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Estrogen Receptor ß Activates the Human Retinoic Acid Receptor -1 Promoter in Response to Tamoxifen and Other Estrogen Receptor Antagonists, but Not in Response to Estrogen

Departments of Retinoid Research (A.Z., P.F., E.A.A.), New Leads Discovery (K.B.M., K.E.A.), and Endocrine Research (E.M.B., D.E.M.) Ligand Pharmaceuticals, Inc. San Diego, California 92121

Human estrogen receptor- (hER) or -ß (hERß) transfected into Hep G2 or COS1 cells each responded to estrogen to increase transcription from an estrogen-responsive element (ERE)-driven reporter vector with similar fold induction through a classical mechanism involving direct receptor binding to DNA. ER antagonists inhibited this estrogen induction through both hER and hERß, although raloxifene was more potent through ER than ERß, and tamoxifen was more potent via ERß than ER. We have shown previously that estrogen stimulated the human retinoic acid receptor--1 (hRAR-1) promoter through nonclassical EREs by a mechanism that was ER dependent, but that did not involve direct receptor binding to DNA. We show here that in contrast to hER, hERß did not induce reporter activity driven by the hRAR-1 promoter in the presence of estrogen. While hERß did not confer estrogen responsiveness on this promoter, it did elicit transcriptional activation in the presence of 4-hydroxytamoxifen (4-OH-Tam). Additionally, this 4-OH-Tam agonist activity via ERß was completely blocked by estrogen. Like ER, transcriptional activation of this promoter by ERß was not mediated by direct receptor binding to DNA. While hER was shown to act through two estrogen-responsive sequences within the promoter, hERß acted only at the 3'-region, through two Sp1 sites, in response to 4-OH-Tam. Other ER antagonists including raloxifene, ICI-164,384 and ICI-182,780 also acted as agonists through ERß via the hRAR-1 promoter. Through the use of mutant and chimeric receptors, it was shown that the 4-OH-Tam activity via ERß from the hRAR-1 promoter in Hep G2 cells required the amino-terminal region of ERß, a region that was not necessary for estrogen-induced ERß activity from an ERE in Hep G2 cells. Additionally, the progesterone receptor (PR) antagonist RU486 acted as a weak (IC₅₀ >1 µM) antagonist via hER and as a fairly potent (IC₅₀ 200 nM) antagonist via hERß from an ERE-driven reporter in cells that do not express PR. Although RU486 bound only weakly to ER or ERß in vitro, it did bind to ERß in whole-cell binding assays, and therefore, it is likely metabolized to an ERß-interacting compound in the cell. Interestingly, RU486 acted as an agonist through ERß to stimulate the hRAR-1 promoter in Hep G2 cells. These findings may have ramifications in breast cancer treatment regimens utilizing tamoxifen or other ER antagonists and may explain some of the known estrogenic or antiestrogenic biological actions of RU486.

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