Estrogen Receptor Translocation and Replenishment by the Antiestrogen Tamoxifen

Abstract

The anti-estrogen tamoxifen binds cytoplasmic estrogen receptor and translocates in into the nucleus, provoking early estrogen responses; only later in normal estrogen action antagonized. These effects were examined in uteri of mature rats given 5 .mu.g estradiol or 50 .mu.g tamoxifen after ovariectomy-adrenalectomy using ligand exchange assays developed for both cytoplasmic and nuclear estrogen receptors. Both estrogen receptor translocation and uterine weight gain are slower and slower with tamoxifen than with estrogen. After estradiol or tamoxifen injections 24-48 h, cytoplasmic estrogen receptor is replenished, contary 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 2 days, which is followed by a loss of uterine weight by day 6. This failure to maintain stimulation is not due to a decline in cytoplasmic or nuclear estrogen receptors. A single dose of 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.