Activation of transcription by estrogen receptor alpha and beta is cell type- and promoter-dependent

Tamoxifen acts as a strong estrogen antagonist in human breast but as an es trogen agonist in the uterus. The action of tamoxifen is mediated through e strogen receptors (ER alpha and ER beta), which bind to a variety of respon sive elements, to activate transcription. To examine the role of these vari ed elements in the response to antiestrogens, we studied the activation of a panel of differing promoters, by these compounds, in human breast, bone, and endometrial derived cell lines. No agonistic activity was observed in b reast cells, whereas all antiestrogens, particularly tamoxifen, exhibited a gonistic effects in uterine cell lines. All antiestrogens studied were agon istic in co-transfections of a collagenase reporter gene and ER beta, but t amoxifen alone was agonist ic with ER alpha in (uterine) HEC-1-A cells. The ER alpha mediated, agonism of tamoxifen was not observed in primary cultur es of human uterine stromal cells, whereas the ER beta-mediated agonism of all selective estrogen receptor modulators was present. This suggests that the two receptors operate by distinct pathways and that the response of cel ls to antiestrogens is dependent on the ER subtypes expressed.