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

  • Dades identificatives

    Identificador: PC:1840
    Autors:
    Jorge JovenElisabet CuyàsSalvador Fernández-ArroyoTomás AlarcónRuth LupuJavier A. Menendez
    Resum:
    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
  • Altres:

    Autor segons l'article: Jorge Joven; Elisabet Cuyàs; Salvador Fernández-Arroyo; Tomás Alarcón; Ruth Lupu; Javier A. Menendez
    Departament: Medicina i Cirurgia
    Autor/s de la URV: JOVEN MARIED, JORGE; Elisabet Cuyàs; Salvador Fernández-Arroyo; Tomás Alarcón; Ruth Lupu; Javier A. Menendez
    Paraules clau: Breast cancer susceptibility BRCA1
    Resum: 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.
    Grup de recerca: Unitat de Recerca Biomèdica
    Àrees temàtiques: Health sciences Ciencias de la salud Ciències de la salut
    Accès a la llicència d'ús: https://creativecommons.org/licenses/by/3.0/es/
    ISSN: 1949-2553
    Identificador de l'autor: N/D; N/D; N/D; N/D; N/D; N/D
    Data d'alta del registre: 2016-09-21
    Pàgina final: 52992
    Volum de revista: 7
    Versió de l'article dipositat: info:eu-repo/semantics/publishedVersion
    Enllaç font original: http://www.oncotarget.com/index.php?journal=oncotarget&page=article&op=view&path[]=9732&pubmed-linkout=1
    URL Document de llicència: https://repositori.urv.cat/ca/proteccio-de-dades/
    DOI de l'article: 10.18632/oncotarget.9732
    Entitat: Universitat Rovira i Virgili
    Any de publicació de la revista: 2016
    Pàgina inicial: 52974
    Tipus de publicació: Article Artículo Article
  • Paraules clau:

    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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