Activation of the human estrogen receptor by the antiestrogens ICI 182,780and tamoxifen in yeast genetic systems: Implications for their mechanism of action

The antiestrogens tamoxifen and ICI 182,780 have been portrayed as competit ive antagonists of the estrogen binding site of the Lu-form of the human es trogen receptor (ER), However, in functional studies, neither compound has consistently been able to block estradiol-induced transcription. In this re port, three yeast genetic systems were used to investigate the effects of t amoxifen and ICI 182.780 on ER dimerization, transcriptional activation, an d the interaction of the receptor with a coactivator, RIP140. Tamoxifen and ICI 182,780 were able to induce ER dimerization and ER-dependent transcrip tion, albeit at up to 15,000-fold higher concentrations than that of estrad iol. In the presence of RIP140, the transcription response maximum was incr eased up to 30-fold for estradiol and both antiestrogens. Whole yeast cell [H-3]estradiol binding studies demonstrated that tamoxifen could displace t he estradiol from the ER, whereas ICI 182,780 treatment resulted in a 4-fol d increase in [H-3]estradiol binding to the receptor. No antagonism of estr adiol was observed with tamoxifen or ICI 182,780 in any of the yeast models employed. We have concluded that the antiestrogen activity of compounds li ke tamoxifen and ICI 182,780 is not caused by their ability to competitivel y antagonize estradiol binding to the hormone binding site, but possibly by their ability to induce ER-dependent transcription, which in mammalian sys tems would result in receptor down-regulation. Compounds such as tamoxifen act through the hormone binding site, whereas ICI 182,780 may cause recepto r activation through an allosteric binding site.