Autor segons l'article: Jorge Joven; Javier A. Menendez; Núria Folguera-Blasco; Elisabet Cuyàs; Salvador Fernández-Arroyo; Tomás Alarcón
Departament: Medicina i Cirurgia
Autor/s de la URV: JOVEN MARIED, JORGE; Javier A. Menendez; Núria Folguera-Blasco; Elisabet Cuyàs; Salvador Fernández-Arroyo; Tomás Alarcón
Paraules clau: Gerotarget Geroncogenesis Cancer
Resum: 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.
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: 2016-04-29
Pàgina final: 11971
Volum de revista: 7
Versió de l'article dipositat: info:eu-repo/semantics/publishedVersion
Enllaç font original: https://www.oncotarget.com/article/7867/text/
URL Document de llicència: https://repositori.urv.cat/ca/proteccio-de-dades/
DOI de l'article: 10.18632/oncotarget.7867
Entitat: Universitat Rovira i Virgili
Any de publicació de la revista: 2016
Pàgina inicial: 11959
Tipus de publicació: Article Artículo Article