Repositori URV

Author, as appears in the article.: Jorge Joven; Elisabet Cuyàs; Salvador Fernández-Arroyo; Tomás Alarcón; Ruth Lupu; Javier A. Menendez

Department: Medicina i Cirurgia

URV's Author/s: JOVEN MARIED, JORGE; Elisabet Cuyàs; Salvador Fernández-Arroyo; Tomás Alarcón; Ruth Lupu; Javier A. Menendez

Keywords: Breast cancer susceptibility BRCA1

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.

Research group: Unitat de Recerca Biomèdica

Thematic Areas: Health sciences Ciencias de la salud Ciències de la salut

licence for use: https://creativecommons.org/licenses/by/3.0/es/

ISSN: 1949-2553

Author identifier: N/D; N/D; N/D; N/D; N/D; N/D

Record's date: 2016-09-21

Last page: 52992

Journal volume: 7

Papper version: info:eu-repo/semantics/publishedVersion

Licence document URL: https://repositori.urv.cat/ca/proteccio-de-dades/

Entity: Universitat Rovira i Virgili

Journal publication year: 2016

First page: 52974

Publication Type: Article Artículo Article