Orphan nuclear receptor DAX-1 in human endometrium and its disorders.
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.
Saito
Sumika
S
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
Ito
Kiyoshi
K
Suzuki
Takashi
T
Utsunomiya
Hiroki
H
Akahira
Jun-ichi
J
Sugihashi
Youko
Y
Niikura
Hitoshi
H
Okamura
Kunihiro
K
Yaegashi
Nobuo
N
Sasano
Hironobu
H
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*
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