Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Cancer Cell. 2012 Jun 12;21(6):793-806. doi: 10.1016/j.ccr.2012.04.027.
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.
关于 TP53 突变在乳腺癌对化疗反应中的作用的研究结果存在争议。在这里，我们表明，与教条相反，具有突变型 p53 的 MMTV-Wnt1 乳腺肿瘤表现出比野生型 p53 肿瘤更好的临床反应。多柔比星治疗的 p53 突变型肿瘤未能阻止增殖，导致异常有丝分裂和细胞死亡，而 p53 野生型肿瘤则停止增殖，避免了有丝分裂灾难。衰老的肿瘤细胞持续存在，分泌具有自分泌/旁分泌活性和有丝分裂潜能的衰老相关细胞因子。野生型 p53 即使在杂合性 p53 点突变或缺乏 p21 的情况下，仍然介导细胞周期停滞并抑制药物反应。因此，我们表明野生型 p53 活性阻碍了化疗反应，并证明需要重新评估 p53 在癌症治疗中的作用模式。
