The effects of tamoxifen (TAM), a widely used agent in the treatment of breast cancer, were examined on phospholipase D (PLD)-mediated phospholipid hydrolysis. In drug-sensitive MCF-7 human breast carcinoma cells TAM, similar to several well-established activators of PLD, had no effect on phospholipid hydrolysis. In an estrogen receptor-deficient multidrug-resistant subline of MCF-7 cells, TAM preferentially stimulated the hydrolysis of phosphatidylethanolamine; two-fold stimulation required 2.5 or 5 μM TAM in the absence or presence of serum, respectively. In NIH 3T3 fibroblasts significant (4- to 4.8-fold) stimulation of phosphatidylethanolamine and phosphatidylcholine hydrolysis in the presence of serum required 10 μM TAM. These data establish that TAM can stimulate PLD activity by an estrogen receptor-independent mechanism.
