title: Suppression of estrogen receptor-mediated transcription and cell growth by interaction with TR2 orphan receptor.
abstract: The transcriptional activity of the estrogen receptor (ER) is known to be highly modulated by the character and amount of coregulator proteins present in the cells. TR2 orphan receptor (TR2), a member of the nuclear receptor superfamily without identified ligands, is found to be expressed in the breast cancer cell lines and to function as a repressor to suppress ER-mediated transcriptional activity. Utilizing an interaction blocker, ER-6 (amino acids 312-340), responsible for TR2 interaction, the suppression of ER by TR2 could be reversed, suggesting that this suppression is conferred by the direct protein-protein interaction. Administration of antisense TR2, resulting in an enhancement of ER transcriptional activity in MCF7 cells, indicates that endogenous TR2 normally suppresses ER-mediated signaling. To gain insights into the molecular mechanism by which TR2 suppresses ER, we found that TR2 could interrupt ER DNA binding via formation of an ER-TR2 heterodimer that disrupted the ER homodimerization. The suppression of ER transcription by TR2 consequently caused the inhibition of estrogen-induced cell growth and G(1)/S transition in estrogen-dependent breast cancer cells. Taken together in addition to the potential roles in spermatogenesis and neurogenesis, our data provide a novel biological function of TR2 that may exert an important repressor in regulating ER activity in mammary glands.
authors.affiliation: George Whipple Laboratory for Cancer Research, Department of Pathology, University of Rochester Medical Center, 601 Elmwood Avenue, Rochester, NY 14642, USA.
authors.forename: Yueh-Chiang
authors.initials: YC
authors.lastname: Hu
authors.forename: Chih-Rong
authors.initials: CR
authors.lastname: Shyr
authors.forename: Wenyi
authors.initials: W
authors.lastname: Che
authors.forename: Xiao-Min
authors.initials: XM
authors.lastname: Mu
authors.forename: Eungseok
authors.initials: E
authors.lastname: Kim
authors.forename: Chawnshang
authors.initials: C
authors.lastname: Chang
mesh_terms: D000818:Animals; D002455:Cell Division; D004247:DNA / Q000378:metabolism; D019281:Dimerization; D005260:Female; D016193:G1 Phase; D006801:Humans; D051379:Mice; D057107:Nuclear Receptor Subfamily 2, Group C, Member 1; D012333:RNA, Messenger / Q000032:analysis; D011817:Rabbits; D011960:Receptors, Estrogen / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D011988:Receptors, Thyroid Hormone / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D016196:S Phase; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured
chemical_list: C539822:NR2C1 protein, human; C539823:Nr2c1 protein, mouse; D057107:Nuclear Receptor Subfamily 2, Group C, Member 1; D012333:RNA, Messenger; D011960:Receptors, Estrogen; D011988:Receptors, Thyroid Hormone; D004247:DNA