A stemness-related ZEB1-MSRB3 axis governs cellular pliancy and breast cancer genome stability.
Nat Med
; 23(5): 568-578, 2017 May.
Article
en En
| MEDLINE
| ID: mdl-28394329
Chromosomal instability (CIN), a feature of most adult neoplasms from their early stages onward, is a driver of tumorigenesis. However, several malignancy subtypes, including some triple-negative breast cancers, display a paucity of genomic aberrations, thus suggesting that tumor development may occur in the absence of CIN. Here we show that the differentiation status of normal human mammary epithelial cells dictates cell behavior after an oncogenic event and predetermines the genetic routes toward malignancy. Whereas oncogene induction in differentiated cells induces massive DNA damage, mammary stem cells are resistant, owing to a preemptive program driven by the transcription factor ZEB1 and the methionine sulfoxide reductase MSRB3. The prevention of oncogene-induced DNA damage precludes induction of the oncosuppressive p53-dependent DNA-damage response, thereby increasing stem cells' intrinsic susceptibility to malignant transformation. In accord with this model, a subclass of breast neoplasms exhibit unique pathological features, including high ZEB1 expression, a low frequency of TP53 mutations and low CIN.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Células Madre
/
Neoplasias de la Mama
/
Carcinoma
/
Regulación Neoplásica de la Expresión Génica
/
Diferenciación Celular
/
Inestabilidad Genómica
/
Células Epiteliales
/
Metionina Sulfóxido Reductasas
/
Homeobox 1 de Unión a la E-Box con Dedos de Zinc
Tipo de estudio:
Prognostic_studies
Límite:
Aged80
Idioma:
En
Revista:
Nat Med
Asunto de la revista:
BIOLOGIA MOLECULAR
/
MEDICINA
Año:
2017
Tipo del documento:
Article
País de afiliación:
Francia
Pais de publicación:
Estados Unidos