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