ErbB2-mediated Src and STAT3 Activation Leads to Transcriptional Upregulation of p21Cip1 and Chemoresistance in Breast Cancer Cells

摘要

Overexpression of the ErbB2 receptor tyrosine kinase is prevalent in approximately 30% of human breast cancers and confers Taxol resistance. Our previous work has demonstrated that ErbB2 inhibits Taxol induced apoptosis in breast cancer cells by transcriptionally upregulating p21^Cip1. However, the mechanism of ErbB2-mediated p21^Cip1 upregulation is unclear. Here we show that ErbB2 upregulates p21^Cip1 transcription through increased Src activity in ErbB2 overexpressing cells. Src activation further activated STAT3 that recognizes an SIE binding site on the p21^Cip1 promoter required for ErbB2-mediated p21^Cip1 transcriptional upregulation. 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 upregulation 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.