Abstract
Overexpression of the ErbB2 receptor tyrosine kinase is prevalent in approximately 30% of human breast cancers and confers Taxol resistance. Our previous work has shown that ErbB2 inhibits Taxol-induced apoptosis in breast cancer cells by transcriptionally up-regulating p21(Cip1). However, the mechanism of ErbB2-mediated p21(Cip1) up-regulation is unclear. Here, we show that ErbB2 up-regulates p21(Cip1) transcription through increased Src activity in ErbB2-overexpressing cells. Src activation further activated signal transducer and activator of transcription 3 (STAT3) that recognizes a SIE binding site on the p21(Cip1) promoter required for ErbB2-mediated p21(Cip1) transcriptional up-regulation. Both Src and STAT3 inhibitors restored Taxol sensitivity in resistant ErbB2-overexpressing breast cancer cells. Our data suggest that ErbB2 overexpression can activate STAT3 through Src leading to transcriptional up-regulation of p21(Cip1) that confers Taxol resistance of breast cancer cells. Our study suggests a potential clinical application of Src and STAT3 inhibitors in Taxol sensitization of ErbB2-overexpressing breast cancers.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Antineoplastic Agents, Phytogenic / pharmacology
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Blotting, Western
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Breast Neoplasms / drug therapy*
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Breast Neoplasms / genetics
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Breast Neoplasms / pathology
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Cell Proliferation / drug effects
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Chromatin Immunoprecipitation
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Cyclin-Dependent Kinase Inhibitor p21 / genetics*
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Cyclin-Dependent Kinase Inhibitor p21 / metabolism
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Drug Resistance, Neoplasm*
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Electrophoretic Mobility Shift Assay
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Female
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Gene Expression Regulation, Neoplastic / physiology*
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Humans
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Immunoprecipitation
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Luciferases / metabolism
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Paclitaxel / pharmacology
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Promoter Regions, Genetic
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Proto-Oncogene Proteins pp60(c-src) / genetics
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Proto-Oncogene Proteins pp60(c-src) / metabolism*
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Receptor, ErbB-2 / genetics
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Receptor, ErbB-2 / metabolism*
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STAT3 Transcription Factor / antagonists & inhibitors
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STAT3 Transcription Factor / genetics
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STAT3 Transcription Factor / metabolism*
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Transcription, Genetic
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Tumor Cells, Cultured
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Up-Regulation
Substances
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Antineoplastic Agents, Phytogenic
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CDKN1A protein, human
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Cyclin-Dependent Kinase Inhibitor p21
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STAT3 Transcription Factor
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STAT3 protein, human
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Luciferases
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ERBB2 protein, human
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Receptor, ErbB-2
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Proto-Oncogene Proteins pp60(c-src)
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Paclitaxel