TAMOXIFEN INDUCES SELECTIVE-MEMBRANE ASSOCIATION OF PROTEIN-KINASE-C-EPSILON IN MCF-7 HUMAN BREAST-CANCER CELLS

Tamoxifen, a synthetic antiestrogen, is known for its antitumoral acti on in vivo; however, it is well accepted that many tamoxifen effects a re elicited via estrogen receptor-independent routes. Previously, we r eported that tamoxifen induces PKC translocation in fibroblasts. In th e present study, we investigated the influence of tamoxifen, and sever al triphenylethylene derivatives, on protein kinase C (PKC) in MCF-7 h uman breast cancer cells. As measured by Western blot analysis, tamoxi fen elicited isozyme-specific membrane association of PKC-epsilon, whi ch was time-dependent (as early as 5 min post-treatment) and dose-depe ndent (5.0-20 mu M) Tamoxifen did not influence translocation of alpha , beta, gamma, delta or zeta PKC isoforms. Structure-activity relation ship studies demonstrated chemical requirements for PKC-epsilon transl ocation, with tamoxifen, 3-OH-tamoxifen and clomiphene being active. C ompounds without the basic amino side chain, such as triphenylethylene , or minus a phenyl group, such as N-dimethyl-2-[(4-phenylmethyl)pheno xyl]ethanamine, were not active. In vitro cell growth assays showed a correlation between agent-induced PKC-epsilon translocation and inhibi tion of cell growth. Exposure of cells to clomiphene resulted in apopt osis. Since PKC-epsilon has been associated with cell differentiation and cellular growth-related processes, the antiproliferative influence of tamoxifen on MCF-7 cells may be related to the interaction with PK C-E. (C) 1998 Wiley-Liss, Inc.