Articles producció científica> Medicina i Cirurgia

Germline BRCA1 mutation reprograms breast epithelial cell metabolism towards mitochondrial-dependent biosynthesis: Evidence for metforminbased "starvation" strategies in BRCA1 carriers

  • Identification data

    Identifier: PC:1840
    Handle: https://hdl.handle.net/20.500.11797/PC1840
    Authors:
    Jorge JovenElisabet CuyàsSalvador Fernández-ArroyoTomás AlarcónRuth LupuJavier A. Menendez
    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

  • Others:

    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
    Link to the original source: http://www.oncotarget.com/index.php?journal=oncotarget&page=article&op=view&path[]=9732&pubmed-linkout=1
    Licence document URL: https://repositori.urv.cat/ca/proteccio-de-dades/
    Article's DOI: 10.18632/oncotarget.9732
    Entity: Universitat Rovira i Virgili
    Journal publication year: 2016
    First page: 52974
    Publication Type: Article Artículo Article

  • Keywords:

    Mama -- Càncer -- Aspectes genètics
    Mama -- Càncer
    Breast cancer susceptibility
    BRCA1
    Health sciences
    Ciencias de la salud
    Ciències de la salut
    1949-2553

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