Structural and Signaling Requirements for C-erbB2 Antiapoptosis in Breast Cancer

The c-erbB2 or HER-2, neu gene encodes a 1 85-kDa transmembrane glycoprotein pi 85, which belongs to the EGF-r family. The c-erbB2 gene was found to be amplified andor overexpressed in approximately 30 of human breast carcinomas. Our previous studies demonstrated that c-erbB2 overexpression could enhance metastatic potential and confer increased chemoresistance to breast cancer cells, thereby leading to poor clinical outcome in breast cancer patients. Also, we demonstrated that overexpression of the c-erbB2 gene can protect human breast cancer cells from apoptosis induced by the chemotherapeutic agent Taxol. One of the mechanisms is overexpression of c-erbB2 can upregulate p21 to the ciP1, which inhibits Taxol-mediated p34 to the Ck2 to the Ck2 activation, delays cell entrance phase, and thereby inhibits Taxol induced apoptosis. This new finding provided an explanation for c-erbB2 mediated chemoresistance of breast cancer cells and also explored the importance of p21 to the CiPI in G2M phase transition. Multiple regulators are involved in regulating the activity of p34Cdc2 kinase and the Taxol sensitivity. With the panel of wild-type and mutant erbB2 gene transfectants kinase-dead His -ErbB2KDM, wild-type extracellular domain of the ErbB2 protein His-ErbB2ECD, we are able to demonstrated that the ErbB2 tyrosine kinase activity is required for in vivo phosphorylation of Cdc2 by ErbB2, rendering the breast cancer cells resistant to Taxol treatment. p34Cdc2 kinase may be an important target for the treatment of Taxol resistance.