The agonist activity of tamoxifen is inhibited by the short heterodimer partner orphan nuclear receptor in human endometrial cancer cells

Short heterodimer partner (SHP) is an orphan nuclear receptor that interacts with ERalpha and ERbeta 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 ERalpha 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 ERalpha or ERbeta. SHP inhibited E2-induced transcriptional activity in ERalpha- or ERbeta-transfected HEC-1A or Chinese hamster ovary-K1 cells. SHP inhibition of E2 activity was greater for ERalpha than ERbeta 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 ERalpha mutant lacking activator function-1 showed reduced inhibition by SHP. In glutathione S-transferase pull-down experiments, SHP inhibited ERa 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.