Tamoxifen induces selective membrane association of protein kinase C epsilon in MCF-7 human breast cancer cells

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Abstract
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‐ϵ, which was time‐dependent (as early as 5 min post‐treatment) and dose‐dependent (5.0–20 μM). Tamoxifen did not influence translocation of α, β, γ, δ or ζ PKC isoforms. Structure‐activity relationship studies demonstrated chemical requirements for PKC‐ϵ 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‐ϵ translocation and inhibition of cell growth. Exposure of cells to clomiphene resulted in apoptosis. Since PKC‐ϵ 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‐ϵ. Int. J. Cancer 77:928–932, 1998.

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