Articles producció científica> Medicina i Cirurgia

Accelerated geroncogenesis in hereditary breast-ovarian cancer syndrome

  • Identification data

    Identifier: PC:1461
    Handle: https://hdl.handle.net/20.500.11797/PC1461
    Authors:
    Jorge JovenJavier A. MenendezNúria Folguera-BlascoElisabet CuyàsSalvador Fernández-ArroyoTomás Alarcón
    Abstract:
    The geroncogenesis hypothesis postulates that the decline in metabolic cellular health that occurs naturally with aging drives a "field effect" predisposing normal tissues for cancer development. We propose that mutations in the cancer susceptibility genes BRCA1/2 might trigger "accelerated geroncogenesis" in breast and ovarian epithelia. By speeding up the rate at which the metabolic threshold becomes "permissive" with survival and expansion of genomically unstable pre-tumoral epithelial cells, BRCA haploinsufficiency-driven metabolic reprogramming would operate as a bona fide oncogenic event enabling malignant transformation and tumor formation in BRCA carriers. The metabolic facet of BRCA1 one-hit might involve tissue-specific alterations in acetyl-CoA, a-ketoglutarate, NAD+, FAD, or S-adenosylmethionine, critical factors for de/methylation or de/acetylation dynamics in the nuclear epigenome. This in turn might induce faulty epigenetic reprogramming at the "install phase" that directs cell-specific differentiation of breast/ovarian epithelial cells, which can ultimately determine the penetrance of BRCA defects during developmental windows of susceptibility. This model offers a framework to study whether metabolic drugs that prevent or revert metabolic reprogramming induced by BRCA haploinsufficiency might displace the "geroncogenic risk" of BRCA carriers to the age typical for those without the mutation. The identification of the key nodes that directly communicate changes in cellular metabolism to the chromatin in BRCA haploinsufficient cells may allow the epigenetic targeting of genomic instability using exclusively metabolic means. The validation of accelerated geroncogenesis as an inherited "one-hit" metabolic "field effect" might offer new strategies to therapeu

  • Others:

    Author, as appears in the article.: Jorge Joven; Javier A. Menendez; Núria Folguera-Blasco; Elisabet Cuyàs; Salvador Fernández-Arroyo; Tomás Alarcón
    Department: Medicina i Cirurgia
    URV's Author/s: JOVEN MARIED, JORGE; Javier A. Menendez; Núria Folguera-Blasco; Elisabet Cuyàs; Salvador Fernández-Arroyo; Tomás Alarcón
    Keywords: Gerotarget Geroncogenesis Cancer
    Abstract: The geroncogenesis hypothesis postulates that the decline in metabolic cellular health that occurs naturally with aging drives a "field effect" predisposing normal tissues for cancer development. We propose that mutations in the cancer susceptibility genes BRCA1/2 might trigger "accelerated geroncogenesis" in breast and ovarian epithelia. By speeding up the rate at which the metabolic threshold becomes "permissive" with survival and expansion of genomically unstable pre-tumoral epithelial cells, BRCA haploinsufficiency-driven metabolic reprogramming would operate as a bona fide oncogenic event enabling malignant transformation and tumor formation in BRCA carriers. The metabolic facet of BRCA1 one-hit might involve tissue-specific alterations in acetyl-CoA, a-ketoglutarate, NAD+, FAD, or S-adenosylmethionine, critical factors for de/methylation or de/acetylation dynamics in the nuclear epigenome. This in turn might induce faulty epigenetic reprogramming at the "install phase" that directs cell-specific differentiation of breast/ovarian epithelial cells, which can ultimately determine the penetrance of BRCA defects during developmental windows of susceptibility. This model offers a framework to study whether metabolic drugs that prevent or revert metabolic reprogramming induced by BRCA haploinsufficiency might displace the "geroncogenic risk" of BRCA carriers to the age typical for those without the mutation. The identification of the key nodes that directly communicate changes in cellular metabolism to the chromatin in BRCA haploinsufficient cells may allow the epigenetic targeting of genomic instability using exclusively metabolic means. The validation of accelerated geroncogenesis as an inherited "one-hit" metabolic "field effect" might offer new strategies to therapeutically revisit the apparently irreversible genetic-hereditary fate of women with hereditary breast-ovarian cancer syndrome.
    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: 2016-04-29
    Last page: 11971
    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: 11959
    Publication Type: Article Artículo Article

  • Keywords:

    ENVELLIMENT-METABOLISME
    CANCER
    Gerotarget
    Geroncogenesis
    Cancer
    Health sciences
    Ciencias de la salud
    Ciències de la salut
    1949-2553

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