Gender differences in modulatory effects of tamoxifen upon the nigrostriatal dopaminergic system.
The antiestrogen tamoxifen competes with estrogen for receptor occupancy, although reports indicate that not all effects of tamoxifen are mediated via this specific interaction. In the present study we sought to determine whether tamoxifen can initiate transmembrane lipid signals. Lipid signaling is a prominent mode by which hormones, growth factors, and phorbol diesters transduce messages. Using the human mammary carcinoma cell line MDA-MB-231, phospholipid metabolism was analyzed in cells prelabeled with3H-fatty acid. After short-term (10 min) exposure to tamoxifen (10 µM), cellular phosphatidic acid (PA) increased by approximately 50%. Dose-response kinetics for PA formation were obtained over a tamoxifen range of 2.5-20 µM. Treatment of MDA-MB-231 cells with phorbol diester (12-O-tetradecanoylphorbol-13-acetate, TPA) also elicited PA generation (60% above control). Interestingly, addition of tamoxifen, a purported protein kinase C inhibitor, to TPA-treated cells, caused further increase in PA (approximately 100% above control). PA, a second messenger lipid produced upon effector-receptor coupling, shares a prominent role in signal transduction events that govern cellular proliferation. It is therefore suggested that some actions of tamoxifen are mediated by promoting production of second messenger lipids that elicit transmembrane signal transduction cascades. This view is in line with ideas on non-estrogen receptor associated actions of tamoxifen by way of alternate binding sites.