How p53 mediates response to DNA damage induced by chemotherapy treatment of breast cancer is not well understood with few mechanistic studies addressing the conflicting reports in the literature. We have used the MMTV-Wnt1 mouse model of breast cancer to examine the role of the p53 pathway in the biochemical, cellular and clinical response to doxorubicin. We found that treatment of p53 wild type breast tumors, or heterozygous tumors that retained the wild type allele, resulted in an initial mean tumor regression of only 35%, followed by stable disease (∼1 to 2 weeks) and relapse by 11 days. Surprisingly, we found that breast tumors with mutant p53 responded better to treatment, with regression of 70% and 24 days to relapse (p<0.001). Investigating the mechanism of these responses, we found that p53 mutant tumors harvested 24 hours after final treatment did not induce p53 targets after treatment when compared to untreated tumors, did not enter proliferative arrest, but did undergo p53-independent apoptosis, consistent with tumor regression data. Conversely, treated p53 wild type tumors induced p53 targets such as p21 and Puma, were negative for the proliferation marker Ki67, and did not induce apoptosis. Further characterization of the partial response in p53 wild type tumors revealed that tumors harvested in the stable arrest phase (7-14 days after treatment) had elevated markers of senescence, including p21, Dec1, Dcr2, p15, p16 and PML, compared to relapsed or resistant tumors. To more precisely address which of the myriad p53 functions was responsible for the poor response in p53 wild type tumors, we bred the MMTV-Wnt1 mice into a p21 null background and treated and monitored mice that formed tumors. We found that genetic loss of p21 in the tumors was sufficient to achieve the dramatic response observed in p53 null tumors. These data show that p53 mediated activation of a senescence program via p21 is the primary outcome in treated MMTV-Wnt1tumors, resulting in an incomplete response, stable disease and eventual early relapse, while treated p53 mutant or p21 null tumors undergo cell death and tumor regression.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1235. doi:10.1158/1538-7445.AM2011-1235

©2011 American Association for Cancer Research
2011