HDL-C. More importantly, her serum cholesterol 942 levels were normalized few days after tumor removal [240]. In line with these findings, 943 the transcriptome analyses of adrenocortical adenomas revealed a major association of 944 HMGR, SQLE, DHCR24, SCARB1, and LDLR with cortisol secretion [241] and, also 945 cortisol-producing adenomas showed a higher content of cholesterol along an 946 upregulation of LDLR, DCHR24, and HMGCR and a downregulation of ABCA1 [242]. 947 Overall, these results emphasize the role of LDL, HDL, and cholesterol synthesized de 948 novo on adrenocortical cancer cell production of steroids. However their effects on 949 carcinogenic pathways remain largely unknown. 950 951 Testicular cancer is a common cancer in middle-aged men. Chemotherapy has achieved 952 a higher survival rate even in patients with metastasis [243]. A large population-based 32 953 cohort Swedish study, with a follow-up of 25 years, found a highly significant positive 954 association between serum cholesterol and the risk of developing testicular cancer; this 955 was particularly relevant with cholesterol levels higher than 7 mM [244]. Early studies 956 demonstrated that the use of LDL under acute hormonal stimulation had little effect on 957 the amount of steroid synthesized in cultured Leydig tumor cells and these cells rather 958 enhanced demand of cholesterol by increasing de novo synthesis [245,246]. However, 959 LDL appears to play a critical role by providing cholesterol substrate to the tumor cells 960 under prolonged hormonal stimulation [245]. It has also been reported that ACAT 1 961 inhibition results in cholesterol accumulation in the Leidyg tumor cells. Furthermore, it 962 should be noted that a high prevalence of metabolic abnormalities is present in testicular 963 cancer patients treated with chemotherapy, including higher LDL-C and lower HDL-C 964 [247]. This indicate that testicular cancer survivors should adopt healthy lifestyle and 965 measures to control their lipid levels. Clearly, more studies are needed to clarify the role 966 of cholesterol on testicular carcinogenic pathways. 33 967 8. Therapeutic strategies 968 969 8.1. LDL and cholesterol-lowering based therapies 970 971 Because of the vital and prooncogenic functions of cholesterol in endocrine-related 972 cancers, impeding active cholesterol metabolism is considered to be a feasible anti- 973 carcinogenesis strategy. Statins are the most common LDL-C-lowering drugs that 974 reduce the incidence of cardiovascular events. For this reason, statins have been the 975 most widely evaluated cholesterol-metabolism-targeting drugs in clinical studies for 976 patients with cancer and, particularly in breast cancer [1]. Fewer studies have addressed 977 the potential of other cholesterol-lowering agents such as ezetimibe and PCSK9 978 inhibitors on cancer development. 979 980 8.1.1. Statins 981 In general, statins are safe at standard doses, showing only mild adverse effects on the 982 muscle and liver that vary depending on the exact statin used, as well as the dosage and 983 combination with other drugs [248]. Statins may exert their anti-tumor effects in 984 different ways. The inhibition of HMGCR is considered the main molecular mechanism 985 underlying most of the anti-tumor effects of statins [249,250]. However, the use of the 986 mevalonate pathway as therapeutic target is difficult, since influences a large number of 987 cellular processes. The inhibition of intracellular cholesterol synthesis can be 988 counteracted by an upregulation in LDLR expression thus adquiring more cholesterol 989 from LDL and promoting tumor growth [46,149,183]. By controlling the mevalonate 990 pathway, it is however possible to alter cholesterol synthesis and prenylation patterns, 991 thereby affecting the function of proteins and oncoproteins that regulate proliferation, 992 migration, invasion, cell cycle, and cell fate, and apoptosis [251,252]. Notably, 993 although statins are well-known hypocholesterolemiant drugs, they might also target 994 different pathways [253,254].Therefore, other anti-tumoral statin effects also include 995 anti-inflammatory properties and immunomodulation, such as restoring tumor immune 996 surveillance mechanisms, either by increasing the immunogenicity of cancer cells or by 997 directly engaging the immune system response against them [250,255]. 998 999 Up to date, several clinical studies exist and have suggested benefits of statin usage on 1000 patient survival for endocrine-related cancers. However, other studies have found no 34 1001 effect of statins, or even a less favorable outcomes. A summary of the main clinical 1002 trials evaluating the association between statins use and endocrine-related cancer risk is 1003 shown in Table 1. Overall, discrepancies among results derived from meta-analyses of 1004 observational case studies exist. We could explain the conflicting results if we take into 1005 account the different nature of of these clinical studies, the heterogeneity in patient 1006 samples and tumor characteristics, as well as the consistent number of confounding 1007 variables and bias this . 35 1008 Table 1. Clinical trials evaluating the association between statins use and cancer risk Tumor type Reference Year Study design Participants Main findings Although there was a preventive effect of statin on cancer Jeong et al. All cancers 2020 Meta-analysis 1 173 269 mortality in some cancer types, the evidence supporting the use [256] of statins to reduce cancer mortality or survival was low. Significant protective effects of lipophilic statin use, but not Liu et al. [257] 2017 Meta-analysis 197 048 hydrophilic statins, against cancer-specific mortality. A median of 5 years of statin therapy had no effect on the Emberson et al. 2012 Meta-analysis 175 000 incidence of, or mortality from any type of cancer (including [258] pancreas, prostate and breast cancer). Baigent et al. There was no evidence that statins increased the incidence 2005 Meta-analysis 90 056 [259] of cancer overall. Manthravadi et Lipophilic statin use was associated with improved recurrence- 2016 Meta-analysis 75 684 al. [260] free survival. Rossebø et al. Cancer occurred more frequently in patients with aortic stenosis 2008 Prospective 1873 [261] treated with simvastatin and ezetimibe. Jacobs et al. Long-term use of statins did not increase nor decrease overall 2011 Retrospective 133255 [262] cancer risk, including pancreatic, prostate and breast cancers Total: 295 925 Reduced cancer-related mortality among statin users as Nielsen et al. Cases: 18 721 compared with those who had never used statins was observed 2012 Case-control [263] Controls: for each of 13 cancer types (including prostate, breast and 277 204 pancreatic cancers). Breast Ference et al. Mendelian Genetic inhibition of HMGCR did not affect breast cancer risk. 2019 654 783 cancer [264] randomization Undela et al. Statin use and long-term statin use did not significantly affect 2012 Meta-analysis >2.4 million [265] breast cancer risk. Bonovas et al. Statin use did not significantly affect breast cancer risk. 2005 Meta-analysis 327 238 [266] 36 There was a significant negative association between prediagnosis statin use and breast cancer mortality and for disease-specific revisar: ¿esto parece contrario? survival. There Wu et al. [267] 2015 Meta-analysis 144 830 was also a significant inverse association between postdiagnosis statin use and breast cancer disease ¿esto parece lo contrario? - specific survival. No significant association was detected between statin use and breast cancer risk. Mansourian et Significant reduction in breast cancer recurrence and death 2016 Meta-analysis 124 669 al. [268] among statin users. Islam et al. There was no association between statin use and breast cancer 2017 Meta-analysis 121 399 [269] risk. Dale et al. [270] 2006 Meta-analysis 86 936 Statins did not reduce the incidence of breast cancer. Murtola et al. Both postdiagnostic and prediagnostic statin uses were associated 2014 Prospective 31 236 [271] with a lowered risk of breast cancer death. Ahern et al. Significant reduction in breast cancer recurrence among patients 2011 Prospective 18 769 [272] using simvastatin after 10 y of follow up. Initiation of cholesterol-lowering medication in postmenopausal women with early stage cancer?, esto no es de lo que estamos Borgquist et al. hablanco: “hormone receptor-positive invasive breast cancer 2017 Prospective 8010 [273] during endocrine therapy was related to improved disease-free survival, breast cancer-free interval and distant recurrence-free interval.” Cauley et al. Older women who used statins had a reduced risk of breast 2003 Prospective 7528 [274] cancer compared with nonusers. Hydrophilic statins were associated with significantly improved Brewer et al. 2013 Prospective 723 progression-free survival compared with no statin in breast [275] cancer patients. Anothaisintawee Use of lipophilic statins, but not hydrophilic statins, could 2016 Retrospective 15 718 et al. [276] significantly reduce the risk of breast cancer Mc Menamin 2016 Retrospective 15 140 There was no evidence of an association between statin use and 37 et al. [277] breast cancer-specific death. Prediagnostic statin use was associated with a decrease in breast Smith et al. 2017 Retrospective 6314 cancer-specific mortality. This reduction was greatest in statin [278] users with ER-positive tumors. Shaitelman et al. Statin use was significantly associated with overall survival in 2017 Retrospective 869 [279] triple-negative breast cancer. Significant reduction in breast cancer recurrence among patients Chae et al. [280] 2011 Retrospective 703 who used statins. No association was found regarding overall survival. Sakellakis et al. Statins may be linked to a favorable outcome in early breast 2016 Retrospective 610 [281] cancer patients, especially in younger age groups. Total: 228 973 Statin use did not significantly affect breast cancer risk. Schairer et al. Cases: 30 004 2018 Case-control [282] Controls: 198 969 Total: 2886 Current users of statins for >10 y had increased risk of invasive McDougall 2013 Case-control Cases: 916 ductal carcinoma and invasive lobular carcinoma compared with et al. [283] Controls: 902 never users of statins. Statin use in patients with prostate cancer receiving radiation Prostate Hutchinson et 2017 Meta-analysis 774 316 therapy did not translate into an overall survival benefit for cancer al. [284] patients The use of statin drugs was not associated with risk of prostate Platz et al. [285] 2006 Prospective 34 989 cancer overall but was associated with a reduced risk of advanced (especially metastatic or fatal) prostate cancer. Larsen et al. Postdiagnosis statin use was associated with reduced mortality 2017 Retrospective 31 790 [286] from prostate cancer. Statin use was associated with a dose-dependent reduction in the Total: 1319 Hamilton et al. risk of biochemical recurrence of prostate cancer, suggesting that 2010 Case-control Cases: 236 [287] statins may slow prostate cancer progression after radical Controls: 1083 prostatectomy. 38 Pancreatic Bonovas et al. Statins do not reduce the risk of pancreatic cancer when taken at 2008 Meta-analysis 914 601 cancer [288] doses for managing hypercholesterolemia An inverse association between statin use and pancreatic cancer Cui et al. [289] 2012 Meta-analysis 7807 risk was found Huang et al. Statin use was associated with lower mortality risk. 2017 Retrospective 2142 [290] The use of simvastatin and atorvastatin was associated with Lee et al. 2016 Retrospective 1761 longer survival in patients with nonmetastatic pancreatic [121] adenocarcinoma Preoperative use of statins was found to be a predictor of Chagpar et al. 2011 Retrospective 518 increased early postoperative mortality in patients with resected [292] pancreatic cancer. Hydrophilic statin use was associated with longer survival in Jeon et al. [293] 2014 Retrospective 263 pancreatic patient with metabolic syndrome. Nakai et al. Statin use was associated with better survival in diabetic patients 2013 Retrospective 250 [294] with pancreatic cancer. 483733 Total, Statins seem to be protective against the development of Khurana et al. 2007 Case-control 163467 cases, pancreatic cancer, and the magnitude of the effect correlates with [295] 320266 controls. the duration of statin use. 9095 Total, Statin use was not associated with the risk of exocrine pancreatic Bradley et al. 2010 Case-control 1141 cases, cancer [296] 7954 controls 1405 Total, 536 Risk reduction of prostate cancer was found and it appeared to be Walker et al. 2015 Case-control cases and 869 sex-specific and more pronounced in long-term users. [297] controls 950 Total, 190 No beneficial association between usage of statin and pancreatic Chiu et al. [298] 2011 Case-control cases, 760 cancer was observed. controls. Carey et al. 2013 Case-control 756 Total, 252 Statins reduce the odds of pancreatic cancer in male smokers. 39 [299] cases, 504 controls Ovarian Majidi et al. 2020 Meta-analysis 22 521 The analysis suggests improved survival in statin users compared cancer [300] to non-users. Li et al. [301] 2018 Meta-analysis 19 904 Post-diagnosis statin use can improve the survival of patients with ovarian cancer. Increased intensity of statin use was significantly associated with improved overall survival. Liu et al. 2014 Meta-analysis 12 904 Statin use was inversely associated with ovarian cancer risk. The [302] association was stronger for long-term statin use (>5 years) Harding et al. 2019 Retrospective 2195 Statin use following a diagnosis with ovarian cancer was [303] associated with a lower risk of cancer death. Urpilainen et al. 2018 Retrospective 244 322 Pre-diagnostic use of statins was observed to be associated with [304] improved prognosis and decreased mortality from ovarian cancer compared with no such use Desai et al. 2018 Retrospective 126 253 In time-dependent models, statins were associated with an [305] increased risk of ovarian cancer, largely attributed to the effect of the hydrophilic statin pravastatin. Couttenier et al. 2017 Retrospective 5416 Evidence of a protective effect of statin use on ovarian cancer- [306] specific and all-cause mortality exists. Simvastatin and rosuvastatin in particular appeared to have the strongest protective association. Verdoodt et al. 2017 Retrospective 4419 No strong evidence of an association between post-diagnostic [307] statin use and reduced mortality in ovarian cancer patients was found. Reduced mortality with statin use was observed in sub- cohorts of new users of statins and of patients not using low-dose aspirin. Chen et al. [308] 2016 Retrospective 60 Statin use was not associated with improved overall survival in patients with advanced-stage ovarian cancer undergoing surgery and chemotherapy. Habis et al. 2014 Retrospective 442 Statin use among patients with non-serous papillary ovarian 40 [309] cancer was associated with improvement in both progression-free survival and disease-specific survival Wang et el. 2019 Case-control Total: 1 999 362 Statin use did not lower the risk of ovarian cancer. The long-term [310] Cases: 19 849 use of statins (>5 years) was not associated with a reduction in Controls: the risk of ovarian cancer. 1 979 513 Akinwunmi et 2019 Case-control Total: 4140 Statins were found to lower the risk for both serous and non- al. [311] Cases: 2040 serous epithelial ovarian cancer and especially mucinous Controls: 2100 epithelial ovarian cancer. Baandrup et al. 2015 Case-control Total: 62 809 A neutral association between ever use of statins and epithelial [312] Cases: 4103 ovarian cancer risk was found, with no apparent risk variation Controls: 58 706 according to duration, intensity or type of statin use. 41 1009 Due to side effects of statins, increasing doses in cancer patients is unadvisable. An 1010 alternative strategy to overcome this situation is to combine statin therapy with other 1011 drugs. Accumulating evidence indicates that targeting cholesterol metabolism sensitizes 1012 endocrine-related cancer cells to other anti-tumor therapies. Accordingly, a synergistic 1013 effect has been observed when statins are combined with other chemotherapeutic drugs. 1014 For instance, in breast cancer cells positive for Erb-b2 tyrosine kinase receptor , 1015 suppression of cholesterol biosynthesis by inhibitors such as lovastatin can trigger 1016 ErbB2 internalization and degradation. In this scenario, adding ErbB2 inhibitors 1017 represses tumor growth [313]. In prostate cancer cells, a combination therapy of 1018 enzalutamide and simvastatin has been shown to have a significant synergistic effect on 1019 tumor suppression [314]. In other cancer cells, cholesterol-metabolism-blockade therapy 1020 causes feedback responses that decrease drug efficacy. Therefore, inhibiting feedback 1021 responses with another therapy might enhance anti-tumor efficacy. For example, a 1022 treatment combining aspirin or metformin with fluvastatin has been found to almost 1023 completely abrogate the colonization capability of breast cancer cells [315]. In another 1024 recent study, statin treatment has been found to significantly decrease levels of the 1025 mevalonate-pathway product coenzyme Q in cancer cells, thus leading to excessive 1026 oxidative stress [316]. Upregulating antioxidant pathways synergizes with statins to 1027 produce a robust antitumor response [316]. Despite these positive results, definitive 1028 evidence of these combination therapeutic strategies on endocrine cancer will require 1029 human clinical trials. 1030 1031 8.1.2. Ezetimibe and PCSK9 inhibitors 1032 Other LDL-C lowering drugs other tha statinsshould also be taken into account. 1033 Ezetimibe, which significantly reduces the absorption of cholesterol from the intestine, 1034 was first hypothesized to increase the incidence of cancer when added to statin therapy 1035 for enhancing LDL-C reduction [261]. Nevertheless, larger trials with statistically 1036 independent evidence, found no adverse effect on cancer when added to statin therapy 1037 [317] la refer 318 dice que no hya diferencias en el riesgo de cancer de tratados con 1038 eze+simva: [318]. In contrast, ezetimibe was an effective inhibitor of tumor 1039 angiogenesis in the progression of prostate cancer cells implanted in mice fed a high fat 1040 high cholesterol diet [319]. However, it should be noted that the predominant 1041 lipoprotein in mice is HDL and they show significant metabolic lipoprotein differences 1042 when compared with that of human [320]. 42 1043 1044 On the other side, drugs inhibiting PCSK9 lead to increased hepatic LDLR abundance, 1045 reducing effectively LDL-C, which may be seen as a strategy to limit the exogenous 1046 lipids to support the proliferation of tumors. It was recently reported that LDL-C-raising 1047 genetic variants of PCSK9 were associated with a higher risk of breast cancer, while 1048 LDL-lowering variants mimicking PCSK9 inhibitors were found to have a significant 1049 lower risk of ER-positive breast cancer [35]. Works performed on mice revealed that 1050 PCSK9 inhibition not only exerts no harmful effects but also could somewhat improve 1051 breast cancer behavior in an experimental model of breast cancer, suggesting safety and 1052 efficacy of PCSK9 inhibitors in conditions other than cardiovascular disease such as 1053 cancer [321]. However, from a clinical perspective, there is no evidence that PCSK9 1054 inhibition might influence the course of endocrine-related cancers, whether beneficially 1055 or deleteriously [322]. 1056 1057 8.2. HDL-C based therapies 1058 1059 Some HDL-based strategies have emerged with the aim to prevent cancer development. 1060 The potential of some HDL and APO mimetics and some specific LXR agonists are 1061 reviewed in two reports of this Special Issue. Interestingly, the effects of the most 1062 effective current drugs for elevation of HDL-C levels, the CETP inhibitors, and other 1063 HDL cholesterol-raising drugs such as fibrates and niacin, have been evaluated in 1064 experimental models and large clinical trials, including some relevant data on 1065 endocrine-related cancer. 1066 1067 Despite CETP inhibitors increase plasma HDL-C levels substantially, drug development 1068 for most CETP inhibitors (i.e., torcetrapib, evacetrapib, dalcetrapib) was stopped 1069 because of futility [323,324] or adverse cardiovascular side effects [325]. Patients 1070 receiving torcetrapib showed significant side effects on blood pressure and adverse 1071 cardiovascular outcomes; furthermore, a higher number of patients in the torcetrapib 1072 group died from cancer (including breast and pancreatic cancer), although the 1073 mechanism underlying this excess of deaths remains unclear [325]. The only exception 1074 was anacetrapib, which reduced cardiovascular disease events on top of statin therapy in 1075 a large trial with patients with atherosclerotic vascular disease without any variation in 1076 the incidence of fatal or non-fatal cancer, including breast cancer [326]. 43 1077 1078 Fibrates are activators of PPAR-α, leading to significant reduction of triglyceride 1079 concentration, but also up-regulating APOA1 and APOA2 expression and ultimately 1080 increasing plasma HDL-C levels. Results regarding fibrates and HDL-C levels on 1081 endocrine-related cancer risk are controversial. A previous work found increased 1082 cancer-related deaths following the use of clofibrate for the primary prevention of 1083 ischemic heart disease [327], however, this excess of mortality was not related with 1084 endocrine cancers [327]. Also, experimental works with rats and mice found increased 1085 hepatic carcinogenesis after fibrate use [328], but fenofibrate considerably inhibited the 1086 growth of the breast tumors in mice [329]. Several large clinical trials found no effect of 1087 fibrates on cancer incidence and cancer-related deaths, independently of the fibrate used 1088 and cancer type [330–333]. Furthermore, some large and long-follow up observational 1089 studies revealed that gemfibrozil had no significant effects in cancer mortality, 1090 including prostate cancer [334–336]. Moreover, bezafibrate treatment was associated 1091 with reduced risk of cancer, including prostate cancer, among patients with coronary 1092 artery disease, however, this association was not sensitive to adjustment for on-trial 1093 lipid levels [337]. Overall, there is not enough evidence suggesting that the increased 1094 HDL-C levels following fibrate treatment might have an impact on any cancer-related 1095 outcomes; thus, their use with anticancer purposes cannot be considered in clinical 1096 practice. 1097 1098 Niacin increases HDL-C by 20-25% and reduces triglycerides and LDL-C by 25-30% 1099 and 20%, respectively [338]. Data on cancer-related outcomes do not suggest significant 1100 beneficial effects of niacin in endocrine cancers. In that sense, cancer deaths in the 1101 Coronary Drug Project were similar between treated and untreated patients, although the 1102 number of cases reported was low [339]. Moreover, in a large study with adults with 1103 vascular disease, the use of niacin in combination with laropiprant did not influence the 1104 overall incidence of cancer, including breast cancer [340]. 1105 1106 In this context, an innovative area of research in which HDL-like particles are used to 1107 vehiculate anticancer drugs and molecules to cancer cells is producing interesting 1108 results [341], however, further preclinical and clinical trials are necessary to verify the 1109 efficacy in terms of endocrine cancer incidence and progression and safety of 1110 therapeutic increase of HDL-C. 44 1111 1112 In conclusion, the effect of these hypolipidemiant drugs in human cancer prevention and 1113 treatment remains controversial and more carefully designed studies are needed before 1114 a definite conclusion regarding endocrine cancer risk and recurrence can be made. 45 1115 9. Concluding remarks 1116 1117 Although the endocrine-related tumors show different specific molecular 1118 signatures, they all require a high demand of cholesterol for the tumor growth and 1119 survival due, at least in part, to the increased hormone and steroid production by these 1120 cells. Although several large clinical trials indicate a positive association between 1121 plasma cholesterol levels and the risk for some endocrine cancers, not all the studies 1122 revealed an association and, even some of them revealed an inverse relationship with 1123 these cancers. Some of these studies pointed to a direct association between LDL-C 1124 levels and breast cancer, but this association was not found in other endocrine cancers. 1125 Beyond LDL-C levels, LDLR may be essential for the progression of endocrine-related 1126 cancers by maintaining the cholesterol distribution of tumor cells. Furthermore, both 1127 LDLR and OLR1 may modulate cellular signaling pathways involved in tumorigenesis. 1128 SR-BI-mediated cholesterol uptake may also enhance cell proliferation and play a 1129 critical role in cancer cells expressing high levels of this protein, such as those of breast, 1130 prostate, and ovarian cancer. However, HDL also exhibits antioxidant and anti- 1131 inflammatory properties that could protect against oxidative stress-mediated 1132 proliferation in some endocrine cancer cells. These divergent HDL actions may 1133 differentially affect endocrine cancers depending of their cholesterol needs and the role 1134 of inflammatory and oxidative processes in tumor development. The excess of 1135 intracellullar unesterified cholesterol may also be converted into 27-HC, which can 1136 promote tumorigenic processes in breast end epithelial thyroid cancer. Deregulation of 1137 genes involved in cholesterol synthesis has also been reported in all endocrine-related 1138 cancer cells but this is highly dependent of tumor cell type and both an upregulation and 1139 downregulation of mevalonate pathway have been reported. Although some large 1140 clinical trials indicated that statins may reduce the incidence of breast, prostate, 1141 pancreatic and ovarian cancer, these findings were not reproduced in all studies. 1142 1143 Collectively, these studies strongly indicate that cholesterol homeostasis 1144 deregulation is a key contributing factor to endocrine-related cancer development. 1145 Therapeutic targeting of lipoprotein-mediated cholesterol uptake and cholesterol storage 1146 pathways might constitute a potentially effective approach to prevent or delay 1147 progression endocrine-related cancers 1148 46 1149 Conflict of interest statement 1150 The authors declare that there are no conflicts of interest. 1151 1152 Acknowledgements 1153 This work was partly funded by the Ministerio de Sanidad y Consumo, Instituto de 1154 Salud Carlos III, and FEDER “Una manera de hacer Europa,” grant FIS 16-00139 and 1155 FIS19-00136 (to J.C.E.-G., A.M., and E.M.). CIBERDEM and CIBER-BBN are 1156 Instituto de Salud Carlos III projects. We especially want to thank all the patients who 1157 participated in this study and the Societat Catalana d’Endocrinologia i Nutrició (SCEN) 1158 (Ajut a la Investigació Bàsica/Clínica 2018) for the financial support for parts of the 1159 experiments described in this paper. Precipita 47 1160 Bibliography 1161 [1] B. Huang, B. Song, C. Xu, Cholesterol metabolism in cancer: mechanisms and 1162 therapeutic opportunities, Nat Metab. 2 (2020) 132–141. 1163 https://doi.org/10.1038/s42255-020-0174-0. 1164 [2] X. Ding, W. Zhang, S. Li, H. Yang, The role of cholesterol metabolism in cancer, 1165 Am J Cancer Res. 9 (2019) 219–227. 1166 [3] A. Chimento, I. Casaburi, P. Avena, F. Trotta, A. De Luca, V. Rago, V. Pezzi, R. 1167 Sirianni, Cholesterol and Its Metabolites in Tumor Growth: Therapeutic Potential of 1168 Statins in Cancer Treatment, Front Endocrinol (Lausanne). 9 (2018) 807. 1169 https://doi.org/10.3389/fendo.2018.00807. 1170 [4] R. Lloyd, R. Osamura, G. Klöppel, J. Rosai, WHO Classification of Tumours of 1171 Endocrine Organs, 4th edition, 2017. 1172 [5] T. Sudhop, D. Lütjohann, A. Kodal, M. Igel, D.L. Tribble, S. Shah, I. Perevozskaya, 1173 K. von Bergmann, Inhibition of intestinal cholesterol absorption by ezetimibe in 1174 humans, Circulation. 106 (2002) 1943–1948. 1175 https://doi.org/10.1161/01.cir.0000034044.95911.dc. 1176 [6] M.Y.M. van der Wulp, H.J. Verkade, A.K. Groen, Regulation of cholesterol 1177 homeostasis, Mol. Cell. Endocrinol. 368 (2013) 1–16. 1178 https://doi.org/10.1016/j.mce.2012.06.007. 1179 [7] M.S. Brown, A. Radhakrishnan, J.L. Goldstein, Retrospective on Cholesterol 1180 Homeostasis: The Central Role of Scap, Annu. Rev. Biochem. 87 (2018) 783–807. 1181 https://doi.org/10.1146/annurev-biochem-062917-011852. 1182 [8] E. Ikonen, Cellular cholesterol trafficking and compartmentalization, Nat. Rev. 1183 Mol. Cell Biol. 9 (2008) 125–138. https://doi.org/10.1038/nrm2336. 1184 [9] A. Rigotti, H.E. Miettinen, M. Krieger, The role of the high-density lipoprotein 1185 receptor SR-BI in the lipid metabolism of endocrine and other tissues, Endocr. Rev. 1186 24 (2003) 357–387. https://doi.org/10.1210/er.2001-0037. 1187 [10] L. Zhang, K. Reue, L.G. Fong, S.G. Young, P. Tontonoz, Feedback regulation 1188 of cholesterol uptake by the LXR-IDOL-LDLR axis, Arterioscler. Thromb. Vasc. 1189 Biol. 32 (2012) 2541–2546. https://doi.org/10.1161/ATVBAHA.112.250571. 1190 [11] A. Kloudova, F.P. Guengerich, P. Soucek, The Role of Oxysterols in Human 1191 Cancer, Trends Endocrinol. Metab. 28 (2017) 485–496. 1192 https://doi.org/10.1016/j.tem.2017.03.002. 1193 [12] K. Georgila, D. Vyrla, E. Drakos, Apolipoprotein A-I (ApoA-I), Immunity, 1194 Inflammation and Cancer, Cancers. 11 (2019) 1097. 1195 https://doi.org/10.3390/cancers11081097. 1196 [13] T. Bacchetti, G. Ferretti, A. Sahebkar, The role of paraoxonase in cancer, Semin. 1197 Cancer Biol. 56 (2019) 72–86. https://doi.org/10.1016/j.semcancer.2017.11.013. 1198 [14] Global Burden of Disease Cancer Collaboration, C. Fitzmaurice, T.F. 1199 Akinyemiju, F.H. Al Lami, T. Alam, R. Alizadeh-Navaei, C. Allen, U. Alsharif, N. 1200 Alvis-Guzman, E. Amini, B.O. Anderson, O. Aremu, A. Artaman, S.W. Asgedom, 1201 R. Assadi, T.M. Atey, L. Avila-Burgos, A. Awasthi, H.O. Ba Saleem, A. Barac, J.R. 1202 Bennett, I.M. Bensenor, N. Bhakta, H. Brenner, L. Cahuana-Hurtado, C.A. 1203 Castañeda-Orjuela, F. Catalá-López, J.-Y.J. Choi, D.J. Christopher, S.-C. Chung, 1204 M.P. Curado, L. Dandona, R. Dandona, J. das Neves, S. Dey, S.D. Dharmaratne, 1205 D.T. Doku, T.R. Driscoll, M. Dubey, H. Ebrahimi, D. Edessa, Z. El-Khatib, A.Y. 1206 Endries, F. Fischer, L.M. Force, K.J. Foreman, S.W. Gebrehiwot, S.V. Gopalani, G. 1207 Grosso, R. Gupta, B. Gyawali, R.R. Hamadeh, S. Hamidi, J. Harvey, H.Y. Hassen, 1208 R.J. Hay, S.I. Hay, B. Heibati, M.K. Hiluf, N. Horita, H.D. Hosgood, O.S. Ilesanmi, 48 1209 K. Innos, F. Islami, M.B. Jakovljevic, S.C. Johnson, J.B. Jonas, A. Kasaeian, T.D. 1210 Kassa, Y.S. Khader, E.A. Khan, G. Khan, Y.-H. Khang, M.H. Khosravi, J. 1211 Khubchandani, J.A. Kopec, G.A. Kumar, M. Kutz, D.P. Lad, A. Lafranconi, Q. Lan, 1212 Y. Legesse, J. Leigh, S. Linn, R. Lunevicius, A. Majeed, R. Malekzadeh, D.C. 1213 Malta, L.G. Mantovani, B.J. McMahon, T. Meier, Y.A. Melaku, M. Melku, P. 1214 Memiah, W. Mendoza, T.J. Meretoja, H.B. Mezgebe, T.R. Miller, S. Mohammed, 1215 A.H. Mokdad, M. Moosazadeh, P. Moraga, S.M. Mousavi, V. Nangia, C.T. 1216 Nguyen, V.M. Nong, F.A. Ogbo, A.T. Olagunju, M. Pa, E.-K. Park, T. Patel, D.M. 1217 Pereira, F. Pishgar, M.J. Postma, F. Pourmalek, M. Qorbani, A. Rafay, S. Rawaf, 1218 D.L. Rawaf, G. Roshandel, S. Safiri, H. Salimzadeh, J.R. Sanabria, M.M. Santric 1219 Milicevic, B. Sartorius, M. Satpathy, S.G. Sepanlou, K.A. Shackelford, M.A. 1220 Shaikh, M. Sharif-Alhoseini, J. She, M.-J. Shin, I. Shiue, M.G. Shrime, A.H. Sinke, 1221 M. Sisay, A. Sligar, M.B. Sufiyan, B.L. Sykes, R. Tabarés-Seisdedos, G.A. 1222 Tessema, R. Topor-Madry, T.T. Tran, B.X. Tran, K.N. Ukwaja, V.V. Vlassov, S.E. 1223 Vollset, E. Weiderpass, H.C. Williams, N.B. Yimer, N. Yonemoto, M.Z. Younis, 1224 C.J.L. Murray, M. Naghavi, Global, Regional, and National Cancer Incidence, 1225 Mortality, Years of Life Lost, Years Lived With Disability, and Disability-Adjusted 1226 Life-Years for 29 Cancer Groups, 1990 to 2016: A Systematic Analysis for the 1227 Global Burden of Disease Study, JAMA Oncol. 4 (2018) 1553–1568. 1228 https://doi.org/10.1001/jamaoncol.2018.2706. 1229 [15] D. Vuong, P.T. Simpson, B. Green, M.C. Cummings, S.R. Lakhani, Molecular 1230 classification of breast cancer, Virchows Arch. 465 (2014) 1–14. 1231 https://doi.org/10.1007/s00428-014-1593-7. 1232 [16] A.R. Cervino, M. Burei, L. Mansi, L. Evangelista, Molecular pathways and 1233 molecular imaging in breast cancer: an update, Nucl. Med. Biol. 40 (2013) 581– 1234 591. https://doi.org/10.1016/j.nucmedbio.2013.03.002. 1235 [17] K.M. Cornejo, D. Kandil, A. Khan, E.F. Cosar, Theranostic and molecular 1236 classification of breast cancer, Arch. Pathol. Lab. Med. 138 (2014) 44–56. 1237 https://doi.org/10.5858/arpa.2012-0442-RA. 1238 [18] C.M. Kitahara, A. Berrington de González, N.D. Freedman, R. Huxley, Y. Mok, 1239 S.H. Jee, J.M. Samet, Total cholesterol and cancer risk in a large prospective study 1240 in Korea, J. Clin. Oncol. 29 (2011) 1592–1598. 1241 https://doi.org/10.1200/JCO.2010.31.5200. 1242 [19] M. His, L. Zelek, M. Deschasaux, C. Pouchieu, E. Kesse-Guyot, S. Hercberg, P. 1243 Galan, P. Latino-Martel, J. Blacher, M. Touvier, Prospective associations between 1244 serum biomarkers of lipid metabolism and overall, breast and prostate cancer risk, 1245 Eur. J. Epidemiol. 29 (2014) 119–132. https://doi.org/10.1007/s10654-014-9884-5. 1246 [20] L.J. Martin, O. Melnichouk, E. Huszti, P.W. Connelly, C.V. Greenberg, S. 1247 Minkin, N.F. Boyd, Serum Lipids, Lipoproteins, and Risk of Breast Cancer: A 1248 Nested Case-Control Study Using Multiple Time Points, JNCI J Natl Cancer Inst. 1249 107 (2015) djv032. https://doi.org/10.1093/jnci/djv032. 1250 [21] H. Ni, H. Liu, R. Gao, Serum Lipids and Breast Cancer Risk: A Meta-Analysis 1251 of Prospective Cohort Studies, Plos One. 10 (2015) e0142669. 1252 https://doi.org/10.1371/journal.pone.0142669. 1253 [22] J.L.F. Bosco, J.R. Palmer, D.A. Boggs, E.E. Hatch, L. Rosenberg, 1254 Cardiometabolic factors and breast cancer risk in U.S. black women, Breast Cancer 1255 Res. Treat. 134 (2012) 1247–1256. https://doi.org/10.1007/s10549-012-2131-4. 1256 [23] M. Ha, J. Sung, Y.-M. Song, Serum total cholesterol and the risk of breast 1257 cancer in postmenopausal Korean women, Cancer Causes Control. 20 (2009) 1055– 1258 1060. https://doi.org/10.1007/s10552-009-9301-7. 49 1259 [24] A.H. Eliassen, G.A. Colditz, B. Rosner, W.C. Willett, S.E. Hankinson, Serum 1260 lipids, lipid-lowering drugs, and the risk of breast cancer, Arch. Intern. Med. 165 1261 (2005) 2264–2271. https://doi.org/10.1001/archinte.165.19.2264. 1262 [25] E.R. Nelson, C. Chang, D.P. McDonnell, Cholesterol and breast cancer 1263 pathophysiology, Trends Endocrinol. Metab. 25 (2014) 649–655. 1264 https://doi.org/10.1016/j.tem.2014.10.001. 1265 [26] J. Hu, C. La Vecchia, M. de Groh, E. Negri, H. Morrison, L. Mery, Canadian 1266 Cancer Registries Epidemiology Research Group, Dietary cholesterol intake and 1267 cancer, Ann. Oncol. 23 (2012) 491–500. https://doi.org/10.1093/annonc/mdr155. 1268 [27] C. Li, L. Yang, D. Zhang, W. Jiang, Systematic review and meta-analysis 1269 suggest that dietary cholesterol intake increases risk of breast cancer, Nutrition 1270 Research. 36 (2016) 627–635. https://doi.org/10.1016/j.nutres.2016.04.009. 1271 [28] G. Llaverias, C. Danilo, I. Mercier, K. Daumer, F. Capozza, T.M. Williams, F. 1272 Sotgia, M.P. Lisanti, P.G. Frank, Role of cholesterol in the development and 1273 progression of breast cancer, Am. J. Pathol. 178 (2011) 402–412. 1274 https://doi.org/10.1016/j.ajpath.2010.11.005. 1275 [29] C.T. Guy, R.D. Cardiff, W.J. Muller, Induction of mammary tumors by 1276 expression of polyomavirus middle T oncogene: a transgenic mouse model for 1277 metastatic disease, Mol. Cell. Biol. 12 (1992) 954–961. 1278 [30] K. Pelton, C.M. Coticchia, A.S. Curatolo, C.P. Schaffner, D. Zurakowski, K.R. 1279 Solomon, M.A. Moses, Hypercholesterolemia induces angiogenesis and accelerates 1280 growth of breast tumors in vivo, Am. J. Pathol. 184 (2014) 2099–2110. 1281 https://doi.org/10.1016/j.ajpath.2014.03.006. 1282 [31] N. Alikhani, R.D. Ferguson, R. Novosyadlyy, E.J. Gallagher, E.J. Scheinman, S. 1283 Yakar, D. LeRoith, Mammary tumor growth and pulmonary metastasis are 1284 enhanced in a hyperlipidemic mouse model, Oncogene. 32 (2013) 961–967. 1285 https://doi.org/10.1038/onc.2012.113. 1286 [32] E.R. Nelson, S.E. Wardell, J.S. Jasper, S. Park, S. Suchindran, M.K. Howe, N.J. 1287 Carver, R.V. Pillai, P.M. Sullivan, V. Sondhi, M. Umetani, J. Geradts, D.P. 1288 McDonnell, 27-Hydroxycholesterol links hypercholesterolemia and breast cancer 1289 pathophysiology, Science. 342 (2013) 1094–1098. 1290 https://doi.org/10.1126/science.1241908. 1291 [33] C. Rodrigues dos Santos, G. Domingues, I. Matias, J. Matos, I. Fonseca, J.M. de 1292 Almeida, S. Dias, LDL-cholesterol signaling induces breast cancer proliferation and 1293 invasion, Lipids Health Dis. 13 (2014) 16. https://doi.org/10.1186/1476-511X-13- 1294 16. 1295 [34] C. Rodrigues dos Santos, I. Fonseca, S. Dias, J.C. Mendes de Almeida, Plasma 1296 level of LDL-cholesterol at diagnosis is a predictor factor of breast tumor 1297 progression, BMC Cancer. 14 (2014) 132. https://doi.org/10.1186/1471-2407-14- 1298 132. 1299 [35] C. Nowak, J. Ärnlöv, A Mendelian randomization study of the effects of blood 1300 lipids on breast cancer risk, Nat Commun. 9 (2018) 3957. 1301 https://doi.org/10.1038/s41467-018-06467-9. 1302 [36] A. Beeghly-Fadiel, N.K. Khankari, R.J. Delahanty, X.-O. Shu, Y. Lu, M.K. 1303 Schmidt, M.K. Bolla, K. Michailidou, Q. Wang, J. Dennis, D. Yannoukakos, A.M. 1304 Dunning, P.D.P. Pharoah, G. Chenevix-Trench, R.L. Milne, D.J. Hunter, H. Per, P. 1305 Kraft, J. Simard, D.F. Easton, W. Zheng, A Mendelian randomization analysis of 1306 circulating lipid traits and breast cancer risk, Int J Epidemiol. (2019). 1307 https://doi.org/10.1093/ije/dyz242. 50 1308 [37] M. Touvier, P. Fassier, M. His, T. Norat, D.S.M. Chan, J. Blacher, S. Hercberg, 1309 P. Galan, N. Druesne-Pecollo, P. Latino-Martel, Cholesterol and breast cancer risk: 1310 a systematic review and meta-analysis of prospective studies, Br. J. Nutr. 114 1311 (2015) 347–357. https://doi.org/10.1017/S000711451500183X. 1312 [38] P.D. Chandler, Y. Song, J. Lin, S. Zhang, H.D. Sesso, S. Mora, E.L. 1313 Giovannucci, K.E. Rexrode, M.V. Moorthy, C. Li, P.M. Ridker, I.-M. Lee, J.E. 1314 Manson, J.E. Buring, L. Wang, Lipid biomarkers and long-term risk of cancer in the 1315 Women’s Health Study, Am J Clin Nutr. 103 (2016) 1397–1407. 1316 https://doi.org/10.3945/ajcn.115.124321. 1317 [39] S. Borgquist, T. Butt, P. Almgren, D. Shiffman, T. Stocks, M. Orho-Melander, J. 1318 Manjer, O. Melander, Apo-lipoproteins, lipids and risk of cancer, Int. J. Cancer. 1319 (2016). https://doi.org/10.1002/ijc.30013. 1320 [40] J.C. Melvin, D. Seth, L. Holmberg, H. Garmo, N. Hammar, I. Jungner, G. 1321 Walldius, M. Lambe, A. Wigertz, M. Van Hemelrijck, Lipid profiles and risk of 1322 breast and ovarian cancer in the Swedish AMORIS study, Cancer Epidemiol. 1323 Biomarkers Prev. 21 (2012) 1381–1384. https://doi.org/10.1158/1055-9965.EPI-12- 1324 0188. 1325 [41] A.A. Llanos, K.H. Makambi, C.A. Tucker, S.F. Wallington, P.G. Shields, L.L. 1326 Adams-Campbell, Cholesterol, lipoproteins, and breast cancer risk in African 1327 American women, Ethn Dis. 22 (2012) 281–287. 1328 [42] C.-W. Lu, Y.-H. Lo, C.-H. Chen, C.-Y. Lin, C.-H. Tsai, P.-J. Chen, Y.-F. Yang, 1329 C.-H. Wang, C.-H. Tan, M.-F. Hou, S.-S.F. Yuan, VLDL and LDL, but not HDL, 1330 promote breast cancer cell proliferation, metastasis and angiogenesis, Cancer Lett. 1331 388 (2017) 130–138. https://doi.org/10.1016/j.canlet.2016.11.033. 1332 [43] C.J. Antalis, T. Arnold, T. Rasool, B. Lee, K.K. Buhman, R.A. Siddiqui, High 1333 ACAT1 expression in estrogen receptor negative basal-like breast cancer cells is 1334 associated with LDL-induced proliferation, Breast Cancer Res. Treat. 122 (2010) 1335 661–670. https://doi.org/10.1007/s10549-009-0594-8. 1336 [44] M. Rotheneder, G.M. Kostner, Effects of low- and high-density lipoproteins on 1337 the proliferation of human breast cancer cells in vitro: differences between 1338 hormone-dependent and hormone-independent cell lines, Int. J. Cancer. 43 (1989) 1339 875–879. https://doi.org/10.1002/ijc.2910430523. 1340 [45] C.J. Antalis, A. Uchida, K.K. Buhman, R.A. Siddiqui, Migration of MDA-MB- 1341 231 breast cancer cells depends on the availability of exogenous lipids and 1342 cholesterol esterification, Clin. Exp. Metastasis. 28 (2011) 733–741. 1343 https://doi.org/10.1007/s10585-011-9405-9. 1344 [46] D. de Gonzalo-Calvo, L. López-Vilaró, L. Nasarre, M. Perez-Olabarria, T. 1345 Vázquez, D. Escuin, L. Badimon, A. Barnadas, E. Lerma, V. Llorente-Cortés, 1346 Intratumor cholesteryl ester accumulation is associated with human breast cancer 1347 proliferation and aggressive potential: a molecular and clinicopathological study, 1348 BMC Cancer. 15 (2015) 460. https://doi.org/10.1186/s12885-015-1469-5. 1349 [47] S.-H. Oh, S.-Y. Choi, H.-J. Choi, H.-M. Ryu, Y.-J. Kim, H.-Y. Jung, J.-H. Cho, 1350 C.-D. Kim, S.-H. Park, T.-H. Kwon, Y.-L. Kim, The emerging role of xanthine 1351 oxidase inhibition for suppression of breast cancer cell migration and metastasis 1352 associated with hypercholesterolemia, FASEB J. 33 (2019) 7301–7314. 1353 https://doi.org/10.1096/fj.201802415RR. 1354 [48] I. Delimaris, E. Faviou, G. Antonakos, E. Stathopoulou, A. Zachari, A. 1355 Dionyssiou-Asteriou, Oxidized LDL, serum oxidizability and serum lipid levels in 1356 patients with breast or ovarian cancer, Clinical Biochemistry. 40 (2007) 1129–1134. 1357 https://doi.org/10.1016/j.clinbiochem.2007.06.007. 51 1358 [49] S. Pucci, C. Polidoro, C. Greggi, F. Amati, E. Morini, M. Murdocca, M. 1359 Biancolella, A. Orlandi, F. Sangiuolo, G. Novelli, Pro-oncogenic action of LOX-1 1360 and its splice variant LOX-1Δ4 in breast cancer phenotypes, Cell Death Dis. 10 1361 (2019) 53. https://doi.org/10.1038/s41419-018-1279-1. 1362 [50] M. Khaidakov, S. Mitra, B.-Y. Kang, X. Wang, S. Kadlubar, G. Novelli, V. Raj, 1363 M. Winters, W.C. Carter, J.L. Mehta, Oxidized LDL receptor 1 (OLR1) as a 1364 possible link between obesity, dyslipidemia and cancer, PLoS ONE. 6 (2011) 1365 e20277. https://doi.org/10.1371/journal.pone.0020277. 1366 [51] M. Liang, P. Zhang, J. Fu, Up-regulation of LOX-1 expression by TNF-α 1367 promotes trans-endothelial migration of MDA-MB-231 breast cancer cells, Cancer 1368 Letters. 258 (2007) 31–37. https://doi.org/10.1016/j.canlet.2007.08.003. 1369 [52] B. Wang, H. Zhao, L. Zhao, Y. Zhang, Q. Wan, Y. Shen, X. Bu, M. Wan, C. 1370 Shen, Up-regulation of OLR1 expression by TBC1D3 through activation of 1371 TNFα/NF-κB pathway promotes the migration of human breast cancer cells, Cancer 1372 Lett. 408 (2017) 60–70. https://doi.org/10.1016/j.canlet.2017.08.021. 1373 [53] M. Khaidakov, J.L. Mehta, Oxidized LDL triggers pro-oncogenic signaling in 1374 human breast mammary epithelial cells partly via stimulation of MiR-21, PLoS 1375 ONE. 7 (2012) e46973. https://doi.org/10.1371/journal.pone.0046973. 1376 [54] H.A. Hirsch, D. Iliopoulos, A. Joshi, Y. Zhang, S.A. Jaeger, M. Bulyk, P.N. 1377 Tsichlis, X. Shirley Liu, K. Struhl, A transcriptional signature and common gene 1378 networks link cancer with lipid metabolism and diverse human diseases, Cancer 1379 Cell. 17 (2010) 348–361. https://doi.org/10.1016/j.ccr.2010.01.022. 1380 [55] X. Li, H. Tang, J. Wang, X. Xie, P. Liu, Y. Kong, F. Ye, Z. Shuang, Z. Xie, X. 1381 Xie, The effect of preoperative serum triglycerides and high-density lipoprotein- 1382 cholesterol levels on the prognosis of breast cancer, Breast. 32 (2017) 1–6. 1383 https://doi.org/10.1016/j.breast.2016.11.024. 1384 [56] A.M. Kucharska-Newton, W.D. Rosamond, P.J. Mink, A.J. Alberg, E. Shahar, 1385 A.R. Folsom, HDL-cholesterol and incidence of breast cancer in the ARIC cohort 1386 study, Ann Epidemiol. 18 (2008) 671–677. 1387 https://doi.org/10.1016/j.annepidem.2008.06.006. 1388 [57] Y. Kim, S.K. Park, W. Han, D.-H. Kim, Y.-C. Hong, E.H. Ha, S.-H. Ahn, D.-Y. 1389 Noh, D. Kang, K.-Y. Yoo, Serum high-density lipoprotein cholesterol and breast 1390 cancer risk by menopausal status, body mass index, and hormonal receptor in 1391 Korea, Cancer Epidemiol. Biomarkers Prev. 18 (2009) 508–515. 1392 https://doi.org/10.1158/1055-9965.EPI-08-0133. 1393 [58] A.-S. Furberg, M.B. Veierød, T. Wilsgaard, L. Bernstein, I. Thune, Serum high- 1394 density lipoprotein cholesterol, metabolic profile, and breast cancer risk, J. Natl. 1395 Cancer Inst. 96 (2004) 1152–1160. https://doi.org/10.1093/jnci/djh216. 1396 [59] M. His, L. Dartois, G. Fagherazzi, A. Boutten, T. Dupré, S. Mesrine, M.-C. 1397 Boutron-Ruault, F. Clavel-Chapelon, L. Dossus, Associations between serum lipids 1398 and breast cancer incidence and survival in the E3N prospective cohort study, 1399 Cancer Causes Control. 28 (2017) 77–88. https://doi.org/10.1007/s10552-016-0832- 1400 4. 1401 [60] D. Gospodarowicz, G.M. Lui, R. Gonzalez, High-density lipoproteins and the 1402 proliferation of human tumor cells maintained on extracellular matrix-coated dishes 1403 and exposed to defined medium, Cancer Res. 42 (1982) 3704–3713. 1404 [61] C. Danilo, J.L. Gutierrez-Pajares, M.A. Mainieri, I. Mercier, M.P. Lisanti, P.G. 1405 Frank, Scavenger receptor class B type I regulates cellular cholesterol metabolism 1406 and cell signaling associated with breast cancer development, Breast Cancer Res. 15 1407 (2013) R87. https://doi.org/10.1186/bcr3483. 52 1408 [62] H. Balci, H. Genc, C. Papila, G. Can, B. Papila, H. Yanardag, H. Uzun, Serum 1409 lipid hydroperoxide levels and paraoxonase activity in patients with lung, breast, 1410 and colorectal cancer, J. Clin. Lab. Anal. 26 (2012) 155–160. 1411 https://doi.org/10.1002/jcla.21503. 1412 [63] M.O. Kaya, S. Sinan, Ö.Ö. Güler, O. Arslan, Is there a relation between genetic 1413 susceptibility with cancer? A study about paraoxanase (PON1) enzyme activity in 1414 breast cancer cases, Journal of Enzyme Inhibition and Medicinal Chemistry. 31 1415 (2016) 1349–1355. https://doi.org/10.3109/14756366.2015.1134523. 1416 [64] Y. Okuturlar, M. Gunaldi, H. Kocoglu, M. Hursitoglu, A. Gedikbasi, D. Acarer, 1417 O. Harmankaya, A. Kumbasar, Serum paraoxonase and arylesterase can be useful 1418 markers to predict neoadjuvant chemotherapy requirement in patients with breast 1419 cancer, J Cancer Res Ther. 14 (2018) S362–S367. https://doi.org/10.4103/0973- 1420 1482.235355. 1421 [65] C. Antognelli, C. Del Buono, V. Ludovini, S. Gori, V.N. Talesa, L. Crinò, F. 1422 Barberini, A. Rulli, CYP17, GSTP1, PON1 and GLO1 gene polymorphisms as risk 1423 factors for breast cancer: an Italian case-control study, BMC Cancer. 9 (2009) 115. 1424 https://doi.org/10.1186/1471-2407-9-115. 1425 [66] M. Saadat, Paraoxonase 1 genetic polymorphisms and susceptibility to breast 1426 cancer: a meta-analysis, Cancer Epidemiol. 36 (2012) e101-103. 1427 https://doi.org/10.1016/j.canep.2011.10.015. 1428 [67] B. Mackness, P.N. Durrington, M.I. Mackness, Human Serum Paraoxonase, 1429 General Pharmacology: The Vascular System. 31 (1998) 329–336. 1430 https://doi.org/10.1016/S0306-3623(98)00028-7. 1431 [68] J. Wu, M. Fang, X. Zhou, B. Zhu, Z. Yang, Paraoxonase 1 gene polymorphisms 1432 are associated with an increased risk of breast cancer in a population of Chinese 1433 women, Oncotarget. 8 (2017) 25362–25371. 1434 https://doi.org/10.18632/oncotarget.15911. 1435 [69] P. Liu, Q. Wang, Y. Cui, J. Wang, A meta-analysis of the relationship between 1436 paraoxonase 1 polymorphisms and cancer, Free Radic. Res. 53 (2019) 1045–1050. 1437 https://doi.org/10.1080/10715762.2019.1645956. 1438 [70] Y. Wen, Z. Huang, X. Zhang, B. Gao, Y. He, Correlation between PON1 gene 1439 polymorphisms and breast cancer risk: a Meta-analysis, Int J Clin Exp Med. 8 1440 (2015) 20343–20348. 1441 [71] V.L. Stevens, C. Rodriguez, A.L. Pavluck, M.J. Thun, E.E. Calle, Association of 1442 polymorphisms in the paraoxonase 1 gene with breast cancer incidence in the CPS- 1443 II Nutrition Cohort, Cancer Epidemiol. Biomarkers Prev. 15 (2006) 1226–1228. 1444 https://doi.org/10.1158/1055-9965.EPI-05-0930. 1445 [72] A. Farmohammadi, A. Momeni, B. Bahmani, H. Ghorbani, R. Ramzanpour, 1446 Association of PON1-L55M Genetic Variation and Breast Cancer Risk: A Case- 1447 Control Trial, Asian Pac. J. Cancer Prev. 21 (2020) 255–258. 1448 https://doi.org/10.31557/APJCP.2020.21.1.255. 1449 [73] H.-L. Huang, T. Stasyk, S. Morandell, H. Dieplinger, G. Falkensammer, A. 1450 Griesmacher, M. Mogg, M. Schreiber, I. Feuerstein, C.W. Huck, G. Stecher, G.K. 1451 Bonn, L.A. Huber, Biomarker discovery in breast cancer serum using 2-D 1452 differential gel electrophoresis/ MALDI-TOF/TOF and data validation by routine 1453 clinical assays, Electrophoresis. 27 (2006) 1641–1650. 1454 https://doi.org/10.1002/elps.200500857. 1455 [74] S.-J. Chang, M.-F. Hou, S.-M. Tsai, S.-H. Wu, L.A. Hou, H. Ma, T.-Y. Shann, 1456 S.-H. Wu, L.-Y. Tsai, The association between lipid profiles and breast cancer 53 1457 among Taiwanese women, Clin. Chem. Lab. Med. 45 (2007) 1219–1223. 1458 https://doi.org/10.1515/CCLM.2007.263. 1459 [75] L. Cedó, A. García-León, L. Baila-Rueda, D. Santos, V. Grijalva, M.R. 1460 Martínez-Cignoni, J.M. Carbó, J. Metso, L. López-Vilaró, A. Zorzano, A.F. 1461 Valledor, A. Cenarro, M. Jauhiainen, E. Lerma, A.M. Fogelman, S.T. Reddy, J.C. 1462 Escolà-Gil, F. Blanco-Vaca, ApoA-I mimetic administration, but not increased 1463 apoA-I-containing HDL, inhibits tumour growth in a mouse model of inherited 1464 breast cancer, Sci Rep. 6 (2016) 36387. https://doi.org/10.1038/srep36387. 1465 [76] L. Cedó, S.T. Reddy, E. Mato, F. Blanco-Vaca, J.C. Escolà-Gil, HDL and LDL: 1466 Potential New Players in Breast Cancer Development, J Clin Med. 8 (2019). 1467 https://doi.org/10.3390/jcm8060853. 1468 [77] C. Ben Hassen, J.L. Gutierrez-Pajares, C. Guimaraes, R. Guibon, M. Pinault, G. 1469 Fromont, P.G. Frank, Apolipoprotein-mediated regulation of lipid metabolism 1470 induces distinctive effects in different types of breast cancer cells, Breast Cancer 1471 Research. 22 (2020) 38. https://doi.org/10.1186/s13058-020-01276-9. 1472 [78] P. Boyle, M. Boniol, A. Koechlin, C. Robertson, F. Valentini, K. Coppens, L.-L. 1473 Fairley, M. Boniol, T. Zheng, Y. Zhang, M. Pasterk, M. Smans, M.P. Curado, P. 1474 Mullie, S. Gandini, M. Bota, G.B. Bolli, J. Rosenstock, P. Autier, Diabetes and 1475 breast cancer risk: a meta-analysis, Br. J. Cancer. 107 (2012) 1608–1617. 1476 https://doi.org/10.1038/bjc.2012.414. 1477 [79] P.J. Hardefeldt, S. Edirimanne, G.D. Eslick, Diabetes increases the risk of breast 1478 cancer: a meta-analysis, Endocr. Relat. Cancer. 19 (2012) 793–803. 1479 https://doi.org/10.1530/ERC-12-0242. 1480 [80] A. Kontush, M.J. Chapman, Why is HDL functionally deficient in type 2 1481 diabetes?, Curr. Diab. Rep. 8 (2008) 51–59. https://doi.org/10.1007/s11892-008- 1482 0010-5. 1483 [81] B. Pan, H. Ren, Y. Ma, D. Liu, B. Yu, L. Ji, L. Pan, J. Li, L. Yang, X. Lv, X. 1484 Shen, B. Chen, Y. Zhang, B. Willard, Y. He, L. Zheng, High-density lipoprotein of 1485 patients with type 2 diabetes mellitus elevates the capability of promoting migration 1486 and invasion of breast cancer cells, Int. J. Cancer. 131 (2012) 70–82. 1487 https://doi.org/10.1002/ijc.26341. 1488 [82] B. Pan, H. Ren, Y. He, X. Lv, Y. Ma, J. Li, L. Huang, B. Yu, J. Kong, C. Niu, 1489 Y. Zhang, W. Sun, L. Zheng, HDL of patients with type 2 diabetes mellitus elevates 1490 the capability of promoting breast cancer metastasis, Clin. Cancer Res. 18 (2012) 1491 1246–1256. https://doi.org/10.1158/1078-0432.CCR-11-0817. 1492 [83] X. Huang, D. He, J. Ming, Y. He, C. Zhou, H. Ren, X. He, C. Wang, J. Jin, L. Ji, 1493 B. Willard, B. Pan, L. Zheng, High-density lipoprotein of patients with breast 1494 cancer complicated with type 2 diabetes mellitus promotes cancer cells adhesion to 1495 vascular endothelium via ICAM-1 and VCAM-1 upregulation, Breast Cancer Res. 1496 Treat. 155 (2016) 441–455. https://doi.org/10.1007/s10549-016-3696-0. 1497 [84] L.A. Pires, R. Hegg, F.R. Freitas, E.R. Tavares, C.P. Almeida, E.C. Baracat, 1498 R.C. Maranhão, Effect of neoadjuvant chemotherapy on low-density lipoprotein 1499 (LDL) receptor and LDL receptor-related protein 1 (LRP-1) receptor in locally 1500 advanced breast cancer, Braz. J. Med. Biol. Res. 45 (2012) 557–564. 1501 [85] W.M. Cao, K. Murao, H. Imachi, X. Yu, H. Abe, A. Yamauchi, M. Niimi, A. 1502 Miyauchi, N.C.W. Wong, T. Ishida, A mutant high-density lipoprotein receptor 1503 inhibits proliferation of human breast cancer cells, Cancer Res. 64 (2004) 1515– 1504 1521. 1505 [86] B. Jamalzei, F.S. Karami Tehrani, M. Atri, Evaluation of LDL receptor and 1506 Scavenger Receptor, Class B, Type 1 in the malignant and benign breast tumors: 54 1507 The correlation with the expression of miR-199a-5p, miR-199b-5p and miR-455-5p, 1508 Gene. 749 (2020) 144720. https://doi.org/10.1016/j.gene.2020.144720. 1509 [87] E.J. Gallagher, Z. Zelenko, B.A. Neel, I.M. Antoniou, L. Rajan, N. Kase, D. 1510 LeRoith, Elevated tumor LDLR expression accelerates LDL cholesterol-mediated 1511 breast cancer growth in mouse models of hyperlipidemia, Oncogene. 36 (2017) 1512 6462–6471. https://doi.org/10.1038/onc.2017.247. 1513 [88] B. Yuan, C. Wu, X. Wang, D. Wang, H. Liu, L. Guo, X.-A. Li, J. Han, H. Feng, 1514 High scavenger receptor class B type I expression is related to tumor aggressiveness 1515 and poor prognosis in breast cancer, Tumour Biol. 37 (2016) 3581–3588. 1516 https://doi.org/10.1007/s13277-015-4141-4. 1517 [89] J. Li, J. Wang, M. Li, L. Yin, X.-A. Li, T.-G. Zhang, Up-regulated expression of 1518 scavenger receptor class B type 1 (SR-B1) is associated with malignant behaviors 1519 and poor prognosis of breast cancer, Pathol. Res. Pract. 212 (2016) 555–559. 1520 https://doi.org/10.1016/j.prp.2016.03.011. 1521 [90] S. Schimanski, P.J. Wild, O. Treeck, F. Horn, A. Sigruener, C. Rudolph, H. 1522 Blaszyk, M. Klinkhammer-Schalke, O. Ortmann, A. Hartmann, G. Schmitz, 1523 Expression of the lipid transporters ABCA3 and ABCA1 is diminished in human 1524 breast cancer tissue, Horm. Metab. Res. 42 (2010) 102–109. 1525 https://doi.org/10.1055/s-0029-1241859. 1526 [91] B. Smith, H. Land, Anticancer activity of the cholesterol exporter ABCA1 gene, 1527 Cell Rep. 2 (2012) 580–590. https://doi.org/10.1016/j.celrep.2012.08.011. 1528 [92] H. Pan, Y. Zheng, Q. Pan, H. Chen, F. Chen, J. Wu, D. Di, Expression of 1529 LXR‑β, ABCA1 and ABCG1 in human triple‑negative breast cancer tissues, Oncol. 1530 Rep. 42 (2019) 1869–1877. https://doi.org/10.3892/or.2019.7279. 1531 [93] L.-L. Vedin, S.A. Lewandowski, P. Parini, J.-A. Gustafsson, K.R. Steffensen, 1532 The oxysterol receptor LXR inhibits proliferation of human breast cancer cells, 1533 Carcinogenesis. 30 (2009) 575–579. https://doi.org/10.1093/carcin/bgp029. 1534 [94] S. Ehmsen, M.H. Pedersen, G. Wang, M.G. Terp, A. Arslanagic, B.L. Hood, 1535 T.P. Conrads, R. Leth-Larsen, H.J. Ditzel, Increased Cholesterol Biosynthesis Is a 1536 Key Characteristic of Breast Cancer Stem Cells Influencing Patient Outcome, Cell 1537 Rep. 27 (2019) 3927-3938.e6. https://doi.org/10.1016/j.celrep.2019.05.104. 1538 [95] D.W. Russell, Oxysterol biosynthetic enzymes, Biochimica et Biophysica Acta 1539 (BBA) - Molecular and Cell Biology of Lipids. 1529 (2000) 126–135. 1540 https://doi.org/10.1016/S1388-1981(00)00142-6. 1541 [96] Q. Wu, T. Ishikawa, R. Sirianni, H. Tang, J.G. McDonald, I.S. Yuhanna, B. 1542 Thompson, L. Girard, C. Mineo, R.A. Brekken, M. Umetani, D.M. Euhus, Y. Xie, 1543 P.W. Shaul, 27-Hydroxycholesterol promotes cell-autonomous, ER-positive breast 1544 cancer growth, Cell Rep. 5 (2013) 637–645. 1545 https://doi.org/10.1016/j.celrep.2013.10.006. 1546 [97] S. Raza, J.E. Ohm, A. Dhasarathy, J. Schommer, C. Roche, K.D.P. Hammer, O. 1547 Ghribi, The cholesterol metabolite 27-hydroxycholesterol regulates p53 activity and 1548 increases cell proliferation via MDM2 in breast cancer cells, Mol. Cell. Biochem. 1549 410 (2015) 187–195. https://doi.org/10.1007/s11010-015-2551-7. 1550 [98] L.-M. Ma, Z.-R. Liang, K.-R. Zhou, H. Zhou, L.-H. Qu, 27-Hydroxycholesterol 1551 increases Myc protein stability via suppressing PP2A, SCP1 and FBW7 1552 transcription in MCF-7 breast cancer cells, Biochem. Biophys. Res. Commun. 480 1553 (2016) 328–333. https://doi.org/10.1016/j.bbrc.2016.10.038. 1554 [99] D. Zhu, Z. Shen, J. Liu, J. Chen, Y. Liu, C. Hu, Z. Li, Y. Li, The ROS-mediated 1555 activation of STAT-3/VEGF signaling is involved in the 27-hydroxycholesterol- 55 1556 induced angiogenesis in human breast cancer cells, Toxicol. Lett. 264 (2016) 79–86. 1557 https://doi.org/10.1016/j.toxlet.2016.11.006. 1558 [100] C.G. Torres, M.E. Ramírez, P. Cruz, M.J. Epuñan, L.E. Valladares, W.D. 1559 Sierralta, 27-hydroxycholesterol induces the transition of MCF7 cells into a 1560 mesenchymal phenotype, Oncol. Rep. 26 (2011) 389–397. 1561 https://doi.org/10.3892/or.2011.1284. 1562 [101] Z. Shen, D. Zhu, J. Liu, J. Chen, Y. Liu, C. Hu, Z. Li, Y. Li, 27- 1563 Hydroxycholesterol induces invasion and migration of breast cancer cells by 1564 increasing MMP9 and generating EMT through activation of STAT-3, Environ. 1565 Toxicol. Pharmacol. 51 (2017) 1–8. https://doi.org/10.1016/j.etap.2017.02.001. 1566 [102] S.-Z. Shi, E.-J. Lee, Y.-J. Lin, L. Chen, H.-Y. Zheng, X.-Q. He, J.-Y. Peng, S.K. 1567 Noonepalle, A.Y. Shull, F.C. Pei, L.-B. Deng, X.-L. Tian, K.-Y. Deng, H. Shi, H.- 1568 B. Xin, Recruitment of monocytes and epigenetic silencing of intratumoral CYP7B1 1569 primarily contribute to the accumulation of 27-hydroxycholesterol in breast cancer, 1570 Am J Cancer Res. 9 (2019) 2194–2208. 1571 [103] F. Bray, J. Ferlay, I. Soerjomataram, R.L. Siegel, L.A. Torre, A. Jemal, Global 1572 cancer statistics 2018: GLOBOCAN estimates of incidence and mortality 1573 worldwide for 36 cancers in 185 countries, CA Cancer J Clin. 68 (2018) 394–424. 1574 https://doi.org/10.3322/caac.21492. 1575 [104] X. Filella, E. Fernández-Galan, R. Fernández Bonifacio, L. Foj, Emerging 1576 biomarkers in the diagnosis of prostate cancer, Pharmgenomics Pers Med. 11 (2018) 1577 83–94. https://doi.org/10.2147/PGPM.S136026. 1578 [105] J.I. Epstein, W.C. Allsbrook, M.B. Amin, L.L. Egevad, ISUP Grading 1579 Committee, The 2005 International Society of Urological Pathology (ISUP) 1580 Consensus Conference on Gleason Grading of Prostatic Carcinoma, Am. J. Surg. 1581 Pathol. 29 (2005) 1228–1242. https://doi.org/10.1097/01.pas.0000173646.99337.b1. 1582 [106] E.A. Platz, C. Till, P.J. Goodman, H.L. Parnes, W.D. Figg, D. Albanes, M.L. 1583 Neuhouser, E.A. Klein, I.M. Thompson, A.R. Kristal, Men with low serum 1584 cholesterol have a lower risk of high-grade prostate cancer in the placebo arm of the 1585 prostate cancer prevention trial, Cancer Epidemiol. Biomarkers Prev. 18 (2009) 1586 2807–2813. https://doi.org/10.1158/1055-9965.EPI-09-0472. 1587 [107] T.J. Murtola, T.V.J. Kasurinen, K. Talala, K. Taari, T.L.J. Tammela, A. 1588 Auvinen, Serum cholesterol and prostate cancer risk in the Finnish randomized 1589 study of screening for prostate cancer, Prostate Cancer Prostatic Dis. 22 (2019) 66– 1590 76. https://doi.org/10.1038/s41391-018-0087-0. 1591 [108] L. YuPeng, Z. YuXue, L. PengFei, C. Cheng, Z. YaShuang, L. DaPeng, D. 1592 Chen, Cholesterol Levels in Blood and the Risk of Prostate Cancer: A Meta- 1593 analysis of 14 Prospective Studies, Cancer Epidemiol. Biomarkers Prev. 24 (2015) 1594 1086–1093. https://doi.org/10.1158/1055-9965.EPI-14-1329. 1595 [109] S. Cheng, Q. Zheng, G. Ding, G. Li, Influence of serum total cholesterol, LDL, 1596 HDL, and triglyceride on prostate cancer recurrence after radical prostatectomy, 1597 Cancer Manag Res. 11 (2019) 6651–6661. https://doi.org/10.2147/CMAR.S204947. 1598 [110] M. Van Hemelrijck, H. Garmo, L. Holmberg, G. Walldius, I. Jungner, N. 1599 Hammar, M. Lambe, Prostate cancer risk in the Swedish AMORIS study: the 1600 interplay among triglycerides, total cholesterol, and glucose, Cancer. 117 (2011) 1601 2086–2095. https://doi.org/10.1002/cncr.25758. 1602 [111] J. Jamnagerwalla, L.E. Howard, E.H. Allott, A.C. Vidal, D.M. Moreira, R. 1603 Castro-Santamaria, G.L. Andriole, M.R. Freeman, S.J. Freedland, Serum cholesterol 1604 and risk of high-grade prostate cancer: results from the REDUCE study, Prostate 56 1605 Cancer Prostatic Dis. 21 (2018) 252–259. https://doi.org/10.1038/s41391-017-0030- 1606 9. 1607 [112] P. Rawla, Epidemiology of Prostate Cancer, World J Oncol. 10 (2019) 63–89. 1608 https://doi.org/10.14740/wjon1191. 1609 [113] K.M. Di Sebastiano, M. Mourtzakis, The role of dietary fat throughout the 1610 prostate cancer trajectory, Nutrients. 6 (2014) 6095–6109. 1611 https://doi.org/10.3390/nu6126095. 1612 [114] E.A. Mostaghel, K.R. Solomon, K. Pelton, M.R. Freeman, R.B. Montgomery, 1613 Impact of circulating cholesterol levels on growth and intratumoral androgen 1614 concentration of prostate tumors, PLoS ONE. 7 (2012) e30062. 1615 https://doi.org/10.1371/journal.pone.0030062. 1616 [115] A.J.C. Pommier, J. Dufour, G. Alves, E. Viennois, H. De Boussac, A. Trousson, 1617 D.H. Volle, F. Caira, P. Val, P. Arnaud, J.-M.A. Lobaccaro, S. Baron, Liver x 1618 receptors protect from development of prostatic intra-epithelial neoplasia in mice, 1619 PLoS Genet. 9 (2013) e1003483. https://doi.org/10.1371/journal.pgen.1003483. 1620 [116] S. Narita, T. Nara, H. Sato, A. Koizumi, M. Huang, T. Inoue, T. Habuchi, 1621 Research Evidence on High-Fat Diet-Induced Prostate Cancer Development and 1622 Progression, J Clin Med. 8 (2019). https://doi.org/10.3390/jcm8050597. 1623 [117] E. Bidoli, R. Talamini, C. Bosetti, E. Negri, D. Maruzzi, M. Montella, S. 1624 Franceschi, C. La Vecchia, Macronutrients, fatty acids, cholesterol and prostate 1625 cancer risk, Ann. Oncol. 16 (2005) 152–157. 1626 https://doi.org/10.1093/annonc/mdi010. 1627 [118] E.J. Jacobs, V.L. Stevens, C.C. Newton, S.M. Gapstur, Plasma total, LDL, and 1628 HDL cholesterol and risk of aggressive prostate cancer in the Cancer Prevention 1629 Study II Nutrition Cohort, Cancer Causes Control. 23 (2012) 1289–1296. 1630 https://doi.org/10.1007/s10552-012-0006-y. 1631 [119] D.E.G. Kok, J.G.H. van Roermund, K.K.H. Aben, M. den Heijer, D.W. 1632 Swinkels, E. Kampman, L. a. L.M. Kiemeney, Blood lipid levels and prostate 1633 cancer risk; a cohort study, Prostate Cancer Prostatic Dis. 14 (2011) 340–345. 1634 https://doi.org/10.1038/pcan.2011.30. 1635 [120] C.J. Bull, C. Bonilla, J.M.P. Holly, C.M. Perks, N. Davies, P. Haycock, O.H.Y. 1636 Yu, J.B. Richards, R. Eeles, D. Easton, Z. Kote-Jarai, A. Amin Al Olama, S. 1637 Benlloch, K. Muir, G.G. Giles, R.J. MacInnis, F. Wiklund, H. Gronberg, C.A. 1638 Haiman, J. Schleutker, B.G. Nordestgaard, R.C. Travis, D. Neal, N. Pashayan, K.-T. 1639 Khaw, J.L. Stanford, W.J. Blot, S. Thibodeau, C. Maier, A.S. Kibel, C. Cybulski, L. 1640 Cannon-Albright, H. Brenner, J. Park, R. Kaneva, J. Batra, M.R. Teixeira, A. 1641 Micheal, H. Pandha, G.D. Smith, S.J. Lewis, R.M. Martin, PRACTICAL 1642 consortium, Blood lipids and prostate cancer: a Mendelian randomization analysis, 1643 Cancer Med. 5 (2016) 1125–1136. https://doi.org/10.1002/cam4.695. 1644 [121] T.J. Murtola, H. Syvälä, P. Pennanen, M. Bläuer, T. Solakivi, T. Ylikomi, T.L.J. 1645 Tammela, The importance of LDL and cholesterol metabolism for prostate 1646 epithelial cell growth, PLoS ONE. 7 (2012) e39445. 1647 https://doi.org/10.1371/journal.pone.0039445. 1648 [122] S. Yue, J. Li, S.-Y. Lee, H.J. Lee, T. Shao, B. Song, L. Cheng, T.A. Masterson, 1649 X. Liu, T.L. Ratliff, J.-X. Cheng, Cholesteryl ester accumulation induced by PTEN 1650 loss and PI3K/AKT activation underlies human prostate cancer aggressiveness, Cell 1651 Metab. 19 (2014) 393–406. https://doi.org/10.1016/j.cmet.2014.01.019. 1652 [123] F. Wan, X. Qin, G. Zhang, X. Lu, Y. Zhu, H. Zhang, B. Dai, G. Shi, D. Ye, 1653 Oxidized low-density lipoprotein is associated with advanced-stage prostate cancer, 1654 Tumour Biol. 36 (2015) 3573–3582. https://doi.org/10.1007/s13277-014-2994-6. 57 1655 [124] G.A. Asare, E. Owusu-Boateng, B. Asiedu, B.Y. Amoah, E. Essendoh, R.Y. 1656 Otoo, Oxidised low-density lipoprotein, a possible distinguishing lipid profile 1657 biomolecule between prostate cancer and benign prostatic hyperplasia, Andrologia. 1658 51 (2019) e13321. https://doi.org/10.1111/and.13321. 1659 [125] I. González-Chavarría, E. Fernandez, N. Gutierrez, E.E. González-Horta, F. 1660 Sandoval, P. Cifuentes, C. Castillo, R. Cerro, O. Sanchez, J.R. Toledo, LOX-1 1661 activation by oxLDL triggers an epithelial mesenchymal transition and promotes 1662 tumorigenic potential in prostate cancer cells, Cancer Lett. 414 (2018) 34–43. 1663 https://doi.org/10.1016/j.canlet.2017.10.035. 1664 [126] K. Kotani, Y. Sekine, S. Ishikawa, I.Z. Ikpot, K. Suzuki, A.T. Remaley, High- 1665 density lipoprotein and prostate cancer: an overview, J Epidemiol. 23 (2013) 313– 1666 319. https://doi.org/10.2188/jea.je20130006. 1667 [127] M. Ruscica, M. Botta, N. Ferri, E. Giorgio, C. Macchi, G. Franceschini, P. 1668 Magni, L. Calabresi, M. Gomaraschi, High Density Lipoproteins Inhibit Oxidative 1669 Stress-Induced Prostate Cancer Cell Proliferation, Sci Rep. 8 (2018) 2236. 1670 https://doi.org/10.1038/s41598-018-19568-8. 1671 [128] Y. Sekine, S.J. Demosky, J.A. Stonik, Y. Furuya, H. Koike, K. Suzuki, A.T. 1672 Remaley, High-density lipoprotein induces proliferation and migration of human 1673 prostate androgen-independent cancer cells by an ABCA1-dependent mechanism, 1674 Mol. Cancer Res. 8 (2010) 1284–1294. https://doi.org/10.1158/1541-7786.MCR-10- 1675 0008. 1676 [129] Y. Sekine, K. Suzuki, A.T. Remaley, HDL and sphingosine-1-phosphate 1677 activate stat3 in prostate cancer DU145 cells via ERK1/2 and S1P receptors, and 1678 promote cell migration and invasion, Prostate. 71 (2011) 690–699. 1679 https://doi.org/10.1002/pros.21285. 1680 [130] G. Singh, S. Sankanagoudar, P. Dogra, N.C. Chandra, Interlink between 1681 cholesterol & cell cycle in prostate carcinoma, Indian J. Med. Res. 146 (2017) S38– 1682 S44. https://doi.org/10.4103/ijmr.IJMR_1639_15. 1683 [131] K.H. Stopsack, T.A. Gerke, O. Andrén, S.-O. Andersson, E.L. Giovannucci, 1684 L.A. Mucci, J.R. Rider, Cholesterol uptake and regulation in high-grade and lethal 1685 prostate cancers, Carcinogenesis. 38 (2017) 806–811. 1686 https://doi.org/10.1093/carcin/bgx058. 1687 [132] S. Jiang, X. Wang, D. Song, X. Liu, Y. Gu, Z. Xu, X. Wang, X. Zhang, Q. Ye, 1688 Z. Tong, B. Yan, J. Yu, Y. Chen, M. Sun, Y. Wang, S. Gao, Cholesterol Induces 1689 Epithelial-to-Mesenchymal Transition of Prostate Cancer Cells by Suppressing 1690 Degradation of EGFR through APMAP, Cancer Res. 79 (2019) 3063–3075. 1691 https://doi.org/10.1158/0008-5472.CAN-18-3295. 1692 [133] J.V. Swinnen, K. Brusselmans, G. Verhoeven, Increased lipogenesis in cancer 1693 cells: new players, novel targets, Curr Opin Clin Nutr Metab Care. 9 (2006) 358– 1694 365. https://doi.org/10.1097/01.mco.0000232894.28674.30. 1695 [134] H.-J. Jin, J. Kim, J. Yu, Androgen receptor genomic regulation, Transl Androl 1696 Urol. 2 (2013) 157–177. https://doi.org/10.3978/j.issn.2223-4683.2013.09.01. 1697 [135] H.V. Heemers, G. Verhoeven, J.V. Swinnen, Androgen activation of the sterol 1698 regulatory element-binding protein pathway: Current insights, Mol. Endocrinol. 20 1699 (2006) 2265–2277. https://doi.org/10.1210/me.2005-0479. 1700 [136] L. Bonaccorsi, P. Luciani, G. Nesi, E. Mannucci, C. Deledda, F. Dichiara, M. 1701 Paglierani, F. Rosati, L. Masieri, S. Serni, M. Carini, L. Proietti-Pannunzi, S. Monti, 1702 G. Forti, G. Danza, M. Serio, A. Peri, Androgen receptor regulation of the seladin- 1703 1/DHCR24 gene: altered expression in prostate cancer, Lab. Invest. 88 (2008) 1704 1049–1056. https://doi.org/10.1038/labinvest.2008.80. 58 1705 [137] J. Fukuchi, R.A. Hiipakka, J.M. Kokontis, S. Hsu, A.L. Ko, M.L. Fitzgerald, S. 1706 Liao, Androgenic suppression of ATP-binding cassette transporter A1 expression in 1707 LNCaP human prostate cancer cells, Cancer Res. 64 (2004) 7682–7685. 1708 https://doi.org/10.1158/0008-5472.CAN-04-2647. 1709 [138] D. Schörghofer, K. Kinslechner, A. Preitschopf, B. Schütz, C. Röhrl, M. 1710 Hengstschläger, H. Stangl, M. Mikula, The HDL receptor SR-BI is associated with 1711 human prostate cancer progression and plays a possible role in establishing 1712 androgen independence, Reprod. Biol. Endocrinol. 13 (2015) 88. 1713 https://doi.org/10.1186/s12958-015-0087-z. 1714 [139] J. Fukuchi, J.M. Kokontis, R.A. Hiipakka, C.-P. Chuu, S. Liao, Antiproliferative 1715 effect of liver X receptor agonists on LNCaP human prostate cancer cells, Cancer 1716 Res. 64 (2004) 7686–7689. https://doi.org/10.1158/0008-5472.CAN-04-2332. 1717 [140] S. Varambally, S.M. Dhanasekaran, M. Zhou, T.R. Barrette, C. Kumar-Sinha, 1718 M.G. Sanda, D. Ghosh, K.J. Pienta, R.G.A.B. Sewalt, A.P. Otte, M.A. Rubin, A.M. 1719 Chinnaiyan, The polycomb group protein EZH2 is involved in progression of 1720 prostate cancer, Nature. 419 (2002) 624–629. https://doi.org/10.1038/nature01075. 1721 [141] C.-Y. Lin, C. Huo, L.-K. Kuo, R.A. Hiipakka, R.B. Jones, H.-P. Lin, Y. Hung, 1722 L.-C. Su, J.-C. Tseng, Y.-Y. Kuo, Y.-L. Wang, Y. Fukui, Y.-H. Kao, J.M. Kokontis, 1723 C.-C. Yeh, L. Chen, S.-D. Yang, H.-H. Fu, Y.-W. Chen, K.K.C. Tsai, J.-Y. Chang, 1724 C.-P. Chuu, Cholestane-3β, 5α, 6β-triol suppresses proliferation, migration, and 1725 invasion of human prostate cancer cells, PLoS ONE. 8 (2013) e65734. 1726 https://doi.org/10.1371/journal.pone.0065734. 1727 [142] S. Raza, M. Meyer, J. Schommer, K.D.P. Hammer, B. Guo, O. Ghribi, 27- 1728 Hydroxycholesterol stimulates cell proliferation and resistance to docetaxel-induced 1729 apoptosis in prostate epithelial cells, Med. Oncol. 33 (2016) 12. 1730 https://doi.org/10.1007/s12032-015-0725-5. 1731 [143] M. Olsson, O. Gustafsson, C. Skogastierna, A. Tolf, B.D. Rietz, R. Morfin, A. 1732 Rane, L. Ekström, Regulation and expression of human CYP7B1 in prostate: 1733 overexpression of CYP7B1 during progression of prostatic adenocarcinoma, 1734 Prostate. 67 (2007) 1439–1446. https://doi.org/10.1002/pros.20630. 1735 [144] G. Pellegriti, F. Frasca, C. Regalbuto, S. Squatrito, R. Vigneri, Worldwide 1736 increasing incidence of thyroid cancer: update on epidemiology and risk factors, J 1737 Cancer Epidemiol. 2013 (2013) 965212. https://doi.org/10.1155/2013/965212. 1738 [145] C.M. Kitahara, J.A. Sosa, The changing incidence of thyroid cancer, Nat Rev 1739 Endocrinol. 12 (2016) 646–653. https://doi.org/10.1038/nrendo.2016.110. 1740 [146] D. Li, L. Zhou, C. Ma, W. Chen, Y. Zhang, S. Yu, D. Wang, Y. Zou, J. Wu, L. 1741 Qiu, Comparative analysis of the serum proteome profiles of thyroid cancer: An 1742 initial focus on the lipid profile, Oncol Lett. 18 (2019) 3349–3357. 1743 https://doi.org/10.3892/ol.2019.10655. 1744 [147] H.J. Kim, N.K. Kim, J.H. Choi, S.Y. Sohn, S.W. Kim, S.-M. Jin, H.W. Jang, S. 1745 Suh, Y.-K. Min, J.H. Chung, S.W. Kim, Associations between body mass index and 1746 clinico-pathological characteristics of papillary thyroid cancer, Clin. Endocrinol. 1747 (Oxf). 78 (2013) 134–140. https://doi.org/10.1111/j.1365-2265.2012.04506.x. 1748 [148] M. Giusti, L. Mortara, R. Degrandi, F. Cecoli, M. Mussap, G. Rodriguez, D. 1749 Ferone, F. Minuto, Metabolic and cardiovascular risk in patients with a history of 1750 differentiated thyroid carcinoma: A case-controlled cohort study, Thyroid Res. 1 1751 (2008) 2. https://doi.org/10.1186/1756-6614-1-2. 1752 [149] G. Revilla, M. de P. Pons, L. Baila-Rueda, A. García-León, D. Santos, A. 1753 Cenarro, M. Magalhaes, R.M. Blanco, A. Moral, J. Ignacio Pérez, G. Sabé, C. 1754 González, V. Fuste, E. Lerma, M.D.S. Faria, A. de Leiva, R. Corcoy, J. Carles 59 1755 Escolà-Gil, E. Mato, Cholesterol and 27-hydroxycholesterol promote thyroid 1756 carcinoma aggressiveness, Sci Rep. 9 (2019) 10260. https://doi.org/10.1038/s41598- 1757 019-46727-2. 1758 [150] H. Korkmaz, S. Tabur, M. Özkaya, N. Aksoy, H. Yildiz, E. Akarsu, 1759 Paraoxonase and arylesterase activities in patients with papillary thyroid cancer, 1760 Scandinavian Journal of Clinical and Laboratory Investigation. 75 (2015) 259–264. 1761 https://doi.org/10.3109/00365513.2014.1003597. 1762 [151] B. Stewart, C. Wild, World Cancer Report 2014, n.d. 1763 https://publications.iarc.fr/Non-Series-Publications/World-Cancer-Reports/World- 1764 Cancer-Report-2014 (accessed June 2, 2020). 1765 [152] D.P. Ryan, T.S. Hong, N. Bardeesy, Pancreatic adenocarcinoma, N. Engl. J. 1766 Med. 371 (2014) 1039–1049. https://doi.org/10.1056/NEJMra1404198. 1767 [153] G. Bond-Smith, N. Banga, T.M. Hammond, C.J. Imber, Pancreatic 1768 adenocarcinoma, BMJ. 344 (2012) e2476. https://doi.org/10.1136/bmj.e2476. 1769 [154] T. Kamisawa, L.D. Wood, T. Itoi, K. Takaori, Pancreatic cancer, Lancet. 388 1770 (2016) 73–85. https://doi.org/10.1016/S0140-6736(16)00141-0. 1771 [155] R. Carreras-Torres, M. Johansson, V. Gaborieau, P.C. Haycock, K.H. Wade, 1772 C.L. Relton, R.M. Martin, G. Davey Smith, P. Brennan, The Role of Obesity, Type 1773 2 Diabetes, and Metabolic Factors in Pancreatic Cancer: A Mendelian 1774 Randomization Study, J. Natl. Cancer Inst. 109 (2017). 1775 https://doi.org/10.1093/jnci/djx012. 1776 [156] Y. Lu, M. Gentiluomo, J. Lorenzo-Bermejo, L. Morelli, O. Obazee, D. Campa, 1777 F. Canzian, Mendelian randomisation study of the effects of known and putative 1778 risk factors on pancreatic cancer, J. Med. Genet. (2020). 1779 https://doi.org/10.1136/jmedgenet-2019-106200. 1780 [157] R.Z. Stolzenberg-Solomon, P. Pietinen, P.R. Taylor, J. Virtamo, D. Albanes, A 1781 prospective study of medical conditions, anthropometry, physical activity, and 1782 pancreatic cancer in male smokers (Finland), Cancer Causes Control. 13 (2002) 1783 417–426. https://doi.org/10.1023/a:1015729615148. 1784 [158] A. Berrington de Gonzalez, J.E. Yun, S.-Y. Lee, A.P. Klein, S.H. Jee, Pancreatic 1785 cancer and factors associated with the insulin resistance syndrome in the Korean 1786 cancer prevention study, Cancer Epidemiol. Biomarkers Prev. 17 (2008) 359–364. 1787 https://doi.org/10.1158/1055-9965.EPI-07-0507. 1788 [159] D. Johansen, T. Stocks, H. Jonsson, B. Lindkvist, T. Björge, H. Concin, M. 1789 Almquist, C. Häggström, A. Engeland, H. Ulmer, G. Hallmans, R. Selmer, G. 1790 Nagel, S. Tretli, P. Stattin, J. Manjer, Metabolic factors and the risk of pancreatic 1791 cancer: a prospective analysis of almost 580,000 men and women in the Metabolic 1792 Syndrome and Cancer Project, Cancer Epidemiol. Biomarkers Prev. 19 (2010) 1793 2307–2317. https://doi.org/10.1158/1055-9965.EPI-10-0234. 1794 [160] A. Ansary-Moghaddam, R. Huxley, F. Barzi, C. Lawes, T. Ohkubo, X. Fang, 1795 S.H. Jee, M. Woodward, Asia Pacific Cohort Studies Collaboration, The effect of 1796 modifiable risk factors on pancreatic cancer mortality in populations of the Asia- 1797 Pacific region, Cancer Epidemiol. Biomarkers Prev. 15 (2006) 2435–2440. 1798 https://doi.org/10.1158/1055-9965.EPI-06-0368. 1799 [161] G.D. Batty, M. Kivimaki, D. Morrison, R. Huxley, G.D. Smith, R. Clarke, M.G. 1800 Marmot, M.J. Shipley, Risk factors for pancreatic cancer mortality: extended 1801 follow-up of the original Whitehall Study, Cancer Epidemiol. Biomarkers Prev. 18 1802 (2009) 673–675. https://doi.org/10.1158/1055-9965.EPI-08-1032. 1803 [162] A. Schatzkin, R.N. Hoover, P.R. Taylor, R.G. Ziegler, C.L. Carter, D. Albanes, 1804 D.B. Larson, L.M. Licitra, Site-specific analysis of total serum cholesterol and 60 1805 incident cancer in the National Health and Nutrition Examination Survey I 1806 Epidemiologic Follow-up Study, Cancer Res. 48 (1988) 452–458. 1807 [163] S. Strohmaier, M. Edlinger, J. Manjer, T. Stocks, T. Bjørge, W. Borena, C. 1808 Häggström, A. Engeland, G. Nagel, M. Almquist, R. Selmer, S. Tretli, H. Concin, 1809 G. Hallmans, H. Jonsson, P. Stattin, H. Ulmer, Total serum cholesterol and cancer 1810 incidence in the Metabolic syndrome and Cancer Project (Me-Can), PLoS ONE. 8 1811 (2013) e54242. https://doi.org/10.1371/journal.pone.0054242. 1812 [164] J. Wang, W.-J. Wang, L. Zhai, D.-F. Zhang, Association of cholesterol with risk 1813 of pancreatic cancer: a meta-analysis, World J. Gastroenterol. 21 (2015) 3711–3719. 1814 https://doi.org/10.3748/wjg.v21.i12.3711. 1815 [165] X. Chen, T. Zhou, M. Chen, Meta analysis of the association of cholesterol with 1816 pancreatic carcinoma risk, J BUON. 20 (2015) 109–113. 1817 [166] H. Chen, S. Qin, M. Wang, T. Zhang, S. Zhang, Association between cholesterol 1818 intake and pancreatic cancer risk: evidence from a meta-analysis, Sci Rep. 5 (2015) 1819 8243. https://doi.org/10.1038/srep08243. 1820 [167] Y. Lin, A. Tamakoshi, T. Hayakawa, S. Naruse, M. Kitagawa, Y. Ohno, 1821 Nutritional factors and risk of pancreatic cancer: a population-based case-control 1822 study based on direct interview in Japan, J. Gastroenterol. 40 (2005) 297–301. 1823 https://doi.org/10.1007/s00535-004-1537-0. 1824 [168] T. Ogawa, T. Makino, K. Kosahara, A. Koga, F. Nakayama, Promoting effects 1825 of both dietary cholesterol and cholestyramine on pancreatic carcinogenesis 1826 initiated by N-nitrosobis(2-oxopropyl)amine in Syrian golden hamsters, 1827 Carcinogenesis. 13 (1992) 2047–2052. https://doi.org/10.1093/carcin/13.11.2047. 1828 [169] T. Ogawa, T. Makino, N. Hirose, M. Sugano, Lack of influence of low blood 1829 cholesterol levels on pancreatic carcinogenesis after initiation with N-nitrosobis(2- 1830 oxopropyl)amine in Syrian golden hamsters, Carcinogenesis. 15 (1994) 1663–1666. 1831 https://doi.org/10.1093/carcin/15.8.1663. 1832 [170] M. Van Hemelrijck, G. Walldius, I. Jungner, N. Hammar, H. Garmo, E. Binda, 1833 A. Hayday, M. Lambe, L. Holmberg, Low levels of apolipoprotein A-I and HDL 1834 are associated with risk of prostate cancer in the Swedish AMORIS study, Cancer 1835 Causes Control. 22 (2011) 1011–1019. https://doi.org/10.1007/s10552-011-9774-z. 1836 [171] G. Yang, G. Xiong, M. Feng, F. Zhao, J. Qiu, Y. Liu, Z. Cao, H. Wang, J. Yang, 1837 L. You, L. Zheng, T. Zhang, Y. Zhao, OLR1 Promotes Pancreatic Cancer 1838 Metastasis via Increased c-Myc Expression and Transcription of HMGA2, Mol. 1839 Cancer Res. 18 (2020) 685–697. https://doi.org/10.1158/1541-7786.MCR-19-0718. 1840 [172] B. Mytar, M. Woloszyn, A. Macura-Biegun, B. Hajto, I. Ruggiero, B. Piekarska, 1841 M. Zembala, Involvement of pattern recognition receptors in the induction of 1842 cytokines and reactive oxygen intermediates production by human 1843 monocytes/macrophages stimulated with tumour cells, Anticancer Res. 24 (2004) 1844 2287–2293. 1845 [173] C.L. Meinhold, A. Berrington de Gonzalez, D. Albanes, S.J. Weinstein, P.R. 1846 Taylor, J. Virtamo, R.Z. Stolzenberg-Solomon, Predictors of fasting serum insulin 1847 and glucose and the risk of pancreatic cancer in smokers, Cancer Causes Control. 20 1848 (2009) 681–690. https://doi.org/10.1007/s10552-008-9281-z. 1849 [174] G.C. Kabat, M.Y. Kim, R.T. Chlebowski, M.Z. Vitolins, S. Wassertheil- 1850 Smoller, T.E. Rohan, Serum lipids and risk of obesity-related cancers in 1851 postmenopausal women, Cancer Causes Control. 29 (2018) 13–24. 1852 https://doi.org/10.1007/s10552-017-0991-y. 61 1853 [175] V. Michalaki, G. Koutroulis, K. Syrigos, C. Piperi, A. Kalofoutis, Evaluation of 1854 serum lipids and high-density lipoprotein subfractions (HDL2, HDL3) in 1855 postmenopausal patients with breast cancer, Mol. Cell. Biochem. 268 (2005) 19–24. 1856 [176] Q. Wu, G. Chen, W.-M. Wu, L. Zhou, L. You, T.-P. Zhang, Y.-P. Zhao, 1857 Metabolic syndrome components and risk factors for pancreatic adenocarcinoma: a 1858 case-control study in China, Digestion. 86 (2012) 294–301. 1859 https://doi.org/10.1159/000341397. 1860 [177] K. Kashiwagi, T. Seino, S. Fukuhara, K. Minami, M. Horibe, E. Iwasaki, H. 1861 Takaishi, K. Itoh, Y. Sugino, N. Inoue, Y. Iwao, T. Kanai, Pancreatic Fat Content 1862 Detected by Computed Tomography and Its Significant Relationship With 1863 Intraductal Papillary Mucinous Neoplasm, Pancreas. 47 (2018) 1087–1092. 1864 https://doi.org/10.1097/MPA.0000000000001103. 1865 [178] A. Xue, C.J. Scarlett, L. Chung, G. Butturini, A. Scarpa, R. Gandy, S.R. Wilson, 1866 R.C. Baxter, R.C. Smith, Discovery of serum biomarkers for pancreatic 1867 adenocarcinoma using proteomic analysis, Br. J. Cancer. 103 (2010) 391–400. 1868 https://doi.org/10.1038/sj.bjc.6605764. 1869 [179] K. Honda, T. Okusaka, K. Felix, S. Nakamori, N. Sata, H. Nagai, T. Ioka, A. 1870 Tsuchida, T. Shimahara, M. Shimahara, Y. Yasunami, H. Kuwabara, T. Sakuma, Y. 1871 Otsuka, N. Ota, M. Shitashige, T. Kosuge, M.W. Büchler, T. Yamada, Altered 1872 plasma apolipoprotein modifications in patients with pancreatic cancer: protein 1873 characterization and multi-institutional validation, PLoS ONE. 7 (2012) e46908. 1874 https://doi.org/10.1371/journal.pone.0046908. 1875 [180] C. Lin, W.-C. Wu, G.-C. Zhao, D.-S. Wang, W.-H. Lou, D.-Y. Jin, ITRAQ- 1876 based quantitative proteomics reveals apolipoprotein A-I and transferrin as potential 1877 serum markers in CA19-9 negative pancreatic ductal adenocarcinoma, Medicine 1878 (Baltimore). 95 (2016) e4527. https://doi.org/10.1097/MD.0000000000004527. 1879 [181] S.M. Julovi, A. Xue, T.N. Thanh LE, A.J. Gill, J.C. Bulanadi, M. Patel, L.J. 1880 Waddington, K.-A. Rye, M.J. Moghaddam, R.C. Smith, Apolipoprotein A-II Plus 1881 Lipid Emulsion Enhance Cell Growth via SR-B1 and Target Pancreatic Cancer In 1882 Vitro and In Vivo, PLoS ONE. 11 (2016) e0151475. 1883 https://doi.org/10.1371/journal.pone.0151475. 1884 [182] M.N. Akçay, M.F. Polat, I. Yilmaz, G. Akçay, Serum paraoxonase levels in 1885 pancreatic cancer, Hepatogastroenterology. 50 Suppl 2 (2003) ccxxv–ccxxvii. 1886 [183] F. Guillaumond, G. Bidaut, M. Ouaissi, S. Servais, V. Gouirand, O. Olivares, S. 1887 Lac, L. Borge, J. Roques, O. Gayet, M. Pinault, C. Guimaraes, J. Nigri, C. Loncle, 1888 M.-N. Lavaut, S. Garcia, A. Tailleux, B. Staels, E. Calvo, R. Tomasini, J.L. 1889 Iovanna, S. Vasseur, Cholesterol uptake disruption, in association with 1890 chemotherapy, is a promising combined metabolic therapy for pancreatic 1891 adenocarcinoma, Proc. Natl. Acad. Sci. U.S.A. 112 (2015) 2473–2478. 1892 https://doi.org/10.1073/pnas.1421601112. 1893 [184] S.L. Gonias, N. Karimi-Mostowfi, S.S. Murray, E. Mantuano, A.S. Gilder, 1894 Expression of LDL receptor-related proteins (LRPs) in common solid malignancies 1895 correlates with patient survival, PLoS ONE. 12 (2017) e0186649. 1896 https://doi.org/10.1371/journal.pone.0186649. 1897 [185] M. Watanabe, S. Sheriff, K.B. Lewis, J. Cho, S.L. Tinch, A. Balasubramaniam, 1898 M.A. Kennedy, Metabolic Profiling Comparison of Human Pancreatic Ductal 1899 Epithelial Cells and Three Pancreatic Cancer Cell Lines using NMR Based 1900 Metabonomics, J Mol Biomark Diagn. 3 (2012). https://doi.org/10.4172/2155- 1901 9929.S3-002. 62 1902 [186] J. Li, D. Gu, S.S.-Y. Lee, B. Song, S. Bandyopadhyay, S. Chen, S.F. Konieczny, 1903 T.L. Ratliff, X. Liu, J. Xie, J.-X. Cheng, Abrogating cholesterol esterification 1904 suppresses growth and metastasis of pancreatic cancer, Oncogene. 35 (2016) 6378– 1905 6388. https://doi.org/10.1038/onc.2016.168. 1906 [187] J. Li, X. Qu, J. Tian, J.-T. Zhang, J.-X. Cheng, Cholesterol esterification 1907 inhibition and gemcitabine synergistically suppress pancreatic ductal 1908 adenocarcinoma proliferation, PLoS ONE. 13 (2018) e0193318. 1909 https://doi.org/10.1371/journal.pone.0193318. 1910 [188] X. Wang, J. Xie, X. Lu, H. Li, C. Wen, Z. Huo, J. Xie, M. Shi, X. Tang, H. 1911 Chen, C. Peng, Y. Fang, X. Deng, B. Shen, Melittin inhibits tumor growth and 1912 decreases resistance to gemcitabine by downregulating cholesterol pathway 1913 gene CLU in pancreatic ductal adenocarcinoma, Cancer Lett. 399 (2017) 1–9. 1914 https://doi.org/10.1016/j.canlet.2017.04.012. 1915 [189] J.J. Souchek, M.J. Baine, C. Lin, S. Rachagani, S. Gupta, S. Kaur, K. Lester, D. 1916 Zheng, S. Chen, L. Smith, A. Lazenby, S.L. Johansson, M. Jain, S.K. Batra, 1917 Unbiased analysis of pancreatic cancer radiation resistance reveals cholesterol 1918 biosynthesis as a novel target for radiosensitisation, Br. J. Cancer. 111 (2014) 1139– 1919 1149. https://doi.org/10.1038/bjc.2014.385. 1920 [190] C.P. Tanase, S. Dima, M. Mihai, E. Raducan, M.I. Nicolescu, L. Albulescu, B. 1921 Voiculescu, T. Dumitrascu, L.M. Cruceru, M. Leabu, I. Popescu, M.E. Hinescu, 1922 Caveolin-1 overexpression correlates with tumour progression markers in pancreatic 1923 ductal adenocarcinoma, J. Mol. Histol. 40 (2009) 23–29. 1924 https://doi.org/10.1007/s10735-008-9209-7. 1925 [191] V.K. Gupta, N.S. Sharma, K. Kesh, P. Dauer, A. Nomura, B. Giri, V. Dudeja, S. 1926 Banerjee, S. Bhattacharya, A. Saluja, S. Banerjee, Metastasis and chemoresistance 1927 in CD133 expressing pancreatic cancer cells are dependent on their lipid raft 1928 integrity, Cancer Lett. 439 (2018) 101–112. 1929 https://doi.org/10.1016/j.canlet.2018.09.028. 1930 [192] L.A. Torre, B. Trabert, C.E. DeSantis, K.D. Miller, G. Samimi, C.D. Runowicz, 1931 M.M. Gaudet, A. Jemal, R.L. Siegel, Ovarian cancer statistics, 2018, CA Cancer J 1932 Clin. 68 (2018) 284–296. https://doi.org/10.3322/caac.21456. 1933 [193] E. Lengyel, Ovarian cancer development and metastasis, Am. J. Pathol. 177 1934 (2010) 1053–1064. https://doi.org/10.2353/ajpath.2010.100105. 1935 [194] E. Kipps, D.S.P. Tan, S.B. Kaye, Meeting the challenge of ascites in ovarian 1936 cancer: new avenues for therapy and research, Nat. Rev. Cancer. 13 (2013) 273– 1937 282. https://doi.org/10.1038/nrc3432. 1938 [195] D. Luvero, A. Milani, J.A. Ledermann, Treatment options in recurrent ovarian 1939 cancer: latest evidence and clinical potential, Ther Adv Med Oncol. 6 (2014) 229– 1940 239. https://doi.org/10.1177/1758834014544121. 1941 [196] D. Zhang, Y. Xi, Y. Feng, Ovarian cancer risk in relation to blood lipid levels 1942 and hyperlipidemia: a systematic review and meta-analysis of observational 1943 epidemiologic studies, Eur. J. Cancer Prev. (2020). 1944 https://doi.org/10.1097/CEJ.0000000000000597. 1945 [197] T. Bjørge, A. Lukanova, S. Tretli, J. Manjer, H. Ulmer, T. Stocks, R. Selmer, G. 1946 Nagel, M. Almquist, H. Concin, G. Hallmans, H. Jonsson, C. Häggström, P. Stattin, 1947 A. Engeland, Metabolic risk factors and ovarian cancer in the Metabolic Syndrome 1948 and Cancer project, Int J Epidemiol. 40 (2011) 1667–1677. 1949 https://doi.org/10.1093/ije/dyr130. 63 1950 [198] K.J. Helzlsouer, A.J. Alberg, E.P. Norkus, J.S. Morris, S.C. Hoffman, G.W. 1951 Comstock, Prospective study of serum micronutrients and ovarian cancer, J. Natl. 1952 Cancer Inst. 88 (1996) 32–37. https://doi.org/10.1093/jnci/88.1.32. 1953 [199] G. Li, K. Zhang, F. Gong, H. Jin, A study on changes and clinical significance 1954 of blood glucose, blood lipid and inflammation in patients with ovarian cancer, J 1955 BUON. 24 (2019) 2322–2326. 1956 [200] M.I. Qadir, S.A. Malik, Plasma lipid profile in gynecologic cancers, Eur. J. 1957 Gynaecol. Oncol. 29 (2008) 158–161. 1958 [201] E.H. Avall-Lundqvist, C.O. Peterson, Serum cholesterol and apolipoprotein B 1959 levels may reflect disease activity in ovarian cancer patients, Acta Oncol. 35 (1996) 1960 1007–1010. https://doi.org/10.3109/02841869609100719. 1961 [202] H. Gadomska, J. Janecki, L. Marianowski, G. Nowicka, Lipids in serum of 1962 patients with malignant ovarian neoplasms, Int J Gynaecol Obstet. 57 (1997) 287– 1963 293. https://doi.org/10.1016/s0020-7292(97)00071-4. 1964 [203] J.U. Onwuka, A.P. Okekunle, O.M. Olutola, O.M. Akpa, R. Feng, Lipid profile 1965 and risk of ovarian tumours: a meta-analysis, BMC Cancer. 20 (2020) 200. 1966 https://doi.org/10.1186/s12885-020-6679-9. 1967 [204] A. Sadeghi, S. Shab-Bidar, M. Parohan, K. Djafarian, Dietary Fat Intake and 1968 Risk of Ovarian Cancer: A Systematic Review and Dose-Response Meta-Analysis 1969 of Observational Studies, Nutr Cancer. 71 (2019) 939–953. 1970 https://doi.org/10.1080/01635581.2019.1595049. 1971 [205] S.Y. Pan, A.-M. Ugnat, Y. Mao, S.W. Wen, K.C. Johnson, Canadian Cancer 1972 Registries Epidemiology Research Group, A case-control study of diet and the risk 1973 of ovarian cancer, Cancer Epidemiol. Biomarkers Prev. 13 (2004) 1521–1527. 1974 [206] M.S. Rice, E.M. Poole, W.C. Willett, S.S. Tworoger, Adult dietary fat intake 1975 and ovarian cancer risk, Int. J. Cancer. 146 (2020) 2756–2772. 1976 https://doi.org/10.1002/ijc.32635. 1977 [207] J.M. Genkinger, D.J. Hunter, D. Spiegelman, K.E. Anderson, W.L. Beeson, J.E. 1978 Buring, G.A. Colditz, G.E. Fraser, J.L. Freudenheim, R.A. Goldbohm, S.E. 1979 Hankinson, K.L. Koenig, S.C. Larsson, M. Leitzmann, M.L. McCullough, A.B. 1980 Miller, C. Rodriguez, T.E. Rohan, J.A. Ross, A. Schatzkin, L.J. Schouten, E. Smit, 1981 W.C. Willett, A. Wolk, A. Zeleniuch-Jacquotte, S.M. Zhang, S.A. Smith-Warner, A 1982 pooled analysis of 12 cohort studies of dietary fat, cholesterol and egg intake and 1983 ovarian cancer, Cancer Causes Control. 17 (2006) 273–285. 1984 https://doi.org/10.1007/s10552-005-0455-7. 1985 [208] M.A. Merritt, E. Riboli, E. Weiderpass, K.K. Tsilidis, K. Overvad, A. 1986 Tjønneland, L. Hansen, L. Dossus, G. Fagherazzi, L. Baglietto, R.T. Fortner, J. Ose, 1987 A. Steffen, H. Boeing, A. Trichopoulou, D. Trichopoulos, P. Lagiou, G. Masala, S. 1988 Sieri, A. Mattiello, R. Tumino, C. Sacerdote, H.B.A. Bueno-de-Mesquita, N.C. 1989 Onland-Moret, P.H. Peeters, A. Hjartåker, I.T. Gram, J.R. Quirós, M. Obón- 1990 Santacana, E. Molina-Montes, J.M. Huerta Castaño, E. Ardanaz, S. Chamosa, E. 1991 Sonestedt, A. Idahl, E. Lundin, K.-T. Khaw, N. Wareham, R.C. Travis, S. Rinaldi, I. 1992 Romieu, V. Chajes, M.J. Gunter, Dietary fat intake and risk of epithelial ovarian 1993 cancer in the European Prospective Investigation into Cancer and Nutrition, Cancer 1994 Epidemiol. 38 (2014) 528–537. https://doi.org/10.1016/j.canep.2014.07.011. 1995 [209] M.A. Merritt, I. Tzoulaki, P.A. van den Brandt, L.J. Schouten, K.K. Tsilidis, E. 1996 Weiderpass, C.J. Patel, A. Tjønneland, L. Hansen, K. Overvad, M. His, L. Dartois, 1997 M.-C. Boutron-Ruault, R.T. Fortner, R. Kaaks, K. Aleksandrova, H. Boeing, A. 1998 Trichopoulou, P. Lagiou, C. Bamia, D. Palli, V. Krogh, R. Tumino, F. Ricceri, A. 1999 Mattiello, H.B. Bueno-de-Mesquita, N.C. Onland-Moret, P.H. Peeters, G. Skeie, M. 64 2000 Jareid, J.R. Quirós, M. Obón-Santacana, M.-J. Sánchez, S. Chamosa, J.M. Huerta, 2001 A. Barricarte, J.A. Dias, E. Sonestedt, A. Idahl, E. Lundin, N.J. Wareham, K.-T. 2002 Khaw, R.C. Travis, P. Ferrari, E. Riboli, M.J. Gunter, Nutrient-wide association 2003 study of 57 foods/nutrients and epithelial ovarian cancer in the European 2004 Prospective Investigation into Cancer and Nutrition study and the Netherlands 2005 Cohort Study, Am. J. Clin. Nutr. 103 (2016) 161–167. 2006 https://doi.org/10.3945/ajcn.115.118588. 2007 [210] J. Yarmolinsky, C.J. Bull, E.E. Vincent, J. Robinson, A. Walther, G.D. Smith, 2008 S.J. Lewis, C.L. Relton, R.M. Martin, Association Between Genetically Proxied 2009 Inhibition of HMG-CoA Reductase and Epithelial Ovarian Cancer, JAMA. 323 2010 (2020) 646–655. https://doi.org/10.1001/jama.2020.0150. 2011 [211] A.J. Li, R.G. Elmore, I.Y. Chen, B.Y. Karlan, Serum low-density lipoprotein 2012 levels correlate with survival in advanced stage epithelial ovarian cancers, Gynecol. 2013 Oncol. 116 (2010) 78–81. https://doi.org/10.1016/j.ygyno.2009.09.027. 2014 [212] F. Zhu, X. Xu, B. Shi, L. Zeng, L. Wang, X. Wu, H. Zhu, The positive 2015 predictive value of low-density lipoprotein for recurrence-free survival in ovarian 2016 cancer, Int J Gynaecol Obstet. 143 (2018) 232–238. 2017 https://doi.org/10.1002/ijgo.12645. 2018 [213] D. Yam, H. Ben-Hur, A. Fink, R. Dgani, A. Shani, A. Eliraz, V. Insler, E.M. 2019 Berry, Insulin and glucose status, tissue and plasma lipids in patients with tumours 2020 of the ovary or endometrium: possible dietary implications, Br. J. Cancer. 70 (1994) 2021 1186–1187. https://doi.org/10.1038/bjc.1994.470. 2022 [214] Y. Zhang, J. Wu, J.-Y. Liang, X. Huang, L. Xia, D.-W. Ma, X.-Y. Xu, P.-P. Wu, 2023 Association of serum lipids and severity of epithelial ovarian cancer: an 2024 observational cohort study of 349 Chinese patients, J Biomed Res. 32 (2018) 336– 2025 342. https://doi.org/10.7555/JBR.32.20170096. 2026 [215] D.R. Scoles, X. Xu, H. Wang, H. Tran, B. Taylor-Harding, A. Li, B.Y. Karlan, 2027 Liver X receptor agonist inhibits proliferation of ovarian carcinoma cells stimulated 2028 by oxidized low density lipoprotein, Gynecol. Oncol. 116 (2010) 109–116. 2029 https://doi.org/10.1016/j.ygyno.2009.09.034. 2030 [216] S.E. Johnatty, J.P. Tyrer, S. Kar, J. Beesley, Y. Lu, B. Gao, P.A. Fasching, A. 2031 Hein, A.B. Ekici, M.W. Beckmann, D. Lambrechts, E. Van Nieuwenhuysen, I. 2032 Vergote, S. Lambrechts, M.A. Rossing, J.A. Doherty, J. Chang-Claude, F. 2033 Modugno, R.B. Ness, K.B. Moysich, D.A. Levine, L.A. Kiemeney, L.F.A.G. 2034 Massuger, J. Gronwald, J. Lubiński, A. Jakubowska, C. Cybulski, L. Brinton, J. 2035 Lissowska, N. Wentzensen, H. Song, V. Rhenius, I. Campbell, D. Eccles, W. Sieh, 2036 A.S. Whittemore, V. McGuire, J.H. Rothstein, R. Sutphen, H. Anton-Culver, A. 2037 Ziogas, S.A. Gayther, A. Gentry-Maharaj, U. Menon, S.J. Ramus, C.L. Pearce, 2038 M.C. Pike, D.O. Stram, A.H. Wu, J. Kupryjanczyk, A. Dansonka-Mieszkowska, 2039 I.K. Rzepecka, B. Spiewankiewicz, M.T. Goodman, L.R. Wilkens, M.E. Carney, 2040 P.J. Thompson, F. Heitz, A. du Bois, I. Schwaab, P. Harter, J. Pisterer, P. 2041 Hillemanns, AGO Study Group, B.Y. Karlan, C. Walsh, J. Lester, S. Orsulic, S.J. 2042 Winham, M. Earp, M.C. Larson, Z.C. Fogarty, E. Høgdall, A. Jensen, S.K. Kjaer, 2043 B.L. Fridley, J.M. Cunningham, R.A. Vierkant, J.M. Schildkraut, E.S. Iversen, K.L. 2044 Terry, D.W. Cramer, E.V. Bandera, I. Orlow, T. Pejovic, Y. Bean, C. Høgdall, L. 2045 Lundvall, I. McNeish, J. Paul, K. Carty, N. Siddiqui, R. Glasspool, T. Sellers, C. 2046 Kennedy, Y.-E. Chiew, A. Berchuck, S. MacGregor, P.D.P. Pharoah, E.L. Goode, 2047 A. deFazio, P.M. Webb, G. Chenevix-Trench, Australian Ovarian Cancer Study 2048 Group, Genome-wide Analysis Identifies Novel Loci Associated with Ovarian 2049 Cancer Outcomes: Findings from the Ovarian Cancer Association Consortium, Clin. 65 2050 Cancer Res. 21 (2015) 5264–5276. https://doi.org/10.1158/1078-0432.CCR-15- 2051 0632. 2052 [217] H. Gadomska, B. Grzechocińska, J. Janecki, G. Nowicka, M. Powolny, L. 2053 Marianowski, Serum lipids concentration in women with benign and malignant 2054 ovarian tumours, Eur. J. Obstet. Gynecol. Reprod. Biol. 120 (2005) 87–90. 2055 https://doi.org/10.1016/j.ejogrb.2004.02.045. 2056 [218] H. Camuzcuoglu, D.T. Arioz, H. Toy, S. Kurt, H. Celik, O. Erel, Serum 2057 paraoxonase and arylesterase activities in patients with epithelial ovarian cancer, 2058 Gynecol. Oncol. 112 (2009) 481–485. https://doi.org/10.1016/j.ygyno.2008.10.031. 2059 [219] M.R. Russell, C. Graham, A. D’Amato, A. Gentry-Maharaj, A. Ryan, J.K. Kalsi, 2060 C. Ainley, A.D. Whetton, U. Menon, I. Jacobs, R.L.J. Graham, A combined 2061 biomarker panel shows improved sensitivity for the early detection of ovarian 2062 cancer allowing the identification of the most aggressive type II tumours, Br. J. 2063 Cancer. 117 (2017) 666–674. https://doi.org/10.1038/bjc.2017.199. 2064 [220] F. Su, K.R. Kozak, S. Imaizumi, F. Gao, M.W. Amneus, V. Grijalva, C. Ng, A. 2065 Wagner, G. Hough, G. Farias-Eisner, G.M. Anantharamaiah, B.J. Van Lenten, M. 2066 Navab, A.M. Fogelman, S.T. Reddy, R. Farias-Eisner, Apolipoprotein A-I (apoA-I) 2067 and apoA-I mimetic peptides inhibit tumor development in a mouse model of 2068 ovarian cancer, Proc. Natl. Acad. Sci. U.S.A. 107 (2010) 19997–20002. 2069 https://doi.org/10.1073/pnas.1009010107. 2070 [221] G. Pampalakis, A.-L. Politi, A. Papanastasiou, G. Sotiropoulou, Distinct 2071 cholesterogenic and lipidogenic gene expression patterns in ovarian cancer - a new 2072 pool of biomarkers, Genes Cancer. 6 (2015) 472–479. 2073 https://doi.org/10.18632/genesandcancer.87. 2074 [222] D.J. Brennan, J. Brändstedt, E. Rexhepaj, M. Foley, F. Pontén, M. Uhlén, W.M. 2075 Gallagher, D.P. O’Connor, C. O’Herlihy, K. Jirstrom, Tumour-specific HMG- 2076 CoAR is an independent predictor of recurrence free survival in epithelial ovarian 2077 cancer, BMC Cancer. 10 (2010) 125. https://doi.org/10.1186/1471-2407-10-125. 2078 [223] A.R. Goldman, B.G. Bitler, Z. Schug, J.R. Conejo-Garcia, R. Zhang, D.W. 2079 Speicher, The Primary Effect on the Proteome of ARID1A-mutated Ovarian Clear 2080 Cell Carcinoma is Downregulation of the Mevalonate Pathway at the Post- 2081 transcriptional Level, Mol. Cell Proteomics. 15 (2016) 3348–3360. 2082 https://doi.org/10.1074/mcp.M116.062539. 2083 [224] J.B. Greenaway, C. Virtanen, K. Osz, T. Revay, D. Hardy, T. Shepherd, G. 2084 DiMattia, J. Petrik, Ovarian tumour growth is characterized by mevalonate pathway 2085 gene signature in an orthotopic, syngeneic model of epithelial ovarian cancer, 2086 Oncotarget. 7 (2016) 47343–47365. https://doi.org/10.18632/oncotarget.10121. 2087 [225] S. Kim, M. Lee, D.N. Dhanasekaran, Y.S. Song, Activation of LXRɑ/β by 2088 cholesterol in malignant ascites promotes chemoresistance in ovarian cancer, BMC 2089 Cancer. 18 (2018) 1232. https://doi.org/10.1186/s12885-018-5152-5. 2090 [226] D. Criscuolo, R. Avolio, G. Calice, C. Laezza, S. Paladino, G. Navarra, F. 2091 Maddalena, F. Crispo, C. Pagano, M. Bifulco, M. Landriscina, D.S. Matassa, F. 2092 Esposito, Cholesterol Homeostasis Modulates Platinum Sensitivity in Human 2093 Ovarian Cancer, Cells. 9 (2020). https://doi.org/10.3390/cells9040828. 2094 [227] V.N. Ayyagari, X. Wang, P.L. Diaz-Sylvester, K. Groesch, L. Brard, 2095 Assessment of acyl-CoA cholesterol acyltransferase (ACAT-1) role in ovarian 2096 cancer progression-An in vitro study, PLoS ONE. 15 (2020) e0228024. 2097 https://doi.org/10.1371/journal.pone.0228024. 2098 [228] E.L. Hedditch, B. Gao, A.J. Russell, Y. Lu, C. Emmanuel, J. Beesley, S.E. 2099 Johnatty, X. Chen, P. Harnett, J. George, Australian Ovarian Cancer Study Group, 66 2100 R.T. Williams, C. Flemming, D. Lambrechts, E. Despierre, S. Lambrechts, I. 2101 Vergote, B. Karlan, J. Lester, S. Orsulic, C. Walsh, P. Fasching, M.W. Beckmann, 2102 A.B. Ekici, A. Hein, K. Matsuo, S. Hosono, T. Nakanishi, Y. Yatabe, T. Pejovic, Y. 2103 Bean, F. Heitz, P. Harter, A. du Bois, I. Schwaab, E. Hogdall, S.K. Kjaer, A. 2104 Jensen, C. Hogdall, L. Lundvall, S.A. Engelholm, B. Brown, J. Flanagan, M.D. 2105 Metcalf, N. Siddiqui, T. Sellers, B. Fridley, J. Cunningham, J. Schildkraut, E. 2106 Iversen, R.P. Weber, A. Berchuck, E. Goode, D.D. Bowtell, G. Chenevix-Trench, 2107 A. deFazio, M.D. Norris, S. MacGregor, M. Haber, M.J. Henderson, ABCA 2108 transporter gene expression and poor outcome in epithelial ovarian cancer, J. Natl. 2109 Cancer Inst. 106 (2014). https://doi.org/10.1093/jnci/dju149. 2110 [229] P. Goossens, J. Rodriguez-Vita, A. Etzerodt, M. Masse, O. Rastoin, V. 2111 Gouirand, T. Ulas, O. Papantonopoulou, M. Van Eck, N. Auphan-Anezin, M. 2112 Bebien, C. Verthuy, T.P. Vu Manh, M. Turner, M. Dalod, J.L. Schultze, T. 2113 Lawrence, Membrane Cholesterol Efflux Drives Tumor-Associated Macrophage 2114 Reprogramming and Tumor Progression, Cell Metab. 29 (2019) 1376-1389.e4. 2115 https://doi.org/10.1016/j.cmet.2019.02.016. 2116 [230] H. Tuft Stavnes, D.A. Nymoen, T.E. Hetland Falkenthal, J. Kærn, C.G. Tropé, 2117 B. Davidson, APOA1 mRNA expression in ovarian serous carcinoma effusions is a 2118 marker of longer survival, Am. J. Clin. Pathol. 142 (2014) 51–57. 2119 https://doi.org/10.1309/AJCPD8NBSHXRXQL7. 2120 [231] S. He, L. Ma, A.E. Baek, A. Vardanyan, V. Vembar, J.J. Chen, A.T. Nelson, J.E. 2121 Burdette, E.R. Nelson, Host CYP27A1 expression is essential for ovarian cancer 2122 progression, Endocr. Relat. Cancer. 26 (2019) 659–675. 2123 https://doi.org/10.1530/ERC-18-0572. 2124 [232] R. Lappano, A.G. Recchia, E.M. De Francesco, T. Angelone, M.C. Cerra, D. 2125 Picard, M. Maggiolini, The cholesterol metabolite 25-hydroxycholesterol activates 2126 estrogen receptor α-mediated signaling in cancer cells and in cardiomyocytes, PLoS 2127 ONE. 6 (2011) e16631. https://doi.org/10.1371/journal.pone.0016631. 2128 [233] J. Hu, Z. Zhang, W.-J. Shen, S. Azhar, Cellular cholesterol delivery, intracellular 2129 processing and utilization for biosynthesis of steroid hormones, Nutrition & 2130 Metabolism. 7 (2010) 47. https://doi.org/10.1186/1743-7075-7-47. 2131 [234] A.K. Lam, Update on Adrenal Tumours in 2017 World Health Organization 2132 (WHO) of Endocrine Tumours, Endocr Pathol. 28 (2017) 213–227. 2133 https://doi.org/10.1007/s12022-017-9484-5. 2134 [235] R. Rossi, L. Tauchmanova, A. Luciano, M. Di Martino, C. Battista, L. Del 2135 Viscovo, V. Nuzzo, G. Lombardi, Subclinical Cushing’s syndrome in patients with 2136 adrenal incidentaloma: clinical and biochemical features, J. Clin. Endocrinol. 2137 Metab. 85 (2000) 1440–1448. https://doi.org/10.1210/jcem.85.4.6515. 2138 [236] M. Terzolo, A. Pia, A. Alì, G. Osella, G. Reimondo, S. Bovio, F. Daffara, M. 2139 Procopio, P. Paccotti, G. Borretta, A. Angeli, Adrenal Incidentaloma: A New Cause 2140 of the Metabolic Syndrome?, J Clin Endocrinol Metab. 87 (2002) 998–1003. 2141 https://doi.org/10.1210/jcem.87.3.8277. 2142 [237] G. Mintziori, T. Georgiou, P. Anagnostis, F. Adamidou, Z. Efstathiadou, A. 2143 Panagiotou, M. Kita, Could Lipid Profile be Used as a Marker of Autonomous 2144 Cortisol Secretion in Patients with Adrenal Incidentalomas?, Horm Metab Res. 50 2145 (2018) 551–555. https://doi.org/10.1055/a-0630-1397. 2146 [238] M. Higashijima, K. Kato, H. Nawata, H. Ibayashi, Studies on lipoprotein and 2147 adrenal steroidogenesis: II. Utilization of low density lipoprotein- and high density 2148 lipoprotein-cholesterol for steroid production in functioning human adrenocortical 67 2149 adenoma cells in culture, Endocrinol. Jpn. 34 (1987) 647–657. 2150 https://doi.org/10.1507/endocrj1954.34.647. 2151 [239] G. Martin, A. Pilon, C. Albert, M. Vallé, D.W. Hum, J.C. Fruchart, J. Najib, V. 2152 Clavey, B. Staels, Comparison of expression and regulation of the high-density 2153 lipoprotein receptor SR-BI and the low-density lipoprotein receptor in human 2154 adrenocortical carcinoma NCI-H295 cells, Eur. J. Biochem. 261 (1999) 481–491. 2155 https://doi.org/10.1046/j.1432-1327.1999.00296.x. 2156 [240] T. Nakagawa, Y. Ueyama, S. Nozaki, S. Yamashita, M. Menju, T. Funahashi, K. 2157 Kameda-Takemura, M. Kubo, K. Tokunaga, T. Tanaka, Marked 2158 hypocholesterolemia in a case with adrenal adenoma--enhanced catabolism of low 2159 density lipoprotein (LDL) via the LDL receptors of tumor cells, J. Clin. Endocrinol. 2160 Metab. 80 (1995) 92–96. https://doi.org/10.1210/jcem.80.1.7829645. 2161 [241] H. Wilmot Roussel, D. Vezzosi, M. Rizk-Rabin, O. Barreau, B. Ragazzon, F. 2162 René-Corail, A. de Reynies, J. Bertherat, G. Assié, Identification of Gene 2163 Expression Profiles Associated With Cortisol Secretion in Adrenocortical 2164 Adenomas, J Clin Endocrinol Metab. 98 (2013) E1109–E1121. 2165 https://doi.org/10.1210/jc.2012-4237. 2166 [242] E. London, C.A. Wassif, A. Horvath, C. Tatsi, A. Angelousi, A.S. 2167 Karageorgiadis, F.D. Porter, C.A. Stratakis, Cholesterol Biosynthesis and 2168 Trafficking in Cortisol-Producing Lesions of the Adrenal Cortex, J. Clin. 2169 Endocrinol. Metab. 100 (2015) 3660–3667. https://doi.org/10.1210/jc.2015-2212. 2170 [243] N.H. Hanna, L.H. Einhorn, Testicular cancer--discoveries and updates, N. Engl. 2171 J. Med. 371 (2014) 2005–2016. https://doi.org/10.1056/NEJMra1407550. 2172 [244] A.-B. Wiréhn, S. Törnberg, J. Carstensen, Serum cholesterol and testicular 2173 cancer incidence in 45,000 men followed for 25 years, Br. J. Cancer. 92 (2005) 2174 1785–1786. https://doi.org/10.1038/sj.bjc.6602539. 2175 [245] D.A. Freeman, M. Ascoli, Studies on the source of cholesterol used for steroid 2176 biosynthesis in cultured Leydig tumor cells, J. Biol. Chem. 257 (1982) 14231– 2177 14238. 2178 [246] D.A. Freeman, M. Ascoli, The low-density lipoprotein pathway of cultured 2179 Leydig tumor cells. Utilization of low-density lipoprotein-derived cholesterol for 2180 steroidogenesis, Biochim. Biophys. Acta. 754 (1983) 72–81. 2181 https://doi.org/10.1016/0005-2760(83)90083-8. 2182 [247] M.A. Zaid, W.G. Gathirua-Mwangi, C. Fung, P.O. Monahan, O. El-Charif, A.M. 2183 Williams, D.R. Feldman, R.J. Hamilton, D.J. Vaughn, C.J. Beard, R. Cook, S.K. 2184 Althouse, S. Ardeshir-Rouhani-Fard, P.C. Dinh, H.D. Sesso, L.H. Einhorn, S.D. 2185 Fossa, L.B. Travis, Platinum Study Group, Clinical and Genetic Risk Factors for 2186 Adverse Metabolic Outcomes in North American Testicular Cancer Survivors, J 2187 Natl Compr Canc Netw. 16 (2018) 257–265. 2188 https://doi.org/10.6004/jnccn.2017.7046. 2189 [248] J. Armitage, The safety of statins in clinical practice, Lancet. 370 (2007) 1781– 2190 1790. https://doi.org/10.1016/S0140-6736(07)60716-8. 2191 [249] J.L. Goldstein, M.S. Brown, Regulation of the mevalonate pathway, Nature. 343 2192 (1990) 425–430. https://doi.org/10.1038/343425a0. 2193 [250] S. Pisanti, P. Picardi, E. Ciaglia, A. D’Alessandro, M. Bifulco, Novel prospects 2194 of statins as therapeutic agents in cancer, Pharmacol. Res. 88 (2014) 84–98. 2195 https://doi.org/10.1016/j.phrs.2014.06.013. 2196 [251] M. Afzali, M. Vatankhah, S.N. Ostad, Investigation of simvastatin-induced 2197 apoptosis and cell cycle arrest in cancer stem cells of MCF-7, J Cancer Res Ther. 12 2198 (2016) 725–730. https://doi.org/10.4103/0973-1482.146127. 68 2199 [252] T. Alarcon Martinez, N.D. Zeybek, S. Müftüoğlu, Evaluation of the Cytotoxic 2200 and Autophagic Effects of Atorvastatin on MCF-7 Breast Cancer Cells, Balkan Med 2201 J. 35 (2018) 256–262. https://doi.org/10.4274/balkanmedj.2017.0604. 2202 [253] M. Malik, J. Britten, M. Borahay, J. Segars, W.H. Catherino, Simvastatin, at 2203 clinically relevant concentrations, affects human uterine leiomyoma growth and 2204 extracellular matrix production, Fertil. Steril. 110 (2018) 1398-1407.e1. 2205 https://doi.org/10.1016/j.fertnstert.2018.07.024. 2206 [254] C.F. Christie, D. Fang, E.G. Hunt, M.E. Morris, A. Rovini, K.A. Heslop, G.C. 2207 Beeson, C.C. Beeson, E.N. Maldonado, Statin-dependent modulation of 2208 mitochondrial metabolism in cancer cells is independent of cholesterol content, 2209 FASEB J. 33 (2019) 8186–8201. https://doi.org/10.1096/fj.201802723R. 2210 [255] G. Gruenbacher, M. Thurnher, Mevalonate metabolism in cancer, Cancer Lett. 2211 356 (2015) 192–196. https://doi.org/10.1016/j.canlet.2014.01.013. 2212 [256] G.H. Jeong, K.H. Lee, J.Y. Kim, M. Eisenhut, A. Kronbichler, H.J. van der 2213 Vliet, J.I. Shin, G. Gamerith, Statin and Cancer Mortality and Survival: An 2214 Umbrella Systematic Review and Meta-Analysis, J Clin Med. 9 (2020). 2215 https://doi.org/10.3390/jcm9020326. 2216 [257] B. Liu, Z. Yi, X. Guan, Y.-X. Zeng, F. Ma, The relationship between statins and 2217 breast cancer prognosis varies by statin type and exposure time: a meta-analysis, 2218 Breast Cancer Res. Treat. 164 (2017) 1–11. https://doi.org/10.1007/s10549-017- 2219 4246-0. 2220 [258] Cholesterol Treatment Trialists’ (CTT) Collaboration, J.R. Emberson, P.M. 2221 Kearney, L. Blackwell, C. Newman, C. Reith, N. Bhala, L. Holland, R. Peto, A. 2222 Keech, R. Collins, J. Simes, C. Baigent, Lack of effect of lowering LDL cholesterol 2223 on cancer: meta-analysis of individual data from 175,000 people in 27 randomised 2224 trials of statin therapy, PLoS ONE. 7 (2012) e29849. 2225 https://doi.org/10.1371/journal.pone.0029849. 2226 [259] C. Baigent, A. Keech, P.M. Kearney, L. Blackwell, G. Buck, C. Pollicino, A. 2227 Kirby, T. Sourjina, R. Peto, R. Collins, R. Simes, Cholesterol Treatment Trialists’ 2228 (CTT) Collaborators, Efficacy and safety of cholesterol-lowering treatment: 2229 prospective meta-analysis of data from 90,056 participants in 14 randomised trials 2230 of statins, Lancet. 366 (2005) 1267–1278. https://doi.org/10.1016/S0140- 2231 6736(05)67394-1. 2232 [260] S. Manthravadi, A. Shrestha, S. Madhusudhana, Impact of statin use on cancer 2233 recurrence and mortality in breast cancer: A systematic review and meta-analysis: 2234 Breast cancer: A systematic review and meta-analysis, International Journal of 2235 Cancer. 139 (2016) 1281–1288. https://doi.org/10.1002/ijc.30185. 2236 [261] A.B. Rossebø, T.R. Pedersen, K. Boman, P. Brudi, J.B. Chambers, K. Egstrup, 2237 E. Gerdts, C. Gohlke-Bärwolf, I. Holme, Y.A. Kesäniemi, W. Malbecq, C.A. 2238 Nienaber, S. Ray, T. Skjaerpe, K. Wachtell, R. Willenheimer, SEAS Investigators, 2239 Intensive lipid lowering with simvastatin and ezetimibe in aortic stenosis, N. Engl. 2240 J. Med. 359 (2008) 1343–1356. https://doi.org/10.1056/NEJMoa0804602. 2241 [262] E.J. Jacobs, C.C. Newton, M.J. Thun, S.M. Gapstur, Long-term use of 2242 cholesterol-lowering drugs and cancer incidence in a large United States cohort, 2243 Cancer Res. 71 (2011) 1763–1771. https://doi.org/10.1158/0008-5472.CAN-10- 2244 2953. 2245 [263] S.F. Nielsen, B.G. Nordestgaard, S.E. Bojesen, Statin use and reduced cancer- 2246 related mortality, N. Engl. J. Med. 367 (2012) 1792–1802. 2247 https://doi.org/10.1056/NEJMoa1201735. 69 2248 [264] B.A. Ference, K.K. Ray, A.L. Catapano, T.B. Ference, S. Burgess, D.R. Neff, C. 2249 Oliver-Williams, A.M. Wood, A.S. Butterworth, E. Di Angelantonio, J. Danesh, 2250 J.J.P. Kastelein, S.J. Nicholls, Mendelian Randomization Study of ACLY and 2251 Cardiovascular Disease, N. Engl. J. Med. 380 (2019) 1033–1042. 2252 https://doi.org/10.1056/NEJMoa1806747. 2253 [265] K. Undela, V. Srikanth, D. Bansal, Statin use and risk of breast cancer: a meta- 2254 analysis of observational studies, Breast Cancer Res. Treat. 135 (2012) 261–269. 2255 https://doi.org/10.1007/s10549-012-2154-x. 2256 [266] S. Bonovas, K. Filioussi, N. Tsavaris, N.M. Sitaras, Use of statins and breast 2257 cancer: a meta-analysis of seven randomized clinical trials and nine observational 2258 studies, J. Clin. Oncol. 23 (2005) 8606–8612. 2259 https://doi.org/10.1200/JCO.2005.02.7045. 2260 [267] Q.-J. Wu, C. Tu, Y.-Y. Li, J. Zhu, K.-Q. Qian, W.-J. Li, L. Wu, Statin use and 2261 breast cancer survival and risk: a systematic review and meta-analysis, Oncotarget. 2262 6 (2015) 42988–43004. https://doi.org/10.18632/oncotarget.5557. 2263 [268] M. Mansourian, S. Haghjooy-Javanmard, A. Eshraghi, G. Vaseghi, A. 2264 Hayatshahi, J. Thomas, Statins Use and Risk of Breast Cancer Recurrence and 2265 Death: A Systematic Review and Meta-Analysis of Observational Studies, J Pharm 2266 Pharm Sci. 19 (2016) 72–81. https://doi.org/10.18433/J3202B. 2267 [269] M.M. Islam, H.-C. Yang, P.-A. Nguyen, T.N. Poly, C.-W. Huang, S. Kekade, 2268 A.M. Khalfan, T. Debnath, Y.-C.J. Li, S.S. Abdul, Exploring association between 2269 statin use and breast cancer risk: an updated meta-analysis, Arch. Gynecol. Obstet. 2270 296 (2017) 1043–1053. https://doi.org/10.1007/s00404-017-4533-3. 2271 [270] K.M. Dale, C.I. Coleman, N.N. Henyan, J. Kluger, C.M. White, Statins and 2272 cancer risk: a meta-analysis, JAMA. 295 (2006) 74–80. 2273 https://doi.org/10.1001/jama.295.1.74. 2274 [271] T.J. Murtola, K. Visvanathan, M. Artama, H. Vainio, E. Pukkala, Statin use and 2275 breast cancer survival: a nationwide cohort study from Finland, PLoS ONE. 9 2276 (2014) e110231. https://doi.org/10.1371/journal.pone.0110231. 2277 [272] T.P. Ahern, L. Pedersen, M. Tarp, D.P. Cronin-Fenton, J.P. Garne, R.A. 2278 Silliman, H.T. Sørensen, T.L. Lash, Statin prescriptions and breast cancer 2279 recurrence risk: a Danish nationwide prospective cohort study, J. Natl. Cancer Inst. 2280 103 (2011) 1461–1468. https://doi.org/10.1093/jnci/djr291. 2281 [273] S. Borgquist, A. Giobbie-Hurder, T.P. Ahern, J.E. Garber, M. Colleoni, I. Láng, 2282 M. Debled, B. Ejlertsen, R. von Moos, I. Smith, A.S. Coates, A. Goldhirsch, M. 2283 Rabaglio, K.N. Price, R.D. Gelber, M.M. Regan, B. Thürlimann, Cholesterol, 2284 Cholesterol-Lowering Medication Use, and Breast Cancer Outcome in the BIG 1-98 2285 Study, J. Clin. Oncol. 35 (2017) 1179–1188. 2286 https://doi.org/10.1200/JCO.2016.70.3116. 2287 [274] J.A. Cauley, J.M. Zmuda, L.-Y. Lui, T.A. Hillier, R.B. Ness, K.L. Stone, S.R. 2288 Cummings, D.C. Bauer, Lipid-lowering drug use and breast cancer in older women: 2289 a prospective study, J Womens Health (Larchmt). 12 (2003) 749–756. 2290 https://doi.org/10.1089/154099903322447710. 2291 [275] T.M. Brewer, H. Masuda, D.D. Liu, Y. Shen, P. Liu, T. Iwamoto, K. Kai, C.M. 2292 Barnett, W.A. Woodward, J.M. Reuben, P. Yang, G.N. Hortobagyi, N.T. Ueno, 2293 Statin use in primary inflammatory breast cancer: a cohort study, Br. J. Cancer. 109 2294 (2013) 318–324. https://doi.org/10.1038/bjc.2013.342. 2295 [276] T. Anothaisintawee, U. Udomsubpayakul, M. McEvoy, P. Lerdsitthichai, J. 2296 Attia, A. Thakkinstian, Effect of Lipophilic and Hydrophilic Statins on Breast 70 2297 Cancer Risk in Thai Women: A Cross-sectional Study, J Cancer. 7 (2016) 1163– 2298 1168. https://doi.org/10.7150/jca.14941. 2299 [277] Ú.C. Mc Menamin, L.J. Murray, C.M. Hughes, C.R. Cardwell, Statin use and 2300 breast cancer survival: a nationwide cohort study in Scotland, BMC Cancer. 16 2301 (2016) 600. https://doi.org/10.1186/s12885-016-2651-0. 2302 [278] A. Smith, L. Murphy, L. Zgaga, T.I. Barron, K. Bennett, Pre-diagnostic statin 2303 use, lymph node status and mortality in women with stages I-III breast cancer, Br. J. 2304 Cancer. 117 (2017) 588–596. https://doi.org/10.1038/bjc.2017.227. 2305 [279] S.F. Shaitelman, M.C. Stauder, P. Allen, S. Reddy, S. Lakoski, B. Atkinson, J. 2306 Reddy, D. Amaya, W. Guerra, N. Ueno, A. Caudle, W. Tereffe, W.A. Woodward, 2307 Impact of Statin Use on Outcomes in Triple Negative Breast Cancer, J Cancer. 8 2308 (2017) 2026–2032. https://doi.org/10.7150/jca.18743. 2309 [280] Y.K. Chae, M.E. Valsecchi, J. Kim, A.L. Bianchi, D. Khemasuwan, A. Desai, 2310 W. Tester, Reduced risk of breast cancer recurrence in patients using ACE 2311 inhibitors, ARBs, and/or statins, Cancer Invest. 29 (2011) 585–593. 2312 https://doi.org/10.3109/07357907.2011.616252. 2313 [281] M. Sakellakis, K. Akinosoglou, A. Kostaki, D. Spyropoulou, A. Koutras, Statins 2314 and risk of breast cancer recurrence, Breast Cancer (Dove Med Press). 8 (2016) 2315 199–205. https://doi.org/10.2147/BCTT.S116694. 2316 [282] C. Schairer, D.M. Freedman, S.M. Gadalla, R.M. Pfeiffer, Lipid-lowering drugs, 2317 dyslipidemia, and breast cancer risk in a Medicare population, Breast Cancer Res. 2318 Treat. 169 (2018) 607–614. https://doi.org/10.1007/s10549-018-4680-7. 2319 [283] J.A. McDougall, K.E. Malone, J.R. Daling, K.L. Cushing-Haugen, P.L. Porter, 2320 C.I. Li, Long-Term Statin Use and Risk of Ductal and Lobular Breast Cancer 2321 among Women 55 to 74 Years of Age, Cancer Epidemiology Biomarkers & 2322 Prevention. 22 (2013) 1529–1537. https://doi.org/10.1158/1055-9965.epi-13-0414. 2323 [284] J. Hutchinson, L. Marignol, Clinical Potential of Statins in Prostate Cancer 2324 Radiation Therapy, Anticancer Res. 37 (2017) 5363–5372. 2325 https://doi.org/10.21873/anticanres.11962. 2326 [285] E.A. Platz, M.F. Leitzmann, K. Visvanathan, E.B. Rimm, M.J. Stampfer, W.C. 2327 Willett, E. Giovannucci, Statin drugs and risk of advanced prostate cancer, J. Natl. 2328 Cancer Inst. 98 (2006) 1819–1825. https://doi.org/10.1093/jnci/djj499. 2329 [286] S.B. Larsen, C. Dehlendorff, C. Skriver, S.O. Dalton, C.G. Jespersen, M. Borre, 2330 K. Brasso, M. Nørgaard, C. Johansen, H.T. Sørensen, J. Hallas, S. Friis, 2331 Postdiagnosis Statin Use and Mortality in Danish Patients With Prostate Cancer, J. 2332 Clin. Oncol. 35 (2017) 3290–3297. https://doi.org/10.1200/JCO.2016.71.8981. 2333 [287] R.J. Hamilton, L.L. Banez, W.J. Aronson, M.K. Terris, E.A. Platz, C.J. Kane, 2334 J.C. Presti, C.L. Amling, S.J. Freedland, Statin medication use and the risk of 2335 biochemical recurrence after radical prostatectomy: results from the Shared Equal 2336 Access Regional Cancer Hospital (SEARCH) Database, Cancer. 116 (2010) 3389– 2337 3398. https://doi.org/10.1002/cncr.25308. 2338 [288] S. Bonovas, K. Filioussi, N.M. Sitaras, Statins are not associated with a reduced 2339 risk of pancreatic cancer at the population level, when taken at low doses for 2340 managing hypercholesterolemia: evidence from a meta-analysis of 12 studies, Am. 2341 J. Gastroenterol. 103 (2008) 2646–2651. https://doi.org/10.1111/j.1572- 2342 0241.2008.02051.x. 2343 [289] X. Cui, Y. Xie, M. Chen, J. Li, X. Liao, J. Shen, M. Shi, W. Li, H. Zheng, B. 2344 Jiang, Statin use and risk of pancreatic cancer: a meta-analysis, Cancer Causes 2345 Control. 23 (2012) 1099–1111. https://doi.org/10.1007/s10552-012-9979-9. 71 2346 [290] B.Z. Huang, J.I. Chang, E. Li, A.H. Xiang, B.U. Wu, Influence of Statins and 2347 Cholesterol on Mortality Among Patients With Pancreatic Cancer, J. Natl. Cancer 2348 Inst. 109 (2017). https://doi.org/10.1093/jnci/djw275. 2349 [291] H.S. Lee, S.H. Lee, H.J. Lee, M.J. Chung, J.Y. Park, S.W. Park, S.Y. Song, S. 2350 Bang, Statin Use and Its Impact on Survival in Pancreatic Cancer Patients, Medicine 2351 (Baltimore). 95 (2016) e3607. https://doi.org/10.1097/MD.0000000000003607. 2352 [292] R.B. Chagpar, R.C.G. Martin, S.A. Ahmad, H.J. Kim, C. Rupp, S. Weber, A. 2353 Ebelhar, J. Gilbert, A. Brinkman, E. Winslow, C.S. Cho, D. Kooby, C.K. Chu, C.A. 2354 Staley, K.M. McMasters, C.R. Scoggins, Medically managed hypercholesterolemia 2355 and insulin-dependent diabetes mellitus preoperatively predicts poor survival after 2356 surgery for pancreatic cancer, J. Gastrointest. Surg. 15 (2011) 551–557. 2357 https://doi.org/10.1007/s11605-011-1448-3. 2358 [293] C.Y. Jeon, S.J. Pandol, M.T. Goodman, Survival time in pancreatic cancer 2359 patients with metabolic syndrome varies by use of insulin and statins, Cancer Res. 2360 74 (2014) 2173–2173. https://doi.org/10.1158/1538-7445.AM2014-2173. 2361 [294] Y. Nakai, H. Isayama, T. Sasaki, S. Mizuno, N. Sasahira, H. Kogure, K. 2362 Kawakubo, N. Yamamoto, K. Hirano, H. Ijichi, K. Tateishi, M. Tada, K. Koike, 2363 Clinical outcomes of chemotherapy for diabetic and nondiabetic patients with 2364 pancreatic cancer: better prognosis with statin use in diabetic patients, Pancreas. 42 2365 (2013) 202–208. https://doi.org/10.1097/MPA.0b013e31825de678. 2366 [295] V. Khurana, A. Sheth, G. Caldito, J.S. Barkin, Statins reduce the risk of 2367 pancreatic cancer in humans: a case-control study of half a million veterans, 2368 Pancreas. 34 (2007) 260–265. https://doi.org/10.1097/MPA.0b013e318030e963. 2369 [296] M.C. Bradley, C.M. Hughes, M.M. Cantwell, L.J. Murray, Statins and 2370 pancreatic cancer risk: a nested case-control study, Cancer Causes Control. 21 2371 (2010) 2093–2100. https://doi.org/10.1007/s10552-010-9628-0. 2372 [297] E.J. Walker, A.H. Ko, E.A. Holly, P.M. Bracci, Statin use and risk of pancreatic 2373 cancer: results from a large, clinic-based case-control study, Cancer. 121 (2015) 2374 1287–1294. https://doi.org/10.1002/cncr.29256. 2375 [298] H.-F. Chiu, C.-C. Chang, S.-C. Ho, T.-N. Wu, C.-Y. Yang, Statin use and the 2376 risk of pancreatic cancer: a population-based case-control study, Pancreas. 40 2377 (2011) 669–672. https://doi.org/10.1097/MPA.0b013e31821fd5cd. 2378 [299] F.J. Carey, M.W. Little, T.F.G. Pugh, R. Ndokera, H. Ing, A. Clark, A. 2379 Dennison, M.S. Metcalfe, R.J. Robinson, A.R. Hart, The differential effects of 2380 statins on the risk of developing pancreatic cancer: a case-control study in two 2381 centres in the United Kingdom, Dig. Dis. Sci. 58 (2013) 3308–3312. 2382 https://doi.org/10.1007/s10620-013-2778-7. 2383 [300] A. Majidi, R. Na, S. Dixon-Suen, S.J. Jordan, P.M. Webb, Common medications 2384 and survival in women with ovarian cancer: A systematic review and meta-analysis, 2385 Gynecol. Oncol. 157 (2020) 678–685. https://doi.org/10.1016/j.ygyno.2020.03.028. 2386 [301] X. Li, J. Zhou, Impact of postdiagnostic statin use on ovarian cancer mortality: 2387 A systematic review and meta-analysis of observational studies, Br J Clin 2388 Pharmacol. 84 (2018) 1109–1120. https://doi.org/10.1111/bcp.13559. 2389 [302] Y. Liu, A. Qin, T. Li, X. Qin, S. Li, Effect of statin on risk of gynecologic 2390 cancers: a meta-analysis of observational studies and randomized controlled trials, 2391 Gynecol. Oncol. 133 (2014) 647–655. https://doi.org/10.1016/j.ygyno.2014.04.007. 2392 [303] B.N. Harding, J.A. Delaney, R.R. Urban, N.S. Weiss, Use of Statin Medications 2393 Following Diagnosis in Relation to Survival among Women with Ovarian Cancer, 2394 Cancer Epidemiol. Biomarkers Prev. 28 (2019) 1127–1133. 2395 https://doi.org/10.1158/1055-9965.EPI-18-1194. 72 2396 [304] E. Urpilainen, M. Marttila, A. Hautakoski, M. Arffman, R. Sund, P. Ilanne- 2397 Parikka, R. Arima, J. Kangaskokko, U. Puistola, M. Hinkula, E. Läärä, Prognosis of 2398 ovarian cancer in women with type 2 diabetes using metformin and other forms of 2399 antidiabetic medication or statins: a retrospective cohort study, BMC Cancer. 18 2400 (2018) 767. https://doi.org/10.1186/s12885-018-4676-z. 2401 [305] P. Desai, R. Wallace, M.L. Anderson, B.V. Howard, R.M. Ray, C. Wu, M. 2402 Safford, L.W. Martin, T. Rohan, J.E. Manson, M.S. Simon, An analysis of the 2403 association between statin use and risk of endometrial and ovarian cancers in the 2404 Women’s Health Initiative, Gynecol. Oncol. 148 (2018) 540–546. 2405 https://doi.org/10.1016/j.ygyno.2018.01.006. 2406 [306] A. Couttenier, O. Lacroix, E. Vaes, C.R. Cardwell, H. De Schutter, A. Robert, 2407 Statin use is associated with improved survival in ovarian cancer: A retrospective 2408 population-based study, PLoS ONE. 12 (2017) e0189233. 2409 https://doi.org/10.1371/journal.pone.0189233. 2410 [307] F. Verdoodt, M. Kjaer Hansen, S.K. Kjaer, A. Pottegård, S. Friis, C. 2411 Dehlendorff, Statin use and mortality among ovarian cancer patients: A population- 2412 based cohort study, Int. J. Cancer. 141 (2017) 279–286. 2413 https://doi.org/10.1002/ijc.30738. 2414 [308] H.-Y. Chen, Q. Wang, Q.-H. Xu, L. Yan, X.-F. Gao, Y.-H. Lu, L. Wang, Statin 2415 as a Combined Therapy for Advanced-Stage Ovarian Cancer: A Propensity Score 2416 Matched Analysis, Biomed Res Int. 2016 (2016) 9125238. 2417 https://doi.org/10.1155/2016/9125238. 2418 [309] M. Habis, K. Wroblewski, M. Bradaric, N. Ismail, S.D. Yamada, L. Litchfield, 2419 E. Lengyel, I.L. Romero, Statin therapy is associated with improved survival in 2420 patients with non-serous-papillary epithelial ovarian cancer: a retrospective cohort 2421 analysis, PLoS ONE. 9 (2014) e104521. 2422 https://doi.org/10.1371/journal.pone.0104521. 2423 [310] Y. Wang, F. Ren, Z. Song, P. Chen, S. Liu, L. Ouyang, Statin use and the risk of 2424 ovarian and endometrial cancers: a meta-analysis, BMC Cancer. 19 (2019) 730. 2425 https://doi.org/10.1186/s12885-019-5954-0. 2426 [311] B. Akinwunmi, A.F. Vitonis, L. Titus, K.L. Terry, D.W. Cramer, Statin therapy 2427 and association with ovarian cancer risk in the New England Case Control (NEC) 2428 study, Int. J. Cancer. 144 (2019) 991–1000. https://doi.org/10.1002/ijc.31758. 2429 [312] L. Baandrup, C. Dehlendorff, S. Friis, J.H. Olsen, S.K. Kjær, Statin use and risk 2430 for ovarian cancer: a Danish nationwide case-control study, Br. J. Cancer. 112 2431 (2015) 157–161. https://doi.org/10.1038/bjc.2014.574. 2432 [313] J. Zhang, Q. Li, Y. Wu, D. Wang, L. Xu, Y. Zhang, S. Wang, T. Wang, F. Liu, 2433 M.Y. Zaky, S. Hou, S. Liu, K. Zou, H. Lei, L. Zou, Y. Zhang, H. Liu, Cholesterol 2434 content in cell membrane maintains surface levels of ErbB2 and confers a 2435 therapeutic vulnerability in ErbB2-positive breast cancer, Cell Commun. Signal. 17 2436 (2019) 15. https://doi.org/10.1186/s12964-019-0328-4. 2437 [314] Y. Kong, L. Cheng, F. Mao, Z. Zhang, Y. Zhang, E. Farah, J. Bosler, Y. Bai, N. 2438 Ahmad, S. Kuang, L. Li, X. Liu, Inhibition of cholesterol biosynthesis overcomes 2439 enzalutamide resistance in castration-resistant prostate cancer (CRPC), J. Biol. 2440 Chem. 293 (2018) 14328–14341. https://doi.org/10.1074/jbc.RA118.004442. 2441 [315] A. Bhardwaj, H. Singh, C.M. Trinidad, C.T. Albarracin, K.K. Hunt, I. 2442 Bedrosian, The isomiR-140-3p-regulated mevalonic acid pathway as a potential 2443 target for prevention of triple negative breast cancer, Breast Cancer Res. 20 (2018) 2444 150. https://doi.org/10.1186/s13058-018-1074-z. 73 2445 [316] G.H. McGregor, A.D. Campbell, S.K. Fey, S. Tumanov, D. Sumpton, G.R. 2446 Blanco, G. Mackay, C. Nixon, A. Vazquez, O.J. Sansom, J.J. Kamphorst, Targeting 2447 the Metabolic Response to Statin-Mediated Oxidative Stress Produces a Synergistic 2448 Antitumor Response, Cancer Res. 80 (2020) 175–188. https://doi.org/10.1158/0008- 2449 5472.CAN-19-0644. 2450 [317] R. Peto, J. Emberson, M. Landray, C. Baigent, R. Collins, R. Clare, R. Califf, 2451 Analyses of cancer data from three ezetimibe trials, N. Engl. J. Med. 359 (2008) 2452 1357–1366. https://doi.org/10.1056/NEJMsa0806603. 2453 [318] A. Green, D.R. Ramey, M. Emneus, M. Iachina, K. Stavem, K. Bolin, R. 2454 McNally, M. Busch-Sørensen, R. Willenheimer, K. Egstrup, Y.A. Kesäniemi, S. 2455 Ray, N. Basta, C. Kent, T.R. Pedersen, Incidence of cancer and mortality in patients 2456 from the Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) trial, Am. J. Cardiol. 2457 114 (2014) 1518–1522. https://doi.org/10.1016/j.amjcard.2014.08.016. 2458 [319] K.R. Solomon, K. Pelton, K. Boucher, J. Joo, C. Tully, D. Zurakowski, C.P. 2459 Schaffner, J. Kim, M.R. Freeman, Ezetimibe is an inhibitor of tumor angiogenesis, 2460 Am. J. Pathol. 174 (2009) 1017–1026. https://doi.org/10.2353/ajpath.2009.080551. 2461 [320] M. Lee-Rueckert, J.C. Escola-Gil, P.T. Kovanen, HDL functionality in reverse 2462 cholesterol transport – Challenges in translating data emerging from mouse models 2463 to human disease, Biochim. Biophys. Acta. (2016). 2464 https://doi.org/10.1016/j.bbalip.2016.03.004. 2465 [321] A.A. Momtazi-Borojeni, M.E. Nik, M.R. Jaafari, M. Banach, A. Sahebkar, 2466 Effects of immunization against PCSK9 in an experimental model of breast cancer, 2467 Arch Med Sci. 15 (2019) 570–579. https://doi.org/10.5114/aoms.2019.84734. 2468 [322] R.M. Stoekenbroek, G. Lambert, B. Cariou, G.K. Hovingh, Inhibiting PCSK9 - 2469 biology beyond LDL control, Nat Rev Endocrinol. 15 (2018) 52–62. 2470 https://doi.org/10.1038/s41574-018-0110-5. 2471 [323] A.M. Lincoff, S.J. Nicholls, J.S. Riesmeyer, P.J. Barter, H.B. Brewer, K.A.A. 2472 Fox, C.M. Gibson, C. Granger, V. Menon, G. Montalescot, D. Rader, A.R. Tall, E. 2473 McErlean, K. Wolski, G. Ruotolo, B. Vangerow, G. Weerakkody, S.G. Goodman, 2474 D. Conde, D.K. McGuire, J.C. Nicolau, J.L. Leiva-Pons, Y. Pesant, W. Li, D. 2475 Kandath, S. Kouz, N. Tahirkheli, D. Mason, S.E. Nissen, ACCELERATE 2476 Investigators, Evacetrapib and Cardiovascular Outcomes in High-Risk Vascular 2477 Disease, N. Engl. J. Med. 376 (2017) 1933–1942. 2478 https://doi.org/10.1056/NEJMoa1609581. 2479 [324] G.G. Schwartz, A.G. Olsson, M. Abt, C.M. Ballantyne, P.J. Barter, J. Brumm, 2480 B.R. Chaitman, I.M. Holme, D. Kallend, L.A. Leiter, E. Leitersdorf, J.J.V. 2481 McMurray, H. Mundl, S.J. Nicholls, P.K. Shah, J.-C. Tardif, R.S. Wright, dal- 2482 OUTCOMES Investigators, Effects of dalcetrapib in patients with a recent acute 2483 coronary syndrome, N. Engl. J. Med. 367 (2012) 2089–2099. 2484 https://doi.org/10.1056/NEJMoa1206797. 2485 [325] P.J. Barter, M. Caulfield, M. Eriksson, S.M. Grundy, J.J.P. Kastelein, M. 2486 Komajda, J. Lopez-Sendon, L. Mosca, J.-C. Tardif, D.D. Waters, C.L. Shear, J.H. 2487 Revkin, K.A. Buhr, M.R. Fisher, A.R. Tall, B. Brewer, ILLUMINATE 2488 Investigators, Effects of torcetrapib in patients at high risk for coronary events, N. 2489 Engl. J. Med. 357 (2007) 2109–2122. https://doi.org/10.1056/NEJMoa0706628. 2490 [326] HPS3/TIMI55–REVEAL Collaborative Group, L. Bowman, J.C. Hopewell, F. 2491 Chen, K. Wallendszus, W. Stevens, R. Collins, S.D. Wiviott, C.P. Cannon, E. 2492 Braunwald, E. Sammons, M.J. Landray, Effects of Anacetrapib in Patients with 2493 Atherosclerotic Vascular Disease, N. Engl. J. Med. 377 (2017) 1217–1227. 2494 https://doi.org/10.1056/NEJMoa1706444. 74 2495 [327] A co-operative trial in the primary prevention of ischaemic heart disease using 2496 clofibrate. Report from the Committee of Principal Investigators, Br Heart J. 40 2497 (1978) 1069–1118. https://doi.org/10.1136/hrt.40.10.1069. 2498 [328] T.B. Newman, S.B. Hulley, Carcinogenicity of lipid-lowering drugs, JAMA. 2499 275 (1996) 55–60. 2500 [329] X. Lian, G. Wang, H. Zhou, Z. Zheng, Y. Fu, L. Cai, Anticancer Properties of 2501 Fenofibrate: A Repurposing Use, J Cancer. 9 (2018) 1527–1537. 2502 https://doi.org/10.7150/jca.24488. 2503 [330] S. Bonovas, G.K. Nikolopoulos, P.G. Bagos, Use of fibrates and cancer risk: a 2504 systematic review and meta-analysis of 17 long-term randomized placebo- 2505 controlled trials, PLoS ONE. 7 (2012) e45259. 2506 https://doi.org/10.1371/journal.pone.0045259. 2507 [331] J.H. Olsen, C. Johansen, H.T. Sørensen, J.K. McLaughlin, L. Mellemkjaer, F.H. 2508 Steffensen, J.F. Fraumeni, Lipid-lowering medication and risk of cancer, J Clin 2509 Epidemiol. 52 (1999) 167–169. https://doi.org/10.1016/s0895-4356(98)00147-4. 2510 [332] A. Keech, R.J. Simes, P. Barter, J. Best, R. Scott, M.R. Taskinen, P. Forder, A. 2511 Pillai, T. Davis, P. Glasziou, P. Drury, Y.A. Kesäniemi, D. Sullivan, D. Hunt, P. 2512 Colman, M. d’Emden, M. Whiting, C. Ehnholm, M. Laakso, FIELD study 2513 investigators, Effects of long-term fenofibrate therapy on cardiovascular events in 2514 9795 people with type 2 diabetes mellitus (the FIELD study): randomised controlled 2515 trial, Lancet. 366 (2005) 1849–1861. https://doi.org/10.1016/S0140-6736(05)67667- 2516 2. 2517 [333] V. Gardette, V. Bongard, J. Dallongeville, D. Arveiler, A. Bingham, J.-B. 2518 Ruidavets, P. Amouyel, B. Haas, P. Ducimetière, J. Ferrières, Ten-year all-cause 2519 mortality in presumably healthy subjects on lipid-lowering drugs (from the 2520 Prospective Epidemiological Study of Myocardial Infarction [PRIME] prospective 2521 cohort), Am. J. Cardiol. 103 (2009) 381–386. 2522 https://doi.org/10.1016/j.amjcard.2008.09.092. 2523 [334] L. Tenkanen, M. Mänttäri, P.T. Kovanen, H. Virkkunen, V. Manninen, 2524 Gemfibrozil in the treatment of dyslipidemia: an 18-year mortality follow-up of the 2525 Helsinki Heart Study, Arch. Intern. Med. 166 (2006) 743–748. 2526 https://doi.org/10.1001/archinte.166.7.743. 2527 [335] H.B. Rubins, S.J. Robins, D. Collins, C.L. Fye, J.W. Anderson, M.B. Elam, F.H. 2528 Faas, E. Linares, E.J. Schaefer, G. Schectman, T.J. Wilt, J. Wittes, Gemfibrozil for 2529 the secondary prevention of coronary heart disease in men with low levels of high- 2530 density lipoprotein cholesterol. Veterans Affairs High-Density Lipoprotein 2531 Cholesterol Intervention Trial Study Group, N. Engl. J. Med. 341 (1999) 410–418. 2532 https://doi.org/10.1056/NEJM199908053410604. 2533 [336] J.K. Huttunen, O.P. Heinonen, V. Manninen, P. Koskinen, T. Hakulinen, L. 2534 Teppo, M. Mänttäri, M.H. Frick, The Helsinki Heart Study: an 8.5-year safety and 2535 mortality follow-up, J. Intern. Med. 235 (1994) 31–39. 2536 https://doi.org/10.1111/j.1365-2796.1994.tb01029.x. 2537 [337] Z. Iakobishvili, T. Hasin, R. Klempfner, N. Shlomo, I. Goldenberg, R. Brenner, 2538 R. Kornowski, Y. Gerber, Association of Bezafibrate Treatment With Reduced Risk 2539 of Cancer in Patients With Coronary Artery Disease, Mayo Clin. Proc. 94 (2019) 2540 1171–1179. https://doi.org/10.1016/j.mayocp.2018.10.026. 2541 [338] V.S. Kamanna, M.L. Kashyap, Mechanism of action of niacin, Am. J. Cardiol. 2542 101 (2008) 20B-26B. https://doi.org/10.1016/j.amjcard.2008.02.029. 2543 [339] P.L. Canner, K.G. Berge, N.K. Wenger, J. Stamler, L. Friedman, R.J. Prineas, 2544 W. Friedewald, Fifteen year mortality in Coronary Drug Project patients: long-term 75 2545 benefit with niacin, J. Am. Coll. Cardiol. 8 (1986) 1245–1255. 2546 https://doi.org/10.1016/s0735-1097(86)80293-5. 2547 [340] HPS2-THRIVE Collaborative Group, M.J. Landray, R. Haynes, J.C. Hopewell, 2548 S. Parish, T. Aung, J. Tomson, K. Wallendszus, M. Craig, L. Jiang, R. Collins, J. 2549 Armitage, Effects of extended-release niacin with laropiprant in high-risk patients, 2550 N. Engl. J. Med. 371 (2014) 203–212. https://doi.org/10.1056/NEJMoa1300955. 2551 [341] X. Ma, Q. Song, X. Gao, Reconstituted high-density lipoproteins: novel 2552 biomimetic nanocarriers for drug delivery, Acta Pharm Sin B. 8 (2018) 51–63. 2553 https://doi.org/10.1016/j.apsb.2017.11.006. 2554 2555 76 2556 Figure legends, tables, figures, schemes 2557 Figure 1. Molecular pathways involved in accumulation of unesterified cholesterol 2558 (UC) and its effects on downstream oncogenic signaling pathways. (A) Both LDLR 2559 and SR-BI are upregulated in breast cancer cells, thereby increasing lipoprotein 2560 cholesterol uptake. The UC accumulation activates PI3K/Akt/ERK1/2 signaling 2561 together with its conversion to 27-HC, promoting proliferation and metastasis through 2562 the activation of c-Myc and EMT genes. OLR1 expression is also upregulated in breast 2563 cancer cells and induces tumor growth and migration via NF-kB activation. (B) LDLR 2564 is a main driver of UC accumulation in prostate cancer cells and its conversion into 2565 esterified cholesterol (EC) by ACAT1, thereby promoting cancer progression. The loss 2566 of PTEN activates PI3K/Akt/mTOR signaling, which in turn upregulates SREBP2 and 2567 LDLR. Lethal prostate tumors also present higher levels of SQLE. The AR potentiates 2568 UC accumulation by upregulating DHCR24 and SREBP2 and inhibiting ABCA1 2569 expression. OLR1 expression also induces proliferation and metastasis. (C) LDLR is 2570 upregulated in epithelial thyroid cancer cells promoting an accumulation of UC and its 2571 conversion into 27HC, thereby promoting proliferation and metastasis. ( D) Both LDLR 2572 and OLR1 are upregulated in pancreatic cancer cells along an increased expression of 2573 DHCR24, HMGCR and ACAT1, inducing proliferation and metastasis. Caveolin-1 also 2574 promotes tumor growth and metastasis via NF-kβ. (E) Both LDLR and ACAT1 are 2575 upregulated in ovarian cancer cells concomitant with an increase of UC and EC 2576 accumulation. CYP27A1 is highly expressed in ovarian cancer cells, inducing 27-HC 2577 accumulation and promoting proliferation and invasion. IL-4 signalling is increased in 2578 tumor associated macrophages, which in turn promotes PI3K activity and mTOR- 2579 mediated Akt phosphorylation and stimulates ABCA1-mediated cholesterol efflux, 77 2580 transferring cholesterol to ovarian cancer cells through SR-BI. Common pathways are 2581 indicated with the same color in each cancer cell type. 2582 2583 78 2584 2585 Figure 2. HDL antioxidant and anti-inflammatory components are not altered in patients with 2586 thyroid cancer, but HDL promotes proliferation and migration in anaplastic thyroid cell lines. 2587 (A) APOA1 levels and HDL antioxidant and anti-inflammatory activities in patients’ serum. 2588 Values are means ± SEM of 13 PTC, 5 PDTC, 9 FTC, and 13 adenoma samples. (B) Real-time 2589 PCR quantification of relative mRNA expression of ABCA1, ABCG1, and SCARB1 in human 2590 thyroid tumors. Values are means ± SEM of 9 PTC, 4 PDTC, 10 FTC, and 6 adenoma tissues. 2591 (A and B) ANOVA plus Tukey’s post-test was used to compare the groups. (C) Effects of HDL 2592 on proliferation and migration of thyroid follicular epithelial cells (Nthy-ori-3.1) and anaplastic 2593 thyroid cells (CAL-62). Both were treated 24 h with HDL (at 100 and 200 μg/mL of APOA1) 2594 compared with cells maintained in basal conditions (5% of lipoprotein-depleted serum, LPDS). 2595 Values are means ±SEM. Proliferation assay: the number of replicates in Nthy-ori-3.1 2596 experiment was 38, 35 and 40 for LPDS, 100 μg/mL and 200 μg/mL of HDL, respectively; 37, 2597 38 and 40 for LPDS, 100 μg/mL and 200 μg/mL of HDL, respectively, in CAL62 cells. 2598 Migration assay: the number of replicates in Nthy-ori-3.1 experiment was 26, 13 and 15 for 2599 LPDS, 100 μg/mL and 200 μg/mL of HDL, respectively; 32, 10 and 10 for LPDS, 100 μg/mL 2600 and 200 μg/mL of HDL, respectively, in CAL62 cells. The exogenous administration of HDL 2601 upregulated 1.5 and 2.3 fold SCARB1 in Nthy-ori-3.1 and CAL62 cells, respectively (p=0.0009 2602 and 0.014, respectively, vs LPDS 5%). Kruskal-Wallis test was used to compare the groups. 2603 79 2604 Figure 2 2605 80