Cancer Research CTRC-AACR San Antonio Breast Cancer Symposium Susan G. Komen for the Cure-AACR Outstanding Investigator Award for Breast Cancer Research
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[Cancer Research 62, 5703-5710, October 15, 2002]
© 2002 American Association for Cancer Research

Experimental Therapeutics

Enhanced Sensitization to Taxol-induced Apoptosis by Herceptin Pretreatment in ErbB2-overexpressing Breast Cancer Cells1

Sangkyou Lee, Wentao Yang, Keng-Hsueh Lan, Shankar Sellappan, Kristine Klos, Gabriel Hortobagyi, Mien-Chie Hung and Dihua Yu2

Departments of Surgical Oncology [S. L., W. Y., K-H. L., S. S., K. K., D. Y.], Breast Medical Oncology [G. H.], and Molecular and Cellular Oncology [M-C. H., D. Y.], The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030

The recombinant humanized anti-ErbB2/HER2 monoclonal antibody Herceptin (Trastuzumab) has been shown to significantly enhance the tumoricidaleffects of antitumor drugs such as paclitaxel (Taxol) in patients with ErbB2-overexpressing breast cancers. Here, we investigated the molecular mechanisms by which Herceptin enhances the antitumor effects of Taxol. Because activation of p34Cdc2 is required for Taxol-induced apoptosis and because overexpression of ErbB2 blocks Taxol-induced apoptosis by inhibiting p34Cdc2 activation, we studied the effect of Herceptin treatment on p34Cdc2 kinase activation and apoptosis in Taxol-treated human breast carcinoma cell lines MDA-MB-435, SKBr3, MDA-MB-453, and 435.eB, which is an ErbB2 transfectant of MDA-MB-435. Herceptin treatment down-regulated ErbB2, reduced the inhibitory phosphorylation of Cdc2 on Tyr-15, and down-regulated the expression of p21Cip1, a Cdc2 inhibitor. Herceptin plus Taxol treatment led to higher levels of p34Cdc2 kinase activity and apoptosis in ErbB2-overexpressing breast cancer cells, which is likely attributable to inhibition of Cdc2-Tyr-15 phosphorylation and p21Cip1 expression. Because significant dephosphorylation of Cdc2-Tyr-15 and down-regulation of p21Cip1 occur at least 24 h after Herceptin treatment, we investigated whether 24 h Herceptin pretreatment will render ErbB2-overexpressing breast cancer cells more sensitive to Taxol-induced apoptosis compared with the simultaneous treatment of Herceptin plus Taxol. Indeed, Herceptin pretreatment increased Taxol-induced apoptosis and cytotoxicity in vitro and more effectively inhibited the growth of tumor xenografts with enhanced in vivo apoptosis. Thus, Herceptin treatment of ErbB2-overexpressing cells can inhibit ErbB2-mediated Cdc2-Tyr-15 phosphorylation and p21Cip1 up-regulation, which allows effective p34Cdc2 activation and induction of apoptosis upon Taxol treatment. Herceptin pretreatment renders ErbB2-overexpressing breast cancers more susceptible to Taxol-induced cell death, which may have important clinical therapeutic implications.




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Copyright © 2002 by the American Association for Cancer Research.