title: Orphan nuclear receptor DAX-1 in human endometrium and its disorders.
abstract: DAX-1 (dosage-sensitive sex reversal adrenal hypoplasia congenita critical region on the X chromosome gene 1) is a recently characterized member of the orphan nuclear receptor family. DAX-1 functions as a global negative regulator of steroid hormone production. It inhibits adrenal 4 binding protein (Ad4BP)/steroidogenic factor-1 (SF-1) pathway-dependent P450arom expression in cultured human endometriotic stromal cells and acts as a corepressor for estrogen receptors (ER). In this study we first examined the localization of DAX-1 in 46 normal cycling endometria, 36 cases of endometrial hyperplasia and 103 cases of endometrial carcinoma by using immunohistochemistry to elucidate the possible involvement of DAX-1 and its correlation to the status of Ad4BP/SF-1, a universal transcription factor of steroidogenesis. We then evaluated DAX-1 mRNA expression, using quantitative reverse transcription-polymerase chain reaction for DAX-1 in 33 cases of endometrial carcinoma for further characterization. We subsequently correlated these findings with various clinicopathological parameters of the cases. Ad4BP/SF-1 immunoreactivity was not detected in any human endometria examined. A significant inverse correlation was detected between the status of DAX-1 immunoreactivity and histological grade (P = 0.0003) in endometrial carcinoma. The labeling index (LI) values of DAX-1 in normal endometrium during the secretory phase (P < 0.0001) and hyperplasia (P < 0.0001) were significantly higher than that of carcinoma. No significant correlations were detected between DAX-1 immunoreactivity and amounts of aromatase mRNA. There was a statistically significant positive correlation between DAX-1 and ERalpha (P = 0.006) and ERbeta LI (P < 0.001). These findings suggest that DAX-1 may inhibit the proliferation and progression of endometrial carcinoma through inhibition of estrogenic actions, possibly by interacting with ER present in carcinoma cells, rather than regulating in situ steroidogenesis.
authors.affiliation: Department of Obstetrics and Gynecology, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendia 980-8575, Japan. s221t@mail.tains.tohoku.ac.jp
authors.forename: Sumika
authors.initials: S
authors.lastname: Saito
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Ito
authors.forename: Takashi
authors.initials: T
authors.lastname: Suzuki
authors.forename: Hiroki
authors.initials: H
authors.lastname: Utsunomiya
authors.forename: Jun-ichi
authors.initials: J
authors.lastname: Akahira
authors.forename: Youko
authors.initials: Y
authors.lastname: Sugihashi
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Niikura
authors.forename: Kunihiro
authors.initials: K
authors.lastname: Okamura
authors.forename: Nobuo
authors.initials: N
authors.lastname: Yaegashi
authors.forename: Hironobu
authors.initials: H
authors.lastname: Sasano
mesh_terms: D000311:Adrenal Glands / Q000166:cytology; D001141:Aromatase / Q000096:biosynthesis; D002277:Carcinoma / Q000503:physiopathology*; D002460:Cell Line; D057137:DAX-1 Orphan Nuclear Receptor; D004268:DNA-Binding Proteins / Q000032:analysis* / Q000096:biosynthesis / Q000502:physiology*; D004714:Endometrial Hyperplasia / Q000503:physiopathology; D016889:Endometrial Neoplasms / Q000503:physiopathology*; D004717:Endometrium / Q000737:chemistry* / Q000502:physiology; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D005260:Female; D006367:HeLa Cells; D006801:Humans; D007150:Immunohistochemistry; D012333:RNA, Messenger / Q000096:biosynthesis; D018168:Receptors, Retinoic Acid / Q000032:analysis* / Q000096:biosynthesis / Q000502:physiology*; D012097:Repressor Proteins / Q000032:analysis* / Q000096:biosynthesis / Q000502:physiology*
chemical_list: D057137:DAX-1 Orphan Nuclear Receptor; D004268:DNA-Binding Proteins; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; C539965:NR0B1 protein, human; D012333:RNA, Messenger; D018168:Receptors, Retinoic Acid; D012097:Repressor Proteins; D001141:Aromatase