Abstract SY14-02: p53-mediated senescence impairs the apoptotic response to chemotherapy in breast cancer

Studies on the role of p53 mutation in human breast cancer response to chemotherapy are controversial. Using MMTV-Wnt1 murine breast tumor model, we show that tumors with mutant p53 exhibited a superior clinical response compared to tumors with wild-type p53. Doxorubicin treated p53-mutant tumors failed to arrest proliferation leading to abnormal mitoses and cell death, while p53 wild-type tumors underwent arrest and senescence with expression of senescence-associated cytokines that led to autocrine/paracrine activity and mitogenic potential. Wild-type p53 could still mediate arrest and inhibit drug response even in the context of a heterozygous p53 point mutation or absence of p21. Thus, we show wild-type p53 activity hinders chemotherapy response and demonstrate the need to reassess the paradigm for p53 in cancer therapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr SY14-02. doi:1538-7445.AM2012-SY14-02