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. We have used human
breast cancer cells in long term culture 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 is found to have dual dose-dependent estrogenic/antiestrogenic properties. With 1 micrometer
tamoxifen, cell growth and PgR induction are suppressed. These effects are reversed by
estradiol. At lower doses (less than 0.1 micrometer), however,
tamoxifen is a potent
estrogen and rapidly induces (24--48 h) PgR, which increases 4- to 10-fold after 4--6 days and falls if
tamoxifen is removed. Induction of PgR by
estradiol is weaker but follows a similar time course.
Tamoxifen-induced PgR is similar to that induced by
estradiol; it sediments at 8S on
sucrose density gradients, is a tight binder (
R5020 Kd, 1.7 micrometer at 4 C and 0.87 nM at 15 C), and can be translocated to the nucleus by
R5020. The dual properties of
tamoxifen are not due to metabolic formation of an active
antiestrogen from a prohormone precursor. In contrast, the action of the
antiestrogen nafoxidine is not biphasic in MCF-7 cells; it does not induce PgR over a wide dose range and at high doses, the compound inhibits cell growth.