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- W2946478541 abstract "959 Overexpression of receptor tyrosine kisase ErbB2 is prevalent in approximately 30% of human breast carcinomas and confers Taxol resistance. Previous work demonstrates that in breast cancer cells, Taxol induces tubulin polymerization and microtubule formation, inappropriately activates cdc2 kinase causing cells premature entry to G2/M phase of the cell cycle that leads to apoptosis. Overexpression of ErbB2 transcriptionally upregulates p21Cip1 inhibiting cdc2 activation, thus inhibiting apoptosis. The mechanism of ErbB2 mediated p21Cip1 upregulation is unclear. To understand the ErbB2 downstream signaling events leading to p21Cip1 upregulation, various stable ErbB2 overexpressing transfectants were compared with their parental ErbB2-low-expressing cells for activation of ErbB2 downstream signaling events. We found increased phosphorylation of signal transducer and activator of transcription 3 (STAT3) in ErbB2 overexpressing transfectants while total STAT3 protein levels remain the same. Furthermore, activated STAT3 recognizes an SIE binding site on the p21Cip1 promoter. Binding of STAT3 to this site is involved in p21Cip1 upregulation in an ErbB2 level-dependent manner. A luciferase reporter driven by the 2.4kb p21Cip1 promoter shows higher promoter activity in ErbB2 overexpressing transfectants than in the parental cells. Deletion of the 2.4kb p21Cip1 promoter to 660bp (still containing the STAT3 site) is responsive to ErbB2-mediated transcriptional upregulation. Further deletion to 640bp (deleting the STAT3 site) or a 660bp p21Cip1 promoter with STAT3 binding site mutated renders them irresponsive to ErbB2-mediated transcriptional upregulation, suggesting p21Cip1 promoter activation by ErbB2 requires STAT3. Additionally, transfection of STAT3 antisense led to reduced p21Cip1 protein expression. STAT3 antisense also reduced the luciferase activity driven by the 2.4kb and the 660bp p21Cip1 promoters but had no effect on the 640bp or the 660bp p21Cip1 promoter with STAT3 site mutations. Activation of Src kinase has been suggested in STAT3 activation/phosphorylation. We found that Src kinase is activated in ErbB2 overexpressing transfectants. To see if Src is responsible for ErbB2-mediated STAT3 activation and p21Cip1 upregulation, we established breast cancer cells stably expressing dominant negative Src or constitutively active Src and will investigate STAT3 phosphorylation, p21Cip1 promoter activity in response to ErbB2, and sensitivity to Taxol-induced apoptosis in these cells. Our current data suggest that ErbB2 overexpression can confer Taxol resistance of breast cancer cells by transcriptional upregulation of p21Cip1 via activation of STAT3, suggesting a potential clinical role for STAT3 inhibitors in sensitizing ErbB2 overexpressing breast cancers to Taxol therapy." @default.
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- W2946478541 date "2005-05-01" @default.
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- W2946478541 title "Transcriptional upregulation of p21Cip1 by ErbB2 overexpression through STAT3 activation" @default.
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