Estrogen Receptor Translocation and Replenishment by the Antiestrogen Tamoxifen

Abstract

The anti-estrogen tamoxifen binds cytoplasmic estrogen receptor and translocates it into the nucleus, provoking early estrogen responses; only later is normal estrogen action antagonized. We examined these effects in uteri of mature rats given 5 μg estradiol or 50 μg tamoxifen after ovariectomy- adrenalectomy, using ligand exchange assays developed in this laboratory for both cytoplasmic and nuclear estrogen receptors. We show that both estrogen receptor translocation and uterine weight gain are slower with tamoxifen than with estrogen. Twenty-four to 48 h after estradiol or tamoxifen injections cytoplasmic estrogen receptor is replenished, contrary to the hypothesis that anti-estrogens antagonize subsequent estrogen action by failing to replenish cytoplasmic receptor. This new receptor appearing by 48 h after tamoxifen treatment is capable of being translocated by estradiol. Six daily doses of estradiol continue to increase uterine weight and soluble cytosol proteins. The same regimen of daily tamoxifen injections results in an initial uterine weight stimulation, comparable to estradiol for the first two days, which is followed by a loss of uterine weight by day six. This failure to maintain stimulation is not due to a decline in either cytoplasmic or nuclear estrogen receptors; in fact, a single dose of tamoxifen causes receptor to be retained in the nucleus for several days even while additional receptor appears in the cytoplasm. It is possible that the “processing” step which removes receptor-estradiol complexes from the nucleus is somehow defective in the case of at least some anti-estrogens and that this step is required for continued estrogenic stimulation.