OVEREXPRESSION OF ERBB2 BLOCKS TAXOL-INDUCED APOPTOSIS BY UP-REGULATION OF P21(CIP1), WHICH INHIBITS P34(CDC2) KINASE

Overexpression of the receptor tyrosine kinase p185(ErbB2) confers Tax ol 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 bre ast cancer cells, leading to cell cycle arrest at the G2/M phase and, subsequently, apoptosis. A chemical inhibitor of p34(Cdc2) and a domin ant-negative mutant of p34(Cdc2) blocked Taxol-induced apoptosis in th ese cells. Overexpression of p185(ErbB2) in MDA-MB-435 cells by transf ection transcriptionally upregulates p21(Cip1), which associates with p34(Cdc2), inhibits Taxol-mediated p34(Cdc2) activation, delays cell e ntrance to G2/M phase, and thereby inhibits Taxol-induced apoptosis. I n p21(Cip1) antisense-transfected MDA-MB-435 cells or in p21(-/-) MEF cells, p185(ErbB2) was unable to inhibit Taxol-induced apoptosis. Ther efore, p21(Cip1) participates in the regulation of a G2/M checkpoint t hat contributes to resistance to Taxol-induced apoptosis in p185(ErbB2 )-overexpressing breast cancer cells.