Inhibition of growth‐factor‐activated proliferation by anti‐estrogens and effects on early gene expression of mcf‐7 cells

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Abstract
Recently, it was reported that the anti‐estrogen tamoxifen not only inhibits estradiol‐stimulated growth of MCF‐7 cells but also significantly reduces the proliferation rate of cells stimulated by growth factors. We have confirmed this finding and also shown that the new anti‐estrogen droloxifene inhibits the proliferation of epidermal growth factor (EGF) and insulin‐like growth factor‐I (IGF‐I)‐stimulated MCF‐7 cells. The growth‐factor‐induced proliferation was inhibited in a dose‐dependent manner by the anti‐estrogens in the complete absence of estrogen and FCS. Of the anti‐estrogens, droloxifene was considerably more potent than tamoxifen. Because the exprersion of the proto‐oncogenes c‐fos and c‐myc has been considered a key event in development of the mitogenic response, we examined the effects of anti‐estrogens on c‐myc and c‐fos gene expression. We included in these investigations the steroidal anti‐estrogen ICI 164,384 because this compound has no or very little estrogenic activity. The studies revealed that all 3 antiestrogens transiently induced c‐myc mRNA expression. However, the anti‐estrogens inhibited estradiol‐induced c‐myc mRNA expression, although with different potencies. Pre‐incubation of MCF‐7 cells with droloxifene and tamoxifen resulted in elevated levels of growth‐factor‐induced c‐myc mRNA expression. In contrast, the anti‐estrogens did not induce c‐fos mRNA or affect the expression of c‐fos mRNA induced by growth factors. In conclusion, non‐steroidal anti‐estrogens inhibit growth‐factor‐stimulated proliferation of MCF‐7 cells without inhibitinggrowth‐factor‐induced c‐myc or c‐fos mRNA expression.