ErbB2-mediated Src and signal transducer and activator of transcription 3 activation leads to transcriptional up-regulation of p21^Cip1 and chemoresistance in breast cancer cells

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 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.