GROWTH-STIMULATION AND DIFFERENTIAL REGULATION OF TRANSFORMING GROWTH FACTOR-BETA-1 (TGF-BETA-1), TGF-BETA-2, AND TGF-BETA-3 MESSENGER-RNA LEVELS BY NORETHINDRONE IN MCF-7 HUMAN BREAST-CANCER CELLS

Transforming growth factor-beta (TGF-beta) is a potent growth inhibitor in most epithelial cells. We evaluated the effects of norethindrone (which in combination with estrogen is commonly used in oral contraceptives) and other progestins [medioxyprogesterone acetate (MPA) and R5020, which are not used in oral contraceptives] on cell growth and the expression of TGF-beta-1, TGF-beta-2, and TGF-beta-3 mRNAs in MCF-7 human breast cancer cells. Growth of MCF-7 cells was stimulated by norethindrone (10(-8)-10(-5) M), with maximal growth stimulation at 10(-7) M norethindrone after 7 days of treatment. However, the growth of MCF-7 cells was not affected by MPA (10(-8) M) or R5020 (10(-8) M). Treatment with the antiestrogen 4-hydroxytamoxifen at a concentration of 10(-7) M blocked the growth stimulation induced by norethindrone. The norethindrone-induced growth stimulation was accompanied by a dramatic decrease in TGF-beta-2 and TGF-beta-3 mRNA levels, whereas the level of TGF-beta-1 mRNA was not affected by any of the compounds tested. In addition, treatment with MPA or R5020 did not affect TGF-beta-2 and TGF-beta-3 mRNA levels. The inhibitory effect of norethindrone on TGF-beta-2 and TGF-beta-3 mRNA levels could be blocked by the addition of 10(-7) M 4-hydroxytamoxifen. Norethindrone as well as estradiol decreased estrogen receptor mRNA levels and increased progesterone receptor mRNA levels. This is the first report which demonstrates that norethindrone stimulates estrogen-responsive human breast cancer cell growth and inhibits the expression of TGF-beta-2 and TGF-beta-3 mRNAs. These results suggest that the differential regulation of TGF-beta expression by norethindrone may be at least partly responsible for the growth stimulation induced by norethindrone. Thus, the norethindrone component of some oral contraceptives may be sufficiently estrogenic to facilitate the development of breast cancer.