The Mre11 complex suppresses oncogene-driven breast tumorigenesis and metastasis.
Mol Cell
; 52(3): 353-65, 2013 Nov 07.
Article
em En
| MEDLINE
| ID: mdl-24120666
ABSTRACT
The DNA damage response (DDR) is activated by oncogenic stress, but the mechanisms by which this occurs, and the particular DDR functions that constitute barriers to tumorigenesis, remain unclear. We established a mouse model of sporadic oncogene-driven breast tumorigenesis in a series of mutant mouse strains with specific DDR deficiencies to reveal a role for the Mre11 complex in the response to oncogene activation. We demonstrate that an Mre11-mediated DDR restrains mammary hyperplasia by effecting an oncogene-induced G2 arrest. Impairment of Mre11 complex functions promotes the progression of mammary hyperplasias into invasive and metastatic breast cancers, which are often associated with secondary inactivation of the Ink4a-Arf (CDKN2a) locus. These findings provide insight into the mechanism of DDR engagement by activated oncogenes and highlight genetic interactions between the DDR and Ink4a-Arf pathways in suppression of oncogene-driven tumorigenesis and metastasis.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Oncogenes
/
Neoplasias da Mama
/
Proteínas de Ligação a DNA
/
Carcinogênese
Tipo de estudo:
Prognostic_studies
Limite:
Animals
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Female
/
Humans
Idioma:
En
Ano de publicação:
2013
Tipo de documento:
Article