p53-Mediated Senescence Impairs the Apoptotic Response to Chemotherapy and Clinical Outcome in Breast Cancer

Studies on the role of TP53 mutation in breast cancer response to chemotherapy are conflicting. Here, we show that, contrary to dogma, MMTV-Wnt1 mammary 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, whereas p53 wild-type tumors arrested, avoiding mitotic catastrophe. Senescent tumor cells persisted, secreting senescence-associated cytokines exhibiting autocrine/paracrine activity and mitogenic potential. Wild-type p53 still mediated arrest and inhibited drug response even in the context of heterozygous p53 point mutations or absence of p21. Thus, we show that wild-type p53 activity hinders chemotherapy response and demonstrate the need to reassess the paradigm for p53 in cancer therapy. ⺠p53 mutant MMTV-Wnt1 tumors responded to chemotherapy better than p53 wild-type ones ⺠Wild-type p53 activity induced arrest and senescence, preventing aberrant mitoses ⺠Treated p53 mutant tumors entered the cell cycle and exhibited aberrant mitosis ⺠Wild-type p53 mediated arrest and reduced drug response even in the absence of p21