Overexpression of ErbB2 blocks taxol-induced apoptosis by upregulation of p21Cip1, which inhibits p34Cdc2 kinase

Overexpression of the receptor tyrosine kinase p185(ErbB2) confers Taxol resistance in breast cancers. Here, we investigated the underlying mechanisms and found that overexpression of p185(ErbB2) inhibits Taxol-induced apoptosis. Taxol activates p34(Cdc2) kinase in MDA-MB-435 breast cancer cells, leading to cell cycle arrest at the G2/M phase and, subsequently, apoptosis. A chemical inhibitor of p34(Cdc2) and a dominant-negative mutant of p34(Cdc2) blocked Taxol-induced apoptosis in these cells. Overexpression of p185(ErbB2) in MDA-MB-435 cells by transfection transcriptionally upregulates p21(Cip1), which associates with p34(Cdc2), inhibits Taxol-mediated p34(Cdc2) activation, delays cell entrance to G2/M phase, and thereby inhibits Taxol-induced apoptosis. In p21(Cip1) antisense-transfected MDA-MB-435 cells or in p21(-/-) MEF cells, p185(ErbB2) was unable to inhibit Taxol-induced apoptosis. Therefore, p21(Cip1) participates in the regulation of a G2/M checkpoint that contributes to resistance to Taxol-induced apoptosis in p185(ErbB2)-overexpressing breast cancer cells.