Oncotarget

Research Papers:

Germline BRCA1 mutation reprograms breast epithelial cell metabolism towards mitochondrial-dependent biosynthesis: evidence for metformin-based “starvation” strategies in BRCA1 carriers

Elisabet Cuyàs, Salvador Fernández-Arroyo, Tomás Alarcón, Ruth Lupu, Jorge Joven and Javier A. Menendez _

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Oncotarget. 2016; 7:52974-52992. https://doi.org/10.18632/oncotarget.9732

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Abstract

Elisabet Cuyàs1,2,*, Salvador Fernández-Arroyo3,*, Tomás Alarcón4,5,6,7, Ruth Lupu8,9, Jorge Joven3, Javier A. Menendez1,2

1ProCURE (Program Against Cancer Therapeutic Resistance), Metabolism and Cancer Group, Catalan Institute of Oncology, Girona, Catalonia, Spain

2Molecular Oncology Group, Girona Biomedical Research Institute (IDIBGI), Girona, Catalonia, Spain

3Unitat de Recerca Biomèdica, Hospital Universitari de Sant Joan, IISPV, Universitat Rovira i Virgili, Campus of International Excellence Southern Catalonia, Reus, Spain

4Institució Catalana d'Estudis i Recerca Avançats (ICREA), Barcelona, Spain

5Computational and Mathematical Biology Research Group, Centre de Recerca Matemàtic (CRM), Barcelona, Spain

6Departament de Matemàtiques, Universitat Autònoma de Barcelona, Barcelona, Spain

7Barcelona Graduate School of Mathematics (BGSMath), Barcelona, Spain

8Mayo Clinic, Department of Laboratory Medicine and Pathology, Division of Experimental Pathology, Rochester, MN, USA

9Mayo Clinic Cancer Center, Rochester, MN, USA

*These authors contributed equally to this work

Correspondence to:

Javier A. Menendez, email: jmenendez@iconcologia.net, jmenendez@idibgi.org

Keywords: BRCA1, hereditary breast cancer, breast cancer susceptibility, bioenergetics, glutamine

Received: January 22, 2016     Accepted: May 12, 2016     Published: May 31, 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.


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