REVIEW published: 13 August 2021 doi: 10.3389/fonc.2021.705911 Obesity and Breast Cancer: A Paradoxical and Controversial Relationship Influenced by Menopausal Status Laura Garcı́a-Estévez 1,2*, Javier Cortés 3,4,5, Silvia Pérez 1, Isabel Calvo 1, Isabel Gallegos 1 and Gema Moreno-Bueno 2,6,7* 1 Breast Cancer Department, MD Anderson Cancer Center, Madrid, Spain, 2 Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain, 3 International Breast Cancer Center (IBCC), Barcelona, Spain, 4 Medical Scientia Innovation Research (MedSIR), Barcelona, Spain, 5 Vall d’Hebron Institute of Oncology, Barcelona, Spain, 6 Biochemistry Department, Universidad Autónoma de Madrid (UAM), Instituto de Investigaciones Biomédicas ‘Alberto Sols’ (CSIC-UAM), IdiPaz, & Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain, 7 MD Anderson International Foundation, Madrid, Spain Breast cancer is the most common tumor in women worldwide, and an increasing public health concern. Knowledge of both protective and negative risk factors is essential for a Edited by: Assia Konsoulova, better understanding of this heterogenous disease. We undertook a review of the recent Complex Oncological Center (Burgas), literature and evaluated the relationship between obesity mediators and breast cancer Bulgaria development depending on menopausal status. Excess weight is now pandemic and has Reviewed by: George Nikov Chaldakov, replaced tobacco as the main lifestyle-related risk factor for premature death. Although Medical University of Varna, Bulgaria the prevalence of obesity/overweight has increased globally over the last 50 years, the Antonio Colantuoni, potential harm attributable to excess fat has generally been underestimated. The University of Naples Federico II, Italy relationship between overweight/obesity, breast cancer and overall risk appears to be *Correspondence: Laura Garcı´a-Estévez highly dependent on menopausal status. Thus, obesity increases the risk of breast cancer lgestevez@mdanderson.es in postmenopausal women but, conversely, it appears to be protective in premenopausal Gema Moreno-Bueno gmoreno@iib.uam.es women. We evaluate the role of different clinical factors potentially involved in this seemingly contradictory relationship, including estrogen, mammogram density, Specialty section: adipokines, insulin-signaling pathway activation, and inflammatory status. A key focus This article was submitted to Breast Cancer, of this review is to better understand the impact of body mass index and menopausal a section of the journal status on these clinical factors and, hence, provide some clarity into the inter-relationships Frontiers in Oncology involved in this controversial issue. Received: 06 May 2021 Accepted: 22 July 2021 Keywords: overweight, menopause, estrogen, mammogram, adipocytokine, insulin, obesity Published: 13 August 2021 Citation: Garcı´a-Estévez L, Cortés J, INTRODUCTION Pérez S, Calvo I, Gallegos I and Moreno-Bueno G (2021) Obesity The incidence of obesity has nearly tripled since 1975 and it is now considered one of the worst and Breast Cancer: A Paradoxical and Controversial Relationship pandemics of the 21th century. In 2016, more than 1.9 billion people aged over 18 years were Influenced by Menopausal Status. considered to be overweight, and >650 million were obese; representing 39% and 13% of the adult Front. Oncol. 11:705911. global population, respectively (1). The prevalence of obesity varies widely by country; for example doi: 10.3389/fonc.2021.705911 countries such as Vietnam (2.1%) and Japan (4.4%) reporting low rates compared with 37.3% in the Frontiers in Oncology | www.frontiersin.org 1 August 2021 | Volume 11 | Article 705911 Garcı´a-Estévez et al. Obesity and Breast Cancer United States and the highest rates in Oceania (Nauru, 61%; 1.9- to 4.2-fold increased risk for lower BMI, Cook Islands 55%; and Samoa/Tonga, both 46%) (1, 2). Except for some regions in sub-Saharan Africa and Asia, more people Measure of association are now obese than underweight (1); and projected trends for the next 10 years are disheartening, with an estimated 3.3 billion HR, 1.86; 95% CI, 1.60-2.17a RR: 0.54; 95% CI, 0.34-0.85 RR: 0.98; 95% CI, 0.97-0.99 RR: 0.92; 95% CI, 0.88-0.97 RR: 1.29; 95% CI, 1.22-1.36 RR: 1.12; 95% CI, 1.08-1.16 OR: 0.81; 95%CI, 0.61-1.06 HR: 0.81; 95%CI, 0.68-0.96 HR: 0.74; 95%CI, 0.57-0.96 (58%) of the world adult population predicted to be overweight OR: 1.5; 95% CI, 1.2-1.8a or obese by 2030 (3). Obesity and overweight are generally associated with physical depending on age inactivity and a sedentary lifestyle. A survey of nearly 2 million participants in 2016 revealed that over a quarter (27.5%) of the global adult population failed to get enough physical activity with the highest prevalence (43%) in women, particularly in high- income countries (4). Such figures represent a setback for the global target set by the World Health Organisation (WHO) ≥30 kg vs. <10 kg weight gain BMI >31 kg/m2 vs.≤ 21 kg/m2 BMI ≥35 kg/m2 vs. <25 kg/m2 BMI ≥30 kg/m2 vs. 20.0-22.4 member states to reduce physical inactivity by 10% by 2025. Comparative arms 5 kg/m2 difference in BMI 5 kg/m2 increase in BMI 5 kg/m2 increase in BMI BMI ≥27.5 vs. <20.5* Unit increase in BMI BMI >35 kg/m2 PARADOXICAL EFFECTS OF BODY MASS Obese women INDEX ON BREAST CANCER RISK IN TABLE 1 | Summary of large studies/analyses investigating the association of obesity with breast cancer (BC) according to menopausal status. kg/m2 RELATION TO MENOPAUSAL STATUS Overweight is defined as a body mass index (BMI >25 kg/m2, whereas obesity is categorised as a BMI >30 kg/m2 and is Extended follow-up from the WHI Clinical Trial. [67,142 postmenopausal women] Case-control [2097 premenopausal women, 1900 postmenopausal women, and Pooled analysis [7 cohorts; 337,819 women and 4385 incident cases of invasive Prospective cohort study [1,222,630 women: Premenopausal BC 1179 cases, considered to be a chronic disease (5, 6). The association Population-based study [3345 postmenopausal women and 3455 matched between breast cancer risk and excess weight (overweight/ Meta-analysis [Premenopausal (17 studies); postmenopausal (27 studies)] Meta-analysis [Premenopausal (20 studies); postmenopausal (31 studies)] Meta-analysis [Premenopausal (20 studies); postmenopausal (31 studies)] obese) varies according to menopausal status (Table 1), with independent studies reporting a negative correlation between Pooled analysis [19 cohorts: 758,592 premenopausal women] obesity and risk in premenopausal women (9–11). Indeed, a Studies supporting a positive association between obesity and breast cancer risk in postmenopausal women Studies supporting a negative correlation between obesity and breast cancer risk in premenopausal women pooled analysis of 7 studies including a total of 337,819 women (4,385 of whom had invasive breast cancer) reported a risk ratio (RR) of 0.54 [95% confidence interval (95% CI): 0.34-0.85] for Study type breast cancer risk when comparing premenopausal women with Prospective [113,130 premenopausal women] Prospective [45,799 premenopausal women] BMI >31 kg/m2 versus those with a BMI of ≤21 kg/m2 (7). Likewise, a separate meta-analysis involving 9 studies also demonstrated an inverse correlation between obesity and per postmenopausal BC 5629 cases] unit increase in BMI with regards breast cancer risk in HR, Hazard Ratio; OR, Odds Ratio; RR, Relative Risk; WHI, Women’s Health Initiative. premenopausal women [RR: 0.98; 95% CI: 0.97-0.99] (8). Similar findings were reported in an independent meta- 4041 case controls] analysis consisting of 34 datasets of women (a total of >2.5 million women) in which breast cancer risk was investigated relative to BMI (12). In total, breast cancer was reported in 7,930 controls] premenopausal and 23,909 postmenopausal women and, overall, breast cancer risk was shown to be reduced by approximately 8% BC] per 5 kg/m2 BMI increase in premenopausal women [RR: 0.92; 95% CI: 0.88-0.97; p=0.001]. In contrast, the risk was increased Premenopausal breast Cancer Collaborative in postmenopausal women [RR: 1.12; 95% CI: 1.08-1.16; p<0.0001] (12). This latter meta-analysis undertaken by *Age adjusted; aER-positive patients. Renehan and colleagues (2008) included prospective cohort and large observational studies, and provides a stronger level of evidence than earlier case-control reports. van den Brandt 2000 (7) The largest, most recent study investigating the association of Rosenberg 2006 (14) Neuhouser 2015 (16) Bergstrom 2001 (8) Renehan 2008 (12) Renehan 2008 (12) Berstad 2010 (10) obesity with breast cancer risk came from The Premenopausal Reeves 2007 (15) Group 2018 (13) Michels 2010 (9) Harris 2011 (11) Breast Cancer Collaborative Group (13). This multicenter study Reference used pooled individual-level data from 758,592 premenopausal women aged 18 to 54 years. Median follow-up was 9.3 years, during which time 13,082 cases of breast cancer were reported. Frontiers in Oncology | www.frontiersin.org 2 August 2021 | Volume 11 | Article 705911 Garcı´a-Estévez et al. Obesity and Breast Cancer The analysis revealed a significant 4.2-fold increased risk of imbalances, mammogram density, insulin deregulation pathways breast cancer in underweight women versus women with and chronic inflammation. obesity under 24 years, and a 1.9- to 2.5-fold increased risk in older patients. This led to an estimated 12% to 23% reduction in Difference in Estrogen Levels premenopausal breast cancer risk per 5 kg/m2 increase in BMI, Physiologically, estrogen production decreases during aging, depending on age. Moreover, estrogen-receptor (ER) and/or with the natural consequence that postmenopausal women progesterone-receptor (PR) positive breast cancer was have lower blood levels of estrogenic hormones, such as associated with BMI in all age groups, whereas hormone- estradiol, relative to premenopausal women. Estrogen synthesis receptor negative breast cancer was associated with BMI only in premenopausal women mainly localizes to the ovary, whereas in women aged 18-24 years. In this younger age group, the in postmenopausal women estrogen production shifts to strength of the association between ER- and/or PR-receptor peripheral tissues. In postmenopausal women with obesity the positive breast cancer and BMI (HR, 0.75; 95% CI, 0.70 – 0.81) main source of estrogen biosynthesis is adipose tissue. was much stronger than that for ER- and PR-receptor negative The primary mediator of postmenopausal estrogen breast cancer (HR, 0.85; 95% CI, 0.76 – 0.95). The lack of biosynthesis is aromatase (also known as CYP19A1, association of triple-negative breast cancer with BMI in women Cytochrome P450 Family 19 Subfamily A Member 1), an above 25 years-of-age was contrary to previous reports (17). The enzymatic complex found both in breast adipose and tumor authors considered that the discrepancy possibly reflected tissues (18). Aromatase is responsible for the conversion of differences in study design (case-controls versus prospective androgens produced by the adrenal cortex and the study); the former being more susceptible to potential postmenopausal ovary into estrogens. This can lead to an selection bias. increase in local estrogen levels by up to 10-fold in the Unlike premenopausal women, several studies and large endometrium and myometrium compared with that in breast meta-analyses have demonstrated a consistent, direct tissue (19). Significantly, however, higher concentrations of association between obesity and breast cancer risk in estrogens were found in malignant breast tissue compared with postmenopausal women. The Million Women Study followed non-malignant tissue. 1.2 million UK women (45,037 with breast cancer) aged 50-64 Several meta-analyses of prospective studies have confirmed a years for a mean period of 5.4 years. The study identified an relationship between increased serum estrogen levels and approximate 30% higher risk of breast cancer in postmenopausal postmenopausal breast cancer (20–24). Although women with obesity compared to women who were not obese postmenopausal estradiol levels are lower overall, they have (RR: 1.29; 95% CI: 1.22-1.36) (15). These findings are been shown to be higher in women with obesity compared comparable to those of Renehan and colleagues reported above with non-obese women (21 vs 12 pg/mL; with no overlap in (postmenopausal breast cancer risk was positively associated 95% CI) (25). This contrasts with premenopausal data which with each 5 kg/m2 increase in BMI (RR: 1.12; p <0.0001) (12). found significantly lower estradiol levels (independent of age, The increased risk of breast cancer in postmenopausal women race, and smoking) in women who were obese/overweight with obesity was greater in, and may be limited to, those not compared with women having normal bodyweight [32.8 pg/ receiving menopausal hormone therapy. When factoring in mL (95% CI: 30.6-35.2) vs. 39.8 pg/mL (95% CI: 37.0-42.8); hormone-receptor status, the association between BMI and p<0.001)] (25). Low estradiol levels in women with obesity may postmenopausal breast cancer risk appeared to be restricted to partly result from negative feedback in the hypothalamic- ER-positive cases (14, 16). pituitary axis leading to a reduction in gonadotrophin secretion, and suppression of ovarian function and concomitant amenorrhea (26). Irregular menstruation and fewer ovulatory cycles may also result in a reduction in serum POTENTIAL MECHANISMS THAT COULD estradiol levels and this has been promulgated as contributory to EXPLAIN THE PARADOXICAL the inverse association between obesity and breast cancer risk in RELATIONSHIP BETWEEN OBESITY AND premenopausal women (26). BREAST CANCER Mammogram Density Why obesity is a risk factor for breast cancer in postmenopausal Mammographic breast density (MBD) is defined by the women, but appears to be protective during premenopause is proportion of glandular to fatty tissue and is usually classified clearly an important question. A better understanding of the using a scoring classification proposed by the American College mechanisms involved could provide significant clues to the of Radiology (ACR BI-RADS® Atlas, Breast Imaging Reporting underlying pathophysiology and have clinical implications for and Data System) which describes 4 categories for breast density: breast cancer prevention and treatment. Mapping the precise a). almost entirely fatty; b). scattered fibroglandular tissue; c). cellular and molecular landscape of breast tissue in the context of heterogeneously dense fibroglandular tissue; and d). extremely an evolving physiology has shed light into potential driving dense fibroglandular tissue (27). factors responsible for breast cancer risk and progression; In women undergoing screening for breast cancer a high including the role of serum estrogens, leptin and adiponectin MBD poses two major challenges. Firstly, an elevated MBD may Frontiers in Oncology | www.frontiersin.org 3 August 2021 | Volume 11 | Article 705911 Garcı´a-Estévez et al. Obesity and Breast Cancer mask the presence of tumors within the dense tissue and but it is also responsible for the secretion of a variety of diminish the detection sensitivity of screening mammography; metabolites, hormones, and cytokines, collectively known as and secondly, a high MBD is an independent risk factor for adipokines, and in this regard it can be considered as a breast cancer (28). The magnitude of this association is 4.64-fold complex endocrine organ (34). In humans, >100 greater for the highest versus the lowest density categories. A low adipocytokines have been described to date, including resistin, MBD associates with better breast cancer outcomes and lower leptin, adiponectin, visfatin, hepatocyte growth factor, tumor risk of local recurrence without influencing the risk of metastasis necrosis factor-alpha (TNF-a), heparin-binding epidermal or the mortality rates directly resulting from breast cancer. The growth factor-like growth factor, interleukin-6 (IL-6) (35), and strength of the association between MBD and breast cancer risk nerve growth factor (NGF) and brain-derived neurotrophic is greater than for most other established cancer risk factors, with factor (36). Among these, adiponectin and leptin have received the exception of age and some genetic factors (29). special attention as molecular mediators in the association The precise mechanisms underlying the positive association between obesity and breast cancer (37). between elevated MBD and breast cancer risk remain poorly Adiponectin is a 30 kDa monomer, also known as adipocyte understood. It has been suggested that greater tissue density may complement-related protein (Acrp30), which circulates in the be a consequence of increased epithelial cell concentrations, plasma as low- and high-molecular weight multimers (38). elevated levels of growth factors such as insulin-like growth Plasma concentrations are relatively high for a hormone and are factor-I (IGF-1), stromal fibrosis and/or epithelial hyperplasia; usually within the range 2–20 mg/ml. In women, adiponectin levels all of which represent potential breast cancer risk factors (28). correlate negatively with body weight, BMI, body fat, and serum Another plausible explanation is that there is higher aromatase leptin concentrations (38). Adiponectin has multiple physiological expression in dense breast tissue compared to non-dense breast actions, including modulation of the AMP-activated protein tissue (30). In addition, increased breast tissue density is kinase (AMPK) axis by mechanisms involving liver kinase B1 associated with other well-established risk factors, including gene (LKB1), and mediated via two adiponectin receptors, positive associations with hormonal replacement therapy, AdipoR1 and AdipoR2 (39). Activation of AdipoR1 and nulliparity, older age at first birth, and alcohol intake. Inverse AdipoR2 induces the formation of homodimeric and associations have been linked to age, postmenopausal status and heterodimeric complexes and triggers an AMPK-mediated BMI (30). cascade that regulates cell proliferation, apoptosis, angiogenesis In general, MBD correlates negatively with BMI; i.e., women and cellular metabolism. Activated AMPK monitors cellular who are obese or overweight have lower breast density than ‘AMP: ATP’ (adenosine triphosphate) and adenosine leaner women. The seemingly paradoxical relationship between diphosphate ‘(ADP): ATP’ ratios, offseting ATP consumption obesity, breast density, and breast cancer risk lies in the fact that and maintaining energy homeostasis. AMPK regulates several although adiposity has a positive correlation with absolute non- downstream targets including enzymes involved in the synthesis dense area and is a recognized risk factor for breast cancer, some of fatty acids and triglycerides such as acetyl-CoA carboxylase reports indicate that absolute non-dense area correlates (ACC) and fatty acid synthase (FAS), transcription factors, and negatively with breast cancer risk (31). In this regard, Shieh other regulatory proteins. Adiponectin also exhibits strong insulin et al. reported that elevated MBD was associated with an sensitizing and balancing activity, and reduced adiponectin levels increased risk of ER-negative breast cancer independent of enhance insulin signalling associated with neoplasia. In addition, menopausal status or BMI in premenopausal women (32). AMPK activation negatively regulates mitogen-activated protein Given that elevated breast density and overweight/obesity are kinase (MAPK), phosphatidylinositol 3−kinase (PI3K)/protein both risk factors for ER-negative breast cancer, the authors kinase B (Akt) (PI3K/Akt), WNT-b-catenin, nuclear factor hypothesize that they are likely to interact synergistically to kappa-light-chain-enhancer of activated B cells (NF-kB), and augment the risk of ER-negative malignancy in younger JAK2/STAT3 pathways (40). AMPK-mediated inhibition of women (32). In contrast, the study found no correlation mTOR (mammalian target of rapamycin) signaling results in between percent density and BMI in postmenopausal women. disregulated cell proliferation, inhibition of gluconeogenic gene This result is consistent with the conclusions from the Nurses’ transcription, and induction of enzymes engaged with fatty acid Health study, which reported an association between percent oxidation (41). In breast cancer cells, adiponectin increases serine– density and overall breast cancer in postmenopausal women, threonine liver kinase B1 (LKB1) expression, which can negatively independent of BMI (33). impact cell proliferation, increase apoptosis, decrease aromatase There is a tendency for MBD to decrease with age, while activity, an reduce invasive capacity (42). breast cancer incidence generally increases. This apparent Current data in support of a direct involvement of contradiction fundamentally reflects that “true” breast tissue- adiponectin in breast cancer is controversial. A meta-analysis age possibly results from the cumulative exposure to changing by Gu et al. showed that serum adiponectin levels were lower in patterns of hormone and growth factor secretion and levels over breast cancer patients irrespective of menopausal status; time, rather than absolute age. however, no information on BMI was collected (43). In contrast, two previous meta-analyses identified a significant The Role of Adipocytokines association between adiponectin levels and breast cancer risk Breast tissue is primarily composed of adipose and fibrous tissue, in postmenopausal women (44, 45). The most recent meta- and mammary glands. Adipose tissue acts as an energy reservoir, analysis on this topic by Yoon et al. reported that low Frontiers in Oncology | www.frontiersin.org 4 August 2021 | Volume 11 | Article 705911 Garcı´a-Estévez et al. Obesity and Breast Cancer adinopectin and high leptin levels represent high-risk factors for mobilisation when insulin levels are low (e.g., during breast cancer, particularly in postmenopausal patients (46). fasting) (55). Assessment of the role of serum adiponectin in breast cancer Under certain physiological and pathological conditions, cells highlights a trend linking elevated adiponectin levels with may become less responsive to insulin and they eventually reduced breast cancer risk when a combined analysis involving develop insulin resistance, causing both insulin and serum pre- and postmenopausal women was performed. However, the glucose levels to increase (3). Such outcomes may result from a results appear to be driven mainly by a stronger association in combination of factors. For instance, endoplasmic reticulum the postmenopausal group. Unfortunately, similar studies stress, adiponectin reduction, leptin elevation, adipocyte death, investigating an association between adiponectin levels and macrophage infiltration and lipolysis can all contribute to the BMI in breast cancer are lacking. onset of chronic inflammation in obesity, and this is closely Another adipokine, leptin, also represents a key molecular associated with marked insulin resistance and an increased mediator in the relationship between obesity and breast cancer. likelihood of developing type 2 diabetes and other diseases (56, Leptin is a hormone predominantly produced by adipocytes in 57). A primary event in the transmission of inflammatory signals healthy and malignant tissue and is overexpressed in individuals seems to be a reduction of functional insulin receptors and a who are obese/overweight. Serum levels in humans usually range blockage of insulin signaling pathways, and this has been between 5–50 ng/ml, but in individuals with obesity, hypothesized to lead to insulin resistance (58). Moreover, concentrations can exceed 100 ng/mL (47). obesity may cause adipose tissue dysfunction, including Leptin displays pleiotropic effects and regulates adipose and secretion of abnormal levels of cytokines linked to insulin breast tissue cell proliferation. Upon binding to its receptor ObR, resistance, as well as impaired triglyceride storage and leptin activates JAK2/STAT3, MAPK, and PI3K/Akt signaling increased lipolysis. These abnormalities may in turn contribute pathways to promote cell proliferation, hence acting as a growth- to accumulation of non-esterified fatty acids (NEFAs) in the factor in cancer and involved in regulating tumor development, circulation and an overload of NEFAs by skeletal muscle and growth, and metastasis (48, 49). Leptin is also able to induce liver cells, which are liable to instigate decreased insulin aromatase activity, thus potentiating ER signaling in breast responsiveness in these tissues. Increasing plasma NEFA levels cancer cells, and this may play a role in tumor progression might also contribute to a continuous loss of function of (50). In addition, leptin can activate ObR-expressing pancreatic b-cells, thereby causing inadequate insulin macrophages and stimulate secretion of multiple pro- secretion (59). inflammatory and proangiogenic cytokines such as IL-1, TNF- When assessing type 2 diabetes as a risk factor for breast a, IL-6, IL-11 and nitric oxide to modulate macrophage cancer the results appear to vary according to menopausal status. phenotype (anti-inflammatory M2 and pro-inflammatory M1). For example, a meta-analysis of 20 studies from nine different Some studies have also indicated that leptin and ObR are countries showed a 20% increase in breast cancer risk, overexpressed in primary and metastatic invasive ductal breast independent of BMI, in postmenopausal women with diabetes carcinoma cells, compared with non-cancer mammary compared with individuals who were not diabetic; significance tissue (51). was lost in premenopausal women (56). Likewise, a large Several studies strongly support the hypothesis that serum prospective study by Michels et al. confirmed the positive leptin levels correlate with breast cancer occurrence and tumor relationship between type 2 diabetes and breast cancer risk behavior (52, 53). To better clarify this issue Pan et al. conducted (60). Interestingly, the study also found a negative trend a meta-analysis of 35 case-control and cohort studies (54). Their between the two conditions in premenopausal women. results confirmed an association between leptin levels and breast Additionally, a positive association of plasma insulin and C- cancer risk, and the authors outlined two key conclusions from peptide with postmenopausal breast cancer risk has been this meta-analysis: a strong relationship between breast cancer reported, and this was independent of obesity status (at least in risk and higher leptin levels in patients who were overweight/ some studies) (56). In contrast, the situation in premenopausal obese and, secondly, elevated leptin levels in some but not all the women is unclear. The suggestion that relatively high circulating studies was associated with breast cancer risk in postmenopausal insulin levels may protect against breast cancer risk before the but not in premenopausal women. However, a high degree of menopause is consistent with the apparently protective effect of heterogeneity was observed among the studies included in the diabetes observed by others authors; and it resembles closely the meta-analysis. situation seen in obesity (61). Insulin receptors are usually 6- to 10-fold overexpressed Insulin Signaling Pathway in breast cancer epithelial cells compared to healthy cells Insulin is a peptide hormone synthesised by islet b-cells in the (62). Although primarily involved in the regulation of pancreas in response to elevations of glucose. Insulin regulates carbohydrate, lipid, and protein metabolism, insulin also glucose uptake by muscle and adipose tissue and inhibits acts as a growth factor, stimulating cell mitosis and gluconeogenesis and glucose secretion by the liver. High migration, and inhibiting apoptosis (63). These effects may insulin levels lead to an overload of glucose stores in liver and be potentiated under conditions of insulin resistance and muscle. In addition to glucose homeostasis, insulin facilitates concomitant impairment of insulin-regulated metabolic fatty acid transport, promotes lipogenesis, and inhibits lipolysis, pathways. In general, insulin influences metabolic processes thus contributing to the build-up of energy stores ready for such as glucose transport through the PI3K pathway, whereas Frontiers in Oncology | www.frontiersin.org 5 August 2021 | Volume 11 | Article 705911 Garcı´a-Estévez et al. Obesity and Breast Cancer mitogenic stimuli involve the activation of Ras and the mediators and aromatase (the rate-limiting enzyme for estrogen MAPK pathway. biosynthesis), and this provides a plausible explanation for the paradoxical observation that hormone-dependent tumors are Chronic Inflammation more common during the age-related menopausal transition White adipocyte tissue (WAT) comprises the largest energy when circulating estrogen levels have declined (69). storage and the major endo- and paracrine organ in the human Both adipocytes and macrophages release pro-inflammatory body. WAT consists of a variety of cell types (e.g., white mediators associated with WAT inflammation such as TNF-a, adipocytes, immune cells, fibroblasts and endothelial cells) and IL-1b, IL-6 and COX-2–derived prostaglandin E2, which can these support tissue homeostasis and insulin sensitivity. In upregulate aromatase expression (70). Aromatase is produced by healthy-weight individuals, adipose tissue is well vascularized mesenchymal cells and fibroblasts surrounding lipid-filled and the microenvironment is rich in anti-inflammatory adipocytes, rather than in the adipocytes themselves. cytokines such as IL-4, IL-10 and IL-13. WAT contains a variety Aromatase utilises circulating androgens as a substrate to of type 2 immune cells, including alternatively activated (M2-like) produce estrogens, mainly estradiol, which can diffuse into macrophages, group 2 innate lymphoid cells, type 2 T helper tissues, especially breast adipose tissue where it can enter the (TH2) cells and IL-4-producing eosinophils. Thus, in healthy breast duct and stimulate epithelial cell proliferation (71). WAT individuals the adipose tissue molecular milieu is largely inflammation is also associated with elevated circulating levels of comprised of anti-inflammatory immune cells and cytokines leptin, a well-established inducer of aromatase (72). In addition, (64). Weight gain causes adipocytes to become hypertrophic and breast WAT inflammation is paralleled by increased tissue levels die, and this is a key event in the change to an obese adipose tissue of aromatase (Figure 1) (70). microenvironment which is proinflammatory. Adipocyte death triggers innate immune responses which shift the immune milieu towards a type 1 (pro-inflammatory) state which is associated with DISCUSSION the infiltration of leukocytes, including macrophages, as well as CD8-positive T lymphocytes and mast cells (65). The rupture of The precise mechanisms whereby obesity plays a protective role the cell membrane also facilitates the release of cellular contents against breast cancer in premenopausal women, but represents a [e.g., lipids, cytokines and damage-associated molecular by- risk factor after the menopause remain elusive (Figure 2) (74). products (e.g. fatty acids, ATP, reactive oxygen species, Chronic inflammation clearly influences the physiology of the cholesterol and nucleic acids)] into the microenvironment (66). breast differently depending on menopausal state, suggesting a Free fatty acids (FFAs) stimulate multiple inflammatory signaling relevant role for estrogens and adipokine-driven signaling pathways. pathways, and activation of transcription factor NF-kB a key It seems clear that the combination of oestrogens and obesity mediator in the immune response and adipose inflammation are able to protect against breast cancer, however the mechanism (67). These signals enhance recruitment and accumulation of by which this interaction occurs is yet unknown. Zhao et al. macrophages in situ. Up to 90% of macrophages in the obese conducted a study to address the impact of obesity in the breast adipose tissue microenvironment participate in the development according to menopausal status (75). Random fine needle of adipocyte hypertrophy by encircling the dying adipocyte aspirates (rFNAs) of breast tissue were collected from 57 forming crown-like structures (CLS); a hallmark of premenopausal and 55 postmenopausal healthy women inflammation in adipose tissue (68). Macrophages are the main classified as normal-weight, overweight, and obese. Tissue source of type 1 cytokines (e.g. TNF-a, IFNg, IL-1b and IL-6) as samples were processed and subjected to TaqMan Low Density well as pro-inflammatory immune cells (granulocytes, group 1 Array to determine the expression levels of 21 target genes. The innate lymphoid cells, B cells and CD8+ T cells), which act by study also measured breast tissue estradiol levels by liquid preserving a state of chronic inflammation. chromatography-tandem mass spectrometry and serum Iyengar et al. conducted a study in patients undergoing estradiol and follicle stimulating hormone (FSH) levels using mastectomy, as treatment for (n=211) or to reduce the risk of radioimmunoassay and enzyme-linked immunosorbent assays, (n=26) breast cancer, and evaluated WAT inflammation as respectively. RPS6KB1 (an AMPK responsive gene for protein manifested by CLS-B (crown-like structures in the breast) (69). synthesis and cell growth), estrogen receptor a (encoded by the Overall, breast WAT inflammation was independent of BMI in ESR1 gene) and its target gene GATA3, were significantly postmenopausal women (p=0.008), with CLS-B present in 58/93 downregulated in rFNAs from premenopausal women with (62%) postmenopausal versus 64/144 (44%) premenopausal obesity. By contrast, levels of these biomarkers remained women. Moreover, BMI correlated with CLS-B positivity; unchanged in relation to adiposity in postmenopausal women. specifically, CLS-B was present in 43/48 (90%) obese, 39/73 On the other hand, prostaglandin-endoperoxide synthase 2 (53%) overweight, and 40/116 (34%) healthy-weight (BMI (PTGS2), cyclin D1 (CCND1), and TFF1 (an ESR1 target <25Kg/m 2 ) individuals (p<0.001). The results remained gene) were elevated in rFNAs from postmenopausal women statistically significant in a multivariate model after adjusting for with obesity. These results shed some light into mechanisms age, menopausal status, and use of non-steroidal anti- that potentially explain the different effects of obesity in the inflammatory drugs (NSAIDs) or statins (p<0.001). The authors breast depending on menopausal status, hence contributing to noted that WAT inflammation and the presence of CLS-B is our molecular understanding of breast biology in physiological associated with elevated tissue levels of proinflammatory and pathological situations. Frontiers in Oncology | www.frontiersin.org 6 August 2021 | Volume 11 | Article 705911 Garcı´a-Estévez et al. Obesity and Breast Cancer FIGURE 1 | Plausible relationships between obesity and inflammation in breast cancer. Schematic representation of cellular and molecular events influenced by obesity and inflammation in the context of breast cancer development. Lines with arrowheads indicate activation; with flat ends, inhibition. NF-kB, nuclear factor kappa-light-chain-enhancer of activated B cells; TNFa, tumor necrosis factor alpha; IL, interleukin; PGE2, prostaglandin E2; FFA, free fatty acids; IGF-1, insulin growth factor 1; SHBG, sex hormone binding globulin. Regarding adipokines, there exists a distinct relationship association between adiponectin levels and breast cancer in between leptin/adiponectin and breast cancer in postmenopausal premenopausal women; this suggests a differential role for the women and such an association is far from clear in premenopausal adipokine in breast tissue according to menopausal status (73). women (73). According to Zhao and colleagues results, the protective role of obesity in premenopausal women could be favoured by activation of the AMPK signaling pathway and CONCLUSIONS concomitant inhibition of proliferative stimuli via mTOR (75). Adiponectin may trigger activation of AMPK, which would Obesity can have a marked impact in women since it is explain the presence of high adiponectin levels in healthy, associated with an increased risk for many chronic conditions premenopausal women with obesity, but low levels in those with such as diabetes and heart disease, as well as it increases the risk breast cancer. In relation to these observations, our group has of malignancies such as breast cancer. Whilst most evidence initiated a prospective study in premenopausal women with and suggests an inverse relationship between obesity and breast without breast cancer with a BMI of >25 kg/m2 (MDA-ADI-2020- cancer risk during premenopause, no clinical strategy could 01). The aim is to evaluate the blood levels of leptin and contemplate weight-gain as a therapeutic approach taking into adiponectin between these two groups and to confirm the consideration the complications associated with excess fat and previously mentioned hypothesis: obese or overweight the risk of perpetuating a state of overweight through premenopausal women without breast cancer would have high menopausal transition and into the menopause itself. The levels of adiponectin and low levels of leptin despite a high BMI. metabolic and cardiovascular risks associated with excessive By contrast, women with a high BMI and breast cancer would weight would undoubtedly exceed any benefits achieved for have high leptin levels and low adiponectin levels. If this breast cancer. Of greater importance is to research and fully hypothesis is confirmed, levels of adipokine and oestrogen in the understand the complex interplay between the various metabolic blood could help in the prevention of breast cancer in and hormonal factors involved, since this could potentially help premenopausal women. define possible alternative treatment strategies. In an obese In contrast to this hypothesis is the case-control study by environment, the relationship between estrogens and Tworoger et al. showing a positive although non-significant adipokines and the activation of specific signaling pathways Frontiers in Oncology | www.frontiersin.org 7 August 2021 | Volume 11 | Article 705911 Garcı´a-Estévez et al. Obesity and Breast Cancer FIGURE 2 | The controversial effects of obesity according to menopausal status. Some interactions have been confirmed while others have been hypothesized. MBD, Mammogram breast density; NR, Not clearly reported. *The effect of insulin in breast cancer risk could be independent of BMI (73). clearly differs between menopausal stages, and this is an area All authors contributed to the article and approved the where future research can help determine the molecular/ submitted version. biochemical processes involved. Ultimately, a better knowledge of how obesity and adipose tissue inflammation interact with female sex hormones, and how these changes affect the FUNDING pathogenesis of breast cancer, should enable us to develop new therapeutic strategies to reduce breast cancer risk and improve This research did not receive any specific grant from funding patient outcomes in individuals who are obese. agencies in the public, commercial, or not-for-profit sectors. ACKNOWLEDGMENTS AUTHOR CONTRIBUTIONS We would like to thank Dr Steve Clissold for an English language LG-E and GM-B designed and wrote the manuscript. All check of the manuscript. Editorial assistance was provided by authors provided editorial support and read the manuscript. Content Ed Net (Madrid, Spain). 5. Collaboration PS. Body-Mass Index and Cause-Specific Mortality in 900 REFERENCES 000 Adults: Collaborative Analyses of 57 Prospective Studies. Lancet (2009), 1. World Health Organization. Obesity and Overweight. Available at: http:// 373(9669):1083–96. doi: 10.1016/S0140-6736(09)60318-4 www.who.int/news-room/fact-sheets/detail/ (Accessed January 2021). 6. Bray GA, Kim KK, Wilding JPH, World Obesity F. Obesity: A Chronic 2. OECD. Obesity Update. (2017). Available at: https://www.oecd.org/els/ Relapsing Progressive Disease Process. A Position Statement of the World health-systems/Obesity-Update-2017.pdf (Accessed January 2021). Obesity Federation. Obes Rev (2017) 18(7):715–23. doi: 10.1111/obr.12551 3. Finkelstein EA, Khavjou OA, Thompson H, Trogdon JG, Pan L, Sherry B, 7. van den Brandt PA, Spiegelman D, Yaun SS, Adami HO, Beeson L, Folsom et al. Obesity and Severe Obesity Forecasts Through 2030. Am J Prev Med AR, et al. Pooled Analysis of Prospective Cohort Studies on Height, Weight, (2012) 42(6):563–70. doi: 10.1016/j.amepre.2011.10.026 and Breast Cancer Risk. Am J Epidemiol (2000) 152(6):514–27. doi: 10.1093/ 4. Guthold R, Stevens GA, Riley LM, Bull FC. Worldwide Trends in Insufficient aje/152.6.514 Physical Activity From 2001 to 2016: A Pooled Analysis of 358 Population- 8. Bergstrom A, Pisani P, Tenet V, Wolk A, Adami HO. Overweight as an Based Surveys With 1.9 Million Participants. Lancet Glob Health (2018) 6(10): Avoidable Cause of Cancer in Europe. Int J Cancer (2001) 91(3):421–30. doi: e1077–86. doi: 10.1016/S2214-109X(18)30357-7 10.1002/1097-0215(200002)9999:9999<::AID-IJC1053>3.0.CO;2-T Frontiers in Oncology | www.frontiersin.org 8 August 2021 | Volume 11 | Article 705911 Garcı´a-Estévez et al. Obesity and Breast Cancer 9. Michels KB, Terry KL, Willett WC. Longitudinal Study on the Role of Body 29. McCormack VA, dos Santos Silva I. Breast Density and Parenchymal Patterns Size in Premenopausal Breast Cancer. Arch Intern Med (2006) 166(21):2395– as Markers of Breast Cancer Risk: A Meta-Analysis. Cancer Epidemiol 402. doi: 10.1001/archinte.166.21.2395 Biomarkers Prev (2006) 15(6):1159–69. doi: 10.1158/1055-9965.EPI-06-0034 10. Berstad P, Coates RJ, Bernstein L, Folger SG, Malone KE, Marchbanks PA, 30. Vachon CM, Sasano H, Ghosh K, Brandt KR, Watson DA, Reynolds C, et al. et al. A Case-Control Study of Body Mass Index and Breast Cancer Risk in Aromatase Immunoreactivity Is Increased in Mammographically Dense White and African-American Women. Cancer Epidemiol Biomarkers Prev Regions of the Breast. Breast Cancer Res Treat (2011) 125(1):243–52. doi: (2010) 19(6):1532–44. doi: 10.1158/1055-9965.EPI-10-0025 10.1007/s10549-010-0944-6 11. Harris HR, Willett WC, Terry KL, Michels KB. Body Fat Distribution and Risk 31. Pettersson A, Graff RE, Ursin G, Santos Silva ID, McCormack V, Baglietto L, of Premenopausal Breast Cancer in the Nurses’ Health Study II. J Natl Cancer et al. Mammographic Density Phenotypes and Risk of Breast Cancer: A Meta- Inst (2011) 103(3):273–8. doi: 10.1093/jnci/djq500 Analysis. J Natl Cancer Inst (2014) 106(5). doi: 10.1093/jnci/dju078 12. Renehan AG, Tyson M, Egger M, Heller RF, Zwahlen M. Body-Mass Index 32. Shieh Y, Scott CG, Jensen MR, Norman AD, Bertrand KA, Pankratz VS, et al. and Incidence of Cancer: A Systematic Review and Meta-Analysis of Body Mass Index, Mammographic Density, and Breast Cancer Risk by Prospective Observational Studies. Lancet (2008) 371(9612):569–78. doi: Estrogen Receptor Subtype. Breast Cancer Res (2019) 21(1):48. doi: 10.1186/ 10.1016/S0140-6736(08)60269-X s13058-019-1129-9 13. Group PBCC, Schoemaker MJ, Nichols HB, Wright LB, Brook MN, Jones ME, 33. Yaghjyan L, Colditz GA, Rosner B, Tamimi RM. Mammographic Breast et al. Association of Body Mass Index and Age With Subsequent Breast Density and Breast Cancer Risk: Interactions of Percent Density, Absolute Cancer Risk in Premenopausal Women. JAMA Oncol (2018) 4(11):e181771. Dense, and Non-Dense Areas With Breast Cancer Risk Factors. Breast Cancer doi: 10.1001/jamaoncol.2018.1771 Res Treat (2015) 150(1):181–9. doi: 10.1007/s10549-015-3286-6 14. Rosenberg LU, Einarsdottir K, Friman EI, Wedré n S, Dickman PW, Hall P, 34. Chaldakov GN, Stankulov IS, Hristova M, Ghenev PI. Adipobiology of et al. Risk Factors for Hormone Receptor-Defined Breast Cancer in Disease: Adipokines and Adipokine-Targeted Pharmacology. Curr Pharm Postmenopausal Women. Cancer Epidemiol Biomarkers Prev (2006) 15 Des (2003) 9(12):1023–31. doi: 10.2174/1381612033455152 (12):2482–8. doi: 10.1158/1055-9965.EPI-06-0489 35. Cao H. Adipocytokines in Obesity and Metabolic Disease. J Endocrinol (2014) 15. Reeves GK, Pirie K, Beral V, Green J, Spencer E, Bull D, et al. Cancer Incidence 220(2):T47–59. doi: 10.1530/JOE-13-0339 and Mortality in Relation to Body Mass Index in the Million Women Study: 36. Sornelli F, Fiore M, Chaldakov GN, Aloe L. Adipose Tissue-Derived Nerve Cohort Study. BMJ (2007) 335(7630):1134. doi: 10.1136/bmj.39367.495995.AE Growth Factor and Brain-Derived Neurotrophic Factor: Results From 16. Neuhouser ML, Aragaki AK, Prentice RL, Manson JE, Chlebowski R, Carty CL, Experimental Stress and Diabetes. Gen Physiol Biophys (2009) 28:179–83. et al. Overweight, Obesity, and Postmenopausal Invasive Breast Cancer Risk: A 37. Adriaenssens E, Vanhecke E, Saule P, Mougel A, Page A, Romon R, et al. Secondary Analysis of the Women’s Health Initiative Randomized Clinical Trials. Nerve Growth Factor Is a Potential Therapeutic Target in Breast Cancer. JAMA Oncol (2015) 1(5):611–21. doi: 10.1001/jamaoncol.2015.1546 Cancer Res (2008) 68(2):346–51. doi: 10.1158/0008-5472.CAN-07-1183 17. Pierobon M, Frankenfeld CL. Obesity as a Risk Factor for Triple-Negative 38. Ryan AS, Berman DM, Nicklas BJ, Sinha M, Gingerich RL, Meneilly GS, et al. Breast Cancers: A Systematic Review and Meta-Analysis. Breast Cancer Res Plasma Adiponectin and Leptin Levels, Body Composition, and Glucose Treat (2013) 137(1):307–14. doi: 10.1007/s10549-012-2339-3 Utilization in Adult Women With Wide Ranges of Age and Obesity. 18. Miller WR. Aromatase and the Breast: Regulation and Clinical Aspects. Diabetes Care (2003) 26(8):2383–8. doi: 10.2337/diacare.26.8.2383 Maturitas (2006) 54(4):335–41. doi: 10.1016/j.maturitas.2006.04.020 39. Yamauchi T, Kamon J, Ito Y, Tsuchida A, Yokomizo T, Kita S, et al. Cloning 19. van Landeghem AA, Poortman J, Nabuurs M, Thijssen JH. Endogenous of Adiponectin Receptors That Mediate Antidiabetic Metabolic Effects. Concentration and Subcellular Distribution of Estrogens in Normal and Nature (2003) 423(6941):762–9. doi: 10.1038/nature01705 Malignant Human Breast Tissue. Cancer Res (1985) 45(6):2900–6. 40. Kim KY, Baek A, Hwang JE, Choi YA, Jeong J, Lee MS, et al. Adiponectin- 20. Thomas HV, Reeves GK, Key TJ. Endogenous Estrogen and Postmenopausal Activated AMPK Stimulates Dephosphorylation of AKT Through Protein Breast Cancer: A Quantitative Review. Cancer Causes Control (1997) 8 Phosphatase 2A Activation. Cancer Res (2009) 69(9):4018–26. doi: 10.1158/ (6):922–8. doi: 10.1023/A:1018476631561 0008-5472.CAN-08-2641 21. Key T, Appleby P, Barnes I, Reeves G, Endogenous H. Breast Cancer 41. Long YC, Zierath JR. AMP-Activated Protein Kinase Signaling in Metabolic Collaborative G: Endogenous Sex Hormones and Breast Cancer in Regulation. J Clin Invest (2006) 116(7):1776–83. doi: 10.1172/JCI29044 Postmenopausal Women: Reanalysis of Nine Prospective Studies. J Natl 42. Taliaferro-Smith L, Nagalingam A, Zhong D, Zhou W, Saxena NK, Sharma D. Cancer Inst (2002) 94(8):606–16. doi: 10.1093/jnci/94.8.606 LKB1 is Required for Adiponectin-Mediated Modulation of AMPK-S6K Axis 22. Missmer SA, Eliassen AH, Barbieri RL, Hankinson SE. Endogenous Estrogen, and Inhibition of Migration and Invasion of Breast Cancer Cells. Oncogene Androgen, and Progesterone Concentrations and Breast Cancer Risk Among (2009) 28(29):2621–33. doi: 10.1038/onc.2009.129 Postmenopausal Women. J Natl Cancer Inst (2004) 96(24):1856–65. doi: 43. Gu L, Cao C, Fu J, Li Q, Li DH, Chen MY. Serum Adiponectin in Breast 10.1093/jnci/djh336 Cancer: A Meta-Analysis. Med (Baltimore) (2018) 97(29):e11433. doi: 23. Kaaks R, Rinaldi S, Key TJ, Berrino F, Peeters PH, Biessy C, et al. 10.1097/MD.0000000000011433 Postmenopausal Serum Androgens, Oestrogens and Breast Cancer Risk: 44. Liu LY, Wang M, Ma ZB, Yu LX, Zhang Q, Gao DZ, et al. The Role of The European Prospective Investigation Into Cancer and Nutrition. Endocr Adiponectin in Breast Cancer: A Meta-Analysis. PloS One (2013) 8(8):e73183. Relat Cancer (2005) 12(4):1071–82. doi: 10.1677/erc.1.01038 doi: 10.1371/journal.pone.0073183 24. Hankinson SE, Willett WC, Manson JE, Colditz GA, Hunter DJ, Spiegelman 45. Ye J, Jia J, Dong S, Zhang C, Yu S, Li L, et al. Circulating Adiponectin Levels D, et al. Plasma Sex Steroid Hormone Levels and Risk of Breast Cancer in and the Risk of Breast Cancer: A Meta-Analysis. Eur J Cancer Prev (2014) 23 Postmenopausal Women. J Natl Cancer Inst (1998) 90(17):1292–9. doi: (3):158–65. doi: 10.1097/CEJ.0b013e328364f293 10.1093/jnci/90.17.1292 46. Yoon YS, Kwon AR, Lee YK, Oh SW. Circulating Adipokines and Risk of 25. Freeman EW, Sammel MD, Lin H, Gracia CR. Obesity and Reproductive Obesity Related Cancers: A Systematic Review and Meta-Analysis. Obes Res Hormone Levels in the Transition to Menopause. Menopause (2010) 17 Clin Pract (2019) 13(4):329–39. doi: 10.1016/j.orcp.2019.03.006 (4):718–26. doi: 10.1097/gme.0b013e3181cec85d 47. Oksanen L, Ohman M, Heiman M, Kainulainen K, Kaprio J, Mustajoki P, 26. Dowsett M, Folkerd E. Reduced Progesterone Levels Explain the Reduced Risk et al. Markers for the Gene Ob and Serum Leptin Levels in Human of Breast Cancer in Obese Premenopausal Women: A New Hypothesis. Breast Morbid Obesity. Hum Genet (1997) 99(5):559–64. doi: 10.1007/ Cancer Res Treat (2015) 149(1):1–4. doi: 10.1007/s10549-014-3211-4 s004390050406 27. D’Orsi CJ, Sickles EA, Mendelson EB, Morris EA. ACR BI-RADS Atlas: Breast 48. Tartaglia LA, Dembski M, Weng X, Deng N, Culpepper J, Devos R, et al. Imaging Re-Porting and Data System. Reston, VA, USA: American College of Identification and Expression Cloning of a Leptin Receptor, OB-R. Cell (1995) Radiology (2013). 83(7):1263–71. doi: 10.1016/0092-8674(95)90151-5 28. Boyd NF, Martin LJ, Yaffe MJ, Minkin S. Mammographic Density and Breast 49. Barone I, Giordano C, Bonofiglio D, Ando S, Catalano S. Leptin, Obesity and Cancer Risk: Current Understanding and Future Prospects. Breast Cancer Res Breast Cancer: Progress to Understanding the Molecular Connections. Curr (2011) 13(6):223. doi: 10.1186/bcr2942 Opin Pharmacol (2016) 31:83–9. doi: 10.1016/j.coph.2016.10.003 Frontiers in Oncology | www.frontiersin.org 9 August 2021 | Volume 11 | Article 705911 Garcı´a-Estévez et al. Obesity and Breast Cancer 50. Catalano S, Marsico S, Giordano C, Mauro L, Rizza P, Panno ML, et al. Leptin 66. Wen H, Gris D, Lei Y, Jha S, Zhang L, Huang MT, et al. Fatty Acid-Induced Enhances, via AP-1, Expression of Aromatase in the MCF-7 Cell Line. J Biol NLRP3-ASC Inflammasome Activation Interferes With Insulin Signaling. Nat Chem (2003) 278(31):28668–76. doi: 10.1074/jbc.M301695200 Immunol (2011) 12(5):408–15. doi: 10.1038/ni.2022 51. Garofalo C, Koda M, Cascio S, Sulkowska M, Kanczuga-Koda L, Golaszewska 67. Hotamisligil GS. Endoplasmic Reticulum Stress and the Inflammatory Basis of J, et al. Increased Expression of Leptin and the Leptin Receptor as a Marker of Metabolic Disease. Cell (2010) 140(6):900–17. doi: 10.1016/j.cell.2010.02.034 Breast Cancer Progression: Possible Role of Obesity-Related Stimuli. Clin 68. Cinti S, Mitchell G, Barbatelli G, Murano I, Ceresi E, Faloia E, et al. Adipocyte Cancer Res (2006) 12(5):1447–53. doi: 10.1158/1078-0432.CCR-05-1913 Death Defines Macrophage Localization and Function in Adipose Tissue of 52. Niu J, Jiang L, Guo W, Shao L, Liu Y, Wang L. The Association Between Obese Mice and Humans. J Lipid Res (2005) 46(11):2347–55. doi: 10.1194/ Leptin Level and Breast Cancer: A Meta-Analysis. PloS One (2013) 8(6): jlr.M500294-JLR200 e67349. doi: 10.1371/journal.pone.0067349 69. Iyengar NM, Morris PG, Zhou XK, Gucalp A, Giri D, Harbus MD, et al. 53. Rodrigo C, Tennekoon KH, Karunanayake EH, De Silva K, Amarasinghe I, Menopause Is a Determinant of Breast Adipose Inflammation. Cancer Wijayasiri A. Circulating Leptin, Soluble Leptin Receptor, Free Leptin Index, Prev Res (Phila) (2015) 8(5):349–58. doi: 10.1158/1940-6207.CAPR-14- Visfatin and Selected Leptin and Leptin Receptor Gene Polymorphisms in 0243 Sporadic Breast Cancer. Endocr J (2017) 64(4):393–401. doi: 10.1507/ 70. Subbaramaiah K, Morris PG, Zhou XK, Morrow M, Du B, Giri D, et al. endocrj.EJ16-0448 Increased Levels of COX-2 and Prostaglandin E2 Contribute to Elevated 54. Pan H, Deng LL, Cui JQ, Shi L, Yang YC, Luo JH, et al. Association Between Aromatase Expression in Inflamed Breast Tissue of Obese Women. Cancer Serum Leptin Levels and Breast Cancer Risk: An Updated Systematic Review Discov (2012) 2(4):356–65. doi: 10.1158/2159-8290.CD-11-0241 and Meta-Analysis. Med (Baltimore) (2018) 97(27):e11345. doi: 10.1097/ 71. Simpson ER, Brown KA. Obesity and Breast Cancer: Role of Inflammation MD.0000000000011345 and Aromatase. J Mol Endocrinol (2013) 51(3):T51–9. doi: 10.1530/JME-13- 55. Haeusler RA, McGraw TE, Accili D. Biochemical and Cellular Properties of 0217 Insulin Receptor Signalling. Nat Rev Mol Cell Biol (2018) 19(1):31–44. doi: 72. Brown KA, Simpson ER. Obesity and Breast Cancer: Progress to 10.1038/nrm.2017.89 Understanding the Relationship. Cancer Res (2010) 70(1):4–7. doi: 10.1158/ 56. Larsson SC, Mantzoros CS, Wolk A. Diabetes Mellitus and Risk of Breast 0008-5472.CAN-09-2257 Cancer: A Meta-Analysis. Int J Cancer (2007) 121(4):856–62. doi: 10.1002/ 73. Tworoger SS, Eliassen AH, Kelesidis T, Colditz GA, Willett WC, Mantzoros ijc.22717 CS, et al. Plasma Adiponectin Concentrations and Risk of Incident Breast 57. Ye J, McGuinness OP. Inflammation During Obesity is Not All Bad: Evidence Cancer. J Clin Endocrinol Metab (2007) 92(4):1510–6. doi: 10.1210/jc.2006- From Animal and Human Studies. Am J Physiol Endocrinol Metab (2013) 304 1975 (5):E466–77. doi: 10.1152/ajpendo.00266.2012 74. Vona-Davis L, Rose DP. Type 2 Diabetes and Obesity Metabolic Interactions: 58. Rehman K, Akash MS. Mechanisms of Inflammatory Responses and Common Factors for Breast Cancer Risk and Novel Approaches to Prevention Development of Insulin Resistance: How Are They Interlinked? J BioMed and Therapy. Curr Diabetes Rev (2012) 8(2):116–30. doi: 10.2174/ Sci (2016) 23(1):87. doi: 10.1186/s12929-016-0303-y 157339912799424519 59. Kahn SE, Hull RL, Utzschneider KM. Mechanisms Linking Obesity to Insulin 75. Zhao H, Wang J, Fang D, Lee O, Chatterton RT, Stearns V, et al. Adiposity Resistance and Type 2 Diabetes. Nature (2006) 444(7121):840–6. doi: 10.1038/ Results in Metabolic and Inflammation Differences in Premenopausal and nature05482 Postmenopausal Women Consistent With the Difference in Breast Cancer 60. Michels KB, Solomon CG, Hu FB, Rosner BA, Hankinson SE, Colditz GA, Risk. Horm Cancer (2018) 9(4):229–39. doi: 10.1007/s12672-018-0329-6 et al. Nurses’ Healths: Type 2 Diabetes and Subsequent Incidence of Breast Cancer in the Nurses’ Health Study. Diabetes Care (2003) 26(6):1752–8. doi: Conflict of Interest: The authors declare that the research was conducted in the 10.2337/diacare.26.6.1752 absence of any commercial or financial relationships that could be construed as a 61. Baron JA, Weiderpass E, Newcomb PA, Ho GY, Going SB, Beebe-Dimmer J, potential conflict of interest. et al. Metabolic Disorders and Breast Cancer Risk (United States). Cancer Causes Control (2001) 12(10):875–80. doi: 10.1023/A:1013796112348 Publisher’s Note: All claims expressed in this article are solely those of the authors 62. Papa V, Costantino A, Belfiore A. Insulin Receptor What Role in Breast and do not necessarily represent those of their affiliated organizations, or those of Cancer? Trends Endocrinol Metab (1997) 8(8):306–12. doi: 10.1016/S1043- the publisher, the editors and the reviewers. Any product that may be evaluated in 2760(97)00114-8 this article, or claim that may be made by its manufacturer, is not guaranteed or 63. Mauro L, Naimo GD, Ricchio E, Panno ML, Ando S. Cross-Talk Between endorsed by the publisher. Adiponectin and IGF-IR in Breast Cancer. Front Oncol (2015) 5:157. doi: 10.3389/fonc.2015.00157 ́ Copyright © 2021 Garcıa-Este v́ ez, Corteś , Peŕ ez, Calvo, Gallegos and Moreno-Bueno. 64. Quail DF, Dannenberg AJ. The Obese Adipose Tissue Microenvironment in This is an open-access article distributed under the terms of the Creative Commons Cancer Development and Progression. Nat Rev Endocrinol (2019) 15(3):139– Attribution License (CC BY). The use, distribution or reproduction in other forums is 54. doi: 10.1038/s41574-018-0126-x permitted, provided the original author(s) and the copyright owner(s) are credited and 65. Howe LR, Subbaramaiah K, Hudis CA, Dannenberg AJ. Molecular Pathways: that the original publication in this journal is cited, in accordance with accepted Adipose Inflammation as a Mediator of Obesity-Associated Cancer. Clin academic practice. 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