Mre11 Complex Suppresses Oncogene-Driven Breast Tumorigenesis and Metastasis

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 mou...

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Published inMolecular cell Vol. 52; no. 3; pp. 353 - 365
Main Authors Gupta, Gaorav P, Vanness, Katelynd, Barlas, Afsar, Manova-Todorova, Katia O, Wen, Yong H, Petrini, John H.J
Format Journal Article
LanguageEnglish
Published United States Elsevier Inc 07.11.2013
Subjects
animal models
Animals
breast neoplasms
Breast Neoplasms - genetics
Breast Neoplasms - metabolism
Breast Neoplasms - pathology
Carcinogenesis
Cyclin-Dependent Kinase Inhibitor p16 - genetics
Cyclin-Dependent Kinase Inhibitor p16 - metabolism
DNA damage
DNA Damage - genetics
DNA-Binding Proteins - genetics
DNA-Binding Proteins - metabolism
Female
Gene Expression Regulation, Neoplastic
Humans
hyperplasia
Hyperplasia - genetics
loci
Mammary Glands, Animal - growth & development
Mammary Glands, Animal - metabolism
Mammary Glands, Animal - pathology
metastasis
Mice
MRE11 Homologue Protein
mutants
Neoplasm Metastasis - genetics
Oncogenes
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Summary: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.
Bibliography:http://dx.doi.org/10.1016/j.molcel.2013.09.001
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ISSN:1097-2765
1097-4164
DOI:10.1016/j.molcel.2013.09.001