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Growth and Motility Inhibition of Breast Cancer Cells by Epidermal Growth Factor Receptor Degradation Is Correlated with Inactivation of Cdc42

Division of Monoclonal Antibodies, Office of Biotechnology Products, Office of Pharmaceutical Science, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Bethesda, Maryland

Requests for reprints: Wen Jin Wu, Division of Monoclonal Antibodies, Office of Biotechnology Products, Office of Pharmaceutical Science, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Room 3NN-15, Building 29B, 29 Lincoln Drive, Bethesda, MD 20892-4555. Phone: 301-827-0253; Fax: 301-827-0852; E-mail: wen.wu{at}fda.hhs.gov.

Overexpression of epidermal growth factor receptor (EGFR) contributes to increased cell proliferation and migration in breast cancer. However, mechanisms of EGFR overexpression remain elusive and often cannot be attributed to gene amplification. In NIH3T3 fibroblasts, active Cdc42 inhibits c-Cbl-regulated EGFR degradation to induce cellular transformation. Here, we use two EGFR-overexpressing breast cancer cell lines, MDA-MB-231 and BT20, as models to test the hypothesis that up-regulated Cdc42 activity impairs c-Cbl-mediated EGFR degradation and contributes to EGFR overexpression. We show that silencing Cdc42 significantly reduces protein levels of EGFR, leading to a marked reduction in cell proliferation and migration, and c-Cbl knockdown increases the levels of EGFR. Expression of c-Cbl-N480, a c-Cbl mutant that is not regulated by Cdc42 and blocks Cdc42-induced transformation but still binds and ubiquitinates EGFR, enhances the rate of EGFR degradation and subsequently inhibits cell proliferation. Moreover, down-regulated EGFR signaling induced by c-Cbl-N480 decreased activity of Cdc42 and Rac1, resulting in inhibition of cell migration. These findings indicate that Cdc42 and c-Cbl are critical components involved in the regulation of EGFR protein levels and that restoration of proper EGFR degradation by disrupting Cdc42 regulation of c-Cbl can reduce cell proliferation and migration in MDA-MB-231 and BT20 cells. (Cancer Res 2006; 66(7): 3523-30)

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