Short heterodimer partner (SHP) is an orphan nuclear receptor that interacts with ERα and ERβ and inhibits E2-induced transcription. We examined how SHP affects tamoxifen's estrogen agonist activity in endometrial cells. We report that SHP interacts with 4-hydroxytamoxifen (4-OHT) or E2-occupied ERα in a temperature-dependent manner in vitro. In transient transfection assays, SHP inhibited 4-OHT-stimulated reporter gene activity from an estrogen response element (ERE) in ER-positive RL95-2 but not in HEC-1A human endometrial carcinoma cells transfected with ERα or ERβ. SHP inhibited E2-induced transcriptional activity in ERα- or ERβ-transfected HEC-1A or Chinese hamster ovary-K1 cells. SHP inhibition of E2 activity was greater for ERα than ERβ from the nonpalindromic ERE in the pS2 gene promoter in Chinese hamster ovary-K1 but not HEC-1A cells. Thus, ER subtype, cell type, and ERE sequence influence SHP repressor activity. An ERα mutant lacking activator function-1 showed reduced inhibition by SHP. In glutathione S-transferase pulldown experiments, SHP inhibited ERα dimerization, providing a possible mechanism to account for the inhibitory effect of SHP on ER activity. These results identify SHP as novel target for blocking 4-OHT agonist activity in endometrial cells.
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