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
Link to the original source: https://www.oncotarget.com/article/7867/text/
Licence document URL: https://repositori.urv.cat/ca/proteccio-de-dades/
Article's DOI: 10.18632/oncotarget.7867
Entity: Universitat Rovira i Virgili
Journal publication year: 2016
First page: 11959
Publication Type: Article Artículo Article
Repositori URV