California Breast Cancer Research Program

Tamoxifen, a synthetic antiestrogen, is known for its antitumoral action in vivo; however, it is well accepted that many tamoxifen effects are elicited via estrogen receptor-independent routes. Previously, we reported that tamoxifen induces PKC translocation in fibroblasts. In the present study, we investigated the influence of tamoxifen, and several triphenylethylene derivatives, on protein kinase C (PKC) in MCF-7 human breast cancer cells. As measured by Western blot analysis, tamoxifen elicited isozyme-specific membrane association of PKC-epsilon, which was time-dependent (as early as 5 min post-treatment) and dose-dependent (5.0-20 microM). Tamoxifen did not influence translocation of alpha, beta, gamma, delta or zeta PKC isoforms. Structure-activity relationship studies demonstrated chemical requirements for PKC-epsilon translocation, with tamoxifen, 3-OH-tamoxifen and clomiphene being active. Compounds without the basic amino side chain, such as triphenylethylene, or minus a phenyl group, such as N,N-dimethyl-2-[(4-phenylmethyl)phenoxy]ethanamine, were not active. In vitro cell growth assays showed a correlation between agent-induced PKC-epsilon translocation and inhibition of cell growth. Exposure of cells to clomiphene resulted in apoptosis. 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 PKC-epsilon.