Germline BRCA1 mutation reprograms breast epithelial cell metabolism towards mitochondrial-dependent biosynthesis : evidence for metformin-based "starvation" strategies in BRCA1 carriers
Cuyàs, Elisabet (Institut d'Investigació Biomèdica de Girona)
Fernández-Arroyo, Salvador (Hospital Universitari Sant Joan de Reus (Tarragona))
Alarcón Cor, Tomás (Universitat Autònoma de Barcelona. Departament de Matemàtiques)
Joven, Jorge (Hospital Universitari Sant Joan de Reus (Tarragona))
Menendez, Javier A. (Institut d'Investigació Biomèdica de Girona)

Date:	2016
Abstract:	We hypothesized that women inheriting one germline mutation of the BRCA1 gene ("one-hit") undergo cell-type-specific metabolic reprogramming that supports the high biosynthetic requirements of breast epithelial cells to progress to a fully malignant phenotype. Targeted metabolomic analysis was performed in isogenic pairs of nontumorigenic human breast epithelial cells in which the knock-in of 185delAG mutation in a single BRCA1 allele leads to genomic instability. Mutant BRCA1 one-hit epithelial cells displayed constitutively enhanced activation of biosynthetic nodes within mitochondria. This metabolic rewiring involved the increased incorporation of glutamine- and glucose-dependent carbon into tricarboxylic acid (TCA) cycle metabolite pools to ultimately generate elevated levels of acetyl-CoA and malonyl-CoA, the major building blocks for lipid biosynthesis. The significant increase of branched-chain amino acids (BCAAs) including the anabolic trigger leucine, which can not only promote protein translation via mTOR but also feed into the TCA cycle via succinyl-CoA, further underscored the anabolic reprogramming of BRCA1 haploinsufficient cells. The anti-diabetic biguanide metformin "reversed" the metabolomic signature and anabolic phenotype of BRCA1 one-hit cells by shutting down mitochondria-driven generation of precursors for lipogenic pathways and reducing the BCAA pool for protein synthesis and TCA fueling. Metformin-induced restriction of mitochondrial biosynthetic capacity was sufficient to impair the tumor-initiating capacity of BRCA1 one-hit cells in mammosphere assays. Metabolic rewiring of the breast epithelium towards increased anabolism might constitute an unanticipated and inherited form of metabolic reprogramming linked to increased risk of oncogenesis in women bearing pathogenic germline BRCA1 mutations. The ability of metformin to constrain the production of mitochondrial-dependent biosynthetic intermediates might open a new avenue for "starvation" chemopreventive strategies in BRCA1 carriers.
Grants:	Ministerio de Ciencia e Innovación SAF2012-38914 Instituto de Salud Carlos III PI15-00285 Agència de Gestió d'Ajuts Universitaris i de Recerca 2014 SGR1227 Agència de Gestió d'Ajuts Universitaris i de Recerca 2014 SGR229
Note:	Altres ajuts: This work was supported by grants from the European Regional Development Fund [FEDER] to JJ and Grant CD12/00672 to SFA), co-founded by theand Departament d'Economia I Coneixement, Catalonia, Spain.
Note:	Altres ajuts: MSCBS/CD15-00033
Rights:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Language:	Anglès
Document:	Article ; recerca ; Versió publicada
Subject:	BRCA1 ; Hereditary breast cancer ; Breast cancer susceptibility ; Bioenergetics ; Glutamine
Published in:	Oncotarget, Vol. 7 (may 2016) , p. 52974-52992, ISSN 1949-2553

DOI: 10.18632/oncotarget.9732
PMID: 27259235

19 p, 13.4 MB

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