Abstract B21: Defining the DNA damage response-mediated barrier to ErbB2-induced transformation of somatic mammary cells in vivo

Abstract

Abstract The DNA damage response (DDR) represents a signaling cascade, which is comprised of DNA damage sensors (such as γH2AX and 53BP1), ATM, Chk2, p53, among others, that becomes activated when confronted with DNA double strand breaks and other forms of DNA damage. The activation of the DDR, in addition to the ARF pathway, has recently been found to elicit apoptosis and senescence in response to oncogene activation. However, the significance of a DDR in blocking cancer progression has not been tested in breast carcinogenesis. Preneoplastic lesions in four germline transgenic models of breast cancer that express polyoma middle T antigen (PyMT), ErbB2, c-Myc, or H-Ras do not exhibit a DDR. We have previously reported a novel mouse model of mammary cancer, where oncogenes can be introduced into somatic mammary epithelial cells via retroviral infection of RCAS vectors into MMTV-tva mice (termed RCAS-TVA). Hyperplastic lesions in the mammary gland induced by somatic introduction of PyMT using the RCAS-TVA system display a robust DDR accompanied by increased p53 and apoptosis. This observation represents the first study, to our knowledge, to fully recapitulate DDR signaling in response to acute oncogenic stress in the in vivo mammary gland. 20–30% of all breast cancers display amplification of ErbB2, a cellular oncogene which, when activated in somatic murine mammary cells, forms sporadic tumors with a long latency. Like RCAS-PyMT, we found that p53 stabilization and apoptosis, as well as senescence, are induced by somatic activation of RCAS-ErbB2. In advanced RCAS-ErbB2-induced tumors, DDR signaling and ARF induction persist, yet p53 stabilization and apoptosis are lost. Surprisingly, attributes of senescence remain in some of the ErbB2 tumor cells. To demonstrate that the DDR is critical for oncogene-induced apoptosis and senescence, we generated RCAS-ErbB2 lesions in ATM-deficient mice. Strikingly, p53 stabilization, apoptosis, and senescence were no longer activated following ErbB2 activation in the absence of ATM signaling. These data suggest that a DDR plays a critical role in inhibiting breast carcinogenesis by inducing senescence and apoptosis, the latter, but not the former, of which is lost in progression to tumors. Furthermore, these findings indicate that therapies designed to bolster the activity of DDR signaling kinases and effectors may have a broad role in breast cancer prevention. Citation Information: Cancer Res 2009;69(23 Suppl):B21.