Estrogen defines the dynamics and destination of transactivated EGF receptor in breast cancer cells: role of S1P3 receptor and Cdc42

This article appeared in Experimental Cell Research, published by Elsevier Ltd. Under Elsevier's copyright, mandated authors are not permitted to make work available in an institutional repository.Sphingosine-1-phosphate (S1P) receptors mediate transactivation of epidermal growth factor receptor (EGFR) by estrogen (E2). Here we report that the amount of intracellular EGFR remains elevated after stimulation of MCF-7 cells with E2 and S1P, although membrane-localized EGFR and S1P3 receptors are quickly internalized. Co-localization of internalized EGFR and LAMP-2 was lower in cells treated with E2/S1P, suggesting that endosomal EGFR might be directed for recycling instead of degradation. In addition, we found that E2/S1P activated Cdc42 and that knockdown of Cdc42 restores fast EGFR degradation after E2/S1P stimulation. Inhibition of S1P3 receptors prevented E2-induced activation of Cdc42, supporting the important role of the S1P receptor in E2 signaling. This is a novel mechanism further defining the effect of E2/S1P on the EGFR transactivation in breast cancer cells.This work was supported by grants from C.M.E. Kelly Cancer Research Foundation and Lyn Wrigley Breast Cancer Research and Development Fund (Flinders Medical Centre, Australia) (to O.S.); and National Health and Medical Research Council of Australia (to P.X.). PX is a Research Fellow of Cancer Institute New South Wales, Australia