Suppression of estrogen receptor-mediated transcription and cell growth by interaction with TR2 orphan receptor.
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.
Hu
Yueh-Chiang
YC
George Whipple Laboratory for Cancer Research, Department of Pathology, University of Rochester Medical Center, 601 Elmwood Avenue, Rochester, NY 14642, USA.
Shyr
Chih-Rong
CR
Che
Wenyi
W
Mu
Xiao-Min
XM
Kim
Eungseok
E
Chang
Chawnshang
C
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
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