Differential positive and negative transcriptional regulation by tamoxifen.

Tamoxifen, a nonsteroidal antiestrogen and breast cancer chemotherapeutic, exhibits both estrogen agonist and antagonist properties. Rat GC3 cells grown under estrogen-free conditions were analyzed for the expression of model luciferase reporter genes, either positively or negatively regulated by estrogens. Expression assays adding tamoxifen alone or in combination with 17 beta-estradiol were performed to determine agonist or antagonist activities. In rat GC3 cells, tamoxifen acts as an estrogen antagonist for gene activation, but as an agonist for repression. Regulation by tamoxifen is mediated by estrogen receptor (ER), not via nonreceptor tamoxifen effects. Evaluation of human ER shows that although the wild-type receptor behaves similarly to the rat receptor, the Gly400 to Val400 mutant receptor does not. Tamoxifen, an effective agonist for gene repression with rat and wild-type receptor, shows no agonist activity using this mutated Val400 receptor. Yet, 17 beta-estradiol and clomiphene, another mixed agonist/antagonist, are effective agonists for gene repression with all three receptors. In this model system, tamoxifen functions as antagonist or agonist, depending on whether the ER acts to activate or repress its gene target. In other systems regulated by estrogens, functional analyses of ER action might also serve to predict the agonist or antagonist activity of tamoxifen.