Abstract
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.
Copyright © 2012 Elsevier Inc. All rights reserved.
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
Substances
- Antibiotics, Antineoplastic
- Cyclin-Dependent Kinase Inhibitor p21
- Cytokines
- Tumor Suppressor Protein p53
- Wnt1 Protein
- Doxorubicin