Estrogen Control of Progesterone Receptor in Human Breast Cancer: Role of Estradiol and Antiestrogen*

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Abstract
Estrogen antagonists are widely used in the treatment of breast cancer, and studies of their mechanism of action may provide clues to an understanding of tumor growth regulation and mechanisms of normal estrogen action. Human breast cancer cells in long term culture were used as an in vitro model to study the roles of estradiol and the antiestrogens, tamoxifen and nafoxidine, on cell growth and progesterone receptor (PgR) induction. Tamoxifen had dual dose-dependent estrogenic/antiestrogenic properties. With 1 .mu.M tamoxifen, cell growth and PgR induction were suppressed. These effects were reversed by estradiol. At lower doses (< 0.1 .mu.M) tamoxifen was a potent estrogen and rapidly induced (24-48 h) PgR, which increased 4- to 10-fold after 4-6 days and fell if tamoxifen was removed. Induction of PgR by estradiol was weaker but followed a similar time course. Tamoxifen-induced PgR was similar to that induced by estradiol; it sedimented at 8S on sucrose density gradients, was a tight binder (R5020 Kd, 1.7 .mu.M at 4.degree. Cand 0.87 nM at 15.degree. C) and was translocated to the nucleus by R5020. The dual properties of tamoxifen were not due to metabolic formation of an active antiestrogen from a prohormone precursor. The action of the antiestrogen nafoxidine was not biphasic in MCF-7 cells; it did not induce PgR over a wide dose range and at high doses, the compound inhibited cell growth.