Abstract SY33-04: Tumor suppression by the DNA damage response

Abstract

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 variety of mutant mouse strains with specific DDR deficiencies to reveal a novel role for the Mre11 complex (comprised of Mre11, Nbs1, and Rad50) in the response to oncogene activation. We demonstrate that the Mre11-mediated DDR suppresses tumorigenesis by inducing a G2 arrest and a program of chromatin alteration that, when compromised, results in oncogene-induced mammary hyperplasias that progress to invasive and metastatic breast cancers. In contrast, we provide genetic evidence that the intra-S checkpoint and the DNA damage-induced apoptosis functions of the DDR are dispensable for tumor suppression. These findings provide novel insight into the mechanism of DDR engagement by activated oncogenes, and reveal the particular DDR functions that must be overcome during tumorigenesis. We further demonstrate that impairment of these Mre11-dependent functions promotes metastatic dissemination, particularly upon secondary inactivation of the Ink4a-p19Arf (CDKN2a) locus. These findings provide insight into the mechanism of DDR engagement by activated oncogenes, and reveal a novel genetic interaction between the DDR and Ink4a-p19Arf pathways in suppression of oncogene-driven tumorigenesis and metastasis. Citation Format: John Petrini. Tumor suppression by the DNA damage response. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr SY33-04. doi:10.1158/1538-7445.AM2014-SY33-04