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 estrogen agonist in the uterus. The action of tamoxifen is mediated through estrogen receptors (ERalpha and ERbeta), which bind to a variety of responsive elements, to activate transcription. To examine the role of these varied 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 breast cells, whereas all antiestrogens, particularly tamoxifen, exhibited agonistic effects in uterine cell lines. All antiestrogens studied were agonistic in co-transfections of a collagenase reporter gene and ERbeta, but tamoxifen alone was agonistic with ERalpha in (uterine) HEC-1-A cells. The ERalpha mediated, agonism of tamoxifen was not observed in primary cultures of human uterine stromal cells, whereas the ERbeta-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 cells to antiestrogens is dependent on the ER subtypes expressed.