p53-mediated senescence impairs the apoptotic response to chemotherapy and clinical outcome in breast cancer

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aging / drug effects
  • Aging / genetics
  • Animals
  • Antibiotics, Antineoplastic / pharmacology
  • Apoptosis / drug effects
  • Apoptosis / genetics
  • Blotting, Western
  • Breast Neoplasms / drug therapy
  • Breast Neoplasms / genetics
  • Breast Neoplasms / pathology
  • Cell Line, Tumor
  • Cyclin-Dependent Kinase Inhibitor p21 / genetics
  • Cyclin-Dependent Kinase Inhibitor p21 / metabolism
  • Cytokines / genetics
  • Cytokines / metabolism
  • Doxorubicin / pharmacology*
  • Gene Expression Regulation, Neoplastic / drug effects
  • Humans
  • Mammary Neoplasms, Experimental / drug therapy*
  • Mammary Neoplasms, Experimental / genetics
  • Mammary Neoplasms, Experimental / pathology
  • Mammary Tumor Virus, Mouse / genetics
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Mutation
  • RNA Interference
  • Reverse Transcriptase Polymerase Chain Reaction
  • Treatment Outcome
  • Tumor Burden / drug effects*
  • Tumor Burden / genetics
  • Tumor Suppressor Protein p53 / genetics*
  • Tumor Suppressor Protein p53 / metabolism
  • Wnt1 Protein / genetics


  • Antibiotics, Antineoplastic
  • Cyclin-Dependent Kinase Inhibitor p21
  • Cytokines
  • Tumor Suppressor Protein p53
  • Wnt1 Protein
  • Doxorubicin