Accelerated geroncogenesis in hereditary breast-ovarian cancer syndrome

Javier A. Menendez, Núria Folguera-Blasco, Elisabet Cuyàs, Salvador Fernández-Arroyo, Jorge Joven, Tomás Alarcón

    Research output: Contribution to journalArticleResearchpeer-review

    9 Citations (Scopus)

    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.
    Original languageEnglish
    Pages (from-to)11959-11971
    JournalOncotarget
    Volume7
    Issue number11
    DOIs
    Publication statusPublished - 15 Mar 2016

    Keywords

    • BRCA1
    • Cancer
    • Geroncogenesis
    • Gerotarget
    • Metabolism
    • Metformin

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