title: The agonist activity of tamoxifen is inhibited by the short heterodimer partner orphan nuclear receptor in human endometrial cancer cells.
abstract: Short heterodimer partner (SHP) is an orphan nuclear receptor that interacts with ER(alpha) 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 ER(alpha) 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 ER(alpha) or ERbeta. SHP inhibited E2-induced transcriptional activity in ER(alpha)- or ERbeta-transfected HEC-1A or Chinese hamster ovary-K1 cells. SHP inhibition of E2 activity was greater for ER(alpha) 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 ER(alpha) mutant lacking activator function-1 showed reduced inhibition by SHP. In glutathione S-transferase pull-down experiments, SHP inhibited ER(alpha) 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.
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Louisville School of Medicine, Louisville, Kentucky 40292, USA. carolyn.klinge@louisville.edu
authors.forename: Carolyn M
authors.initials: CM
authors.lastname: Klinge
authors.forename: Sarah C
authors.initials: SC
authors.lastname: Jernigan
authors.forename: Kelly E
authors.initials: KE
authors.lastname: Risinger
mesh_terms: D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D015153:Blotting, Western; D016466:CHO Cells; D006224:Cricetinae; D016889:Endometrial Neoplasms / Q000188:drug therapy*; D004958:Estradiol / Q000378:metabolism; D004965:Estrogen Antagonists / Q000494:pharmacology; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D005260:Female; D017930:Genes, Reporter / Q000235:genetics; D005982:Glutathione Transferase / Q000378:metabolism; D006801:Humans; D010957:Plasmids / Q000235:genetics; D018160:Receptors, Cytoplasmic and Nuclear / Q000502:physiology*; D011960:Receptors, Estrogen / Q000037:antagonists & inhibitors; D013629:Tamoxifen / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D014162:Transfection; D014407:Tumor Cells, Cultured
chemical_list: D018931:Antineoplastic Agents, Hormonal; D004965:Estrogen Antagonists; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D018160:Receptors, Cytoplasmic and Nuclear; D011960:Receptors, Estrogen; C099713:nuclear receptor subfamily 0, group B, member 2; D013629:Tamoxifen; C016601:afimoxifene; D004958:Estradiol; D005982:Glutathione Transferase