Germline BRCA1 mutation reprograms breast epithelial cell metabolism towards mitochondrial-dependent biosynthesis: evidence for metformin-based "starvation" strategies in BRCA1 carriers.
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.
ProCURE (Program Against Cancer Therapeutic Resistance), Metabolism and Cancer Group, Catalan Institute of Oncology, Girona, Catalonia, Spain.|Molecular Oncology Group, Girona Biomedical Research Institute (IDIBGI), Girona, Catalonia, Spain.
Elisabet
E
Cuyàs
Unitat de Recerca Biomèdica, Hospital Universitari de Sant Joan, IISPV, Universitat Rovira i Virgili, Campus of International Excellence Southern Catalonia, Reus, Spain.
Salvador
S
Fernández-Arroyo
Institució Catalana d'Estudis i Recerca Avançats (ICREA), Barcelona, Spain.|Computational and Mathematical Biology Research Group, Centre de Recerca Matemàtic (CRM), Barcelona, Spain.|Departament de Matemàtiques, Universitat Autònoma de Barcelona, Barcelona, Spain.|Barcelona Graduate School of Mathematics (BGSMath), Barcelona, Spain.
Tomás
T
Alarcón
Mayo Clinic, Department of Laboratory Medicine and Pathology, Division of Experimental Pathology, Rochester, MN, USA.|Mayo Clinic Cancer Center, Rochester, MN, USA.
Ruth
R
Lupu
Unitat de Recerca Biomèdica, Hospital Universitari de Sant Joan, IISPV, Universitat Rovira i Virgili, Campus of International Excellence Southern Catalonia, Reus, Spain.
Jorge
J
Joven
ProCURE (Program Against Cancer Therapeutic Resistance), Metabolism and Cancer Group, Catalan Institute of Oncology, Girona, Catalonia, Spain.|Molecular Oncology Group, Girona Biomedical Research Institute (IDIBGI), Girona, Catalonia, Spain.
Javier A
JA
Menendez
D019313:BRCA1 Protein / Q000235:genetics* / Q000378:metabolism; D001940:Breast / Q000166:cytology; D002460:Cell Line; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000378:metabolism; D004734:Energy Metabolism / Q000187:drug effects / Q000235:genetics; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism*; D005260:Female; D042822:Genomic Instability / Q000187:drug effects / Q000235:genetics; D018095:Germ-Line Mutation; D006579:Heterozygote; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology; D055442:Metabolome / Q000187:drug effects / Q000235:genetics; D055432:Metabolomics / Q000379:methods; D008687:Metformin / Q000494:pharmacology; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*
D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D007004:Hypoglycemic Agents; D008687:Metformin
BRCA1; bioenergetics; breast cancer susceptibility; glutamine; hereditary breast cancer