ErbB2-Mediated Src and Signal Transducer and Activator of Transcription 3 Activation Leads to Transcriptional Up-Regulation of p21Cip1 and Chemoresistance in Breast Cancer Cells

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Abstract
Overexpression of the ErbB2 receptor tyrosine kinase is prevalent in ∼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 p21Cip1. However, the mechanism of ErbB2-mediated p21Cip1 up-regulation is unclear. Here, we show that ErbB2 up-regulates p21Cip1 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 p21Cip1 promoter required for ErbB2-mediated p21Cip1 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 p21Cip1 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. (Mol Cancer Res 2009;7(4):592–600)