Inhibition of phorbol ester-stimulated phospholipase D activity by chronic tamoxifen treatment in breast cancer cells.

We have shown that in an estrogen receptor-negative multidrug-resistant subline of MCF-7 human breast carcinoma cells longer-term (24 h), but not shorter-term (30 min), treatments with clinically relevant (2–5 μM) concentrations of tamoxifen (TAM) inhibited phorbol ester-stimulated phospholipase D (PLD) activity by 50–80%. TAM caused these inhibitory effects without inducing membrane translocation or down-regulation of protein kinase C-α, the major mediator of phorbol ester effects on PLD activation. The results raise the possibility that prolonged inhibition of the protein kinase C-α-regulated PLD system may contribute to the cytotoxic effects of tamoxifen in estrogen receptor-negative breast cancer cells.