title: The Mre11 complex suppresses oncogene-driven breast tumorigenesis and metastasis.
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.
authors.affiliation: Molecular Biology Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA; Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Gaorav P
authors.initials: GP
authors.lastname: Gupta
authors.forename: Katelynd
authors.initials: K
authors.lastname: Vanness
authors.forename: Afsar
authors.initials: A
authors.lastname: Barlas
authors.forename: Katia O
authors.initials: KO
authors.lastname: Manova-Todorova
authors.forename: Yong H
authors.initials: YH
authors.lastname: Wen
authors.forename: John H J
authors.initials: JH
authors.lastname: Petrini
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D063646:Carcinogenesis; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics / Q000378:metabolism; D004249:DNA Damage / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D006965:Hyperplasia / Q000235:genetics; D000076228:MRE11 Homologue Protein; D008321:Mammary Glands, Animal / Q000254:growth & development / Q000378:metabolism / Q000473:pathology; D051379:Mice; D009362:Neoplasm Metastasis / Q000235:genetics; D009857:Oncogenes
chemical_list: C417743:Cdkn2a protein, mouse; D019941:Cyclin-Dependent Kinase Inhibitor p16; D004268:DNA-Binding Proteins; C121766:MRE11 protein, human; D000076228:MRE11 Homologue Protein