Orphan nuclear receptor DAX-1 in human endometrium and its disorders
Corresponding Author
Sumika Saito
Departments of Obstetrics and Gynecology, and
To whom correspondence should be addressed. E-mail: [email protected]Search for more papers by this authorTakashi Suzuki
Pathology, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan
Search for more papers by this authorHiroki Utsunomiya
Departments of Obstetrics and Gynecology, and
Search for more papers by this authorJun-ichi Akahira
Departments of Obstetrics and Gynecology, and
Pathology, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan
Search for more papers by this authorHironobu Sasano
Pathology, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan
Search for more papers by this authorCorresponding Author
Sumika Saito
Departments of Obstetrics and Gynecology, and
To whom correspondence should be addressed. E-mail: [email protected]Search for more papers by this authorTakashi Suzuki
Pathology, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan
Search for more papers by this authorHiroki Utsunomiya
Departments of Obstetrics and Gynecology, and
Search for more papers by this authorJun-ichi Akahira
Departments of Obstetrics and Gynecology, and
Pathology, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan
Search for more papers by this authorHironobu Sasano
Pathology, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan
Search for more papers by this authorAbstract
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 ERα (P = 0.006) and ERβ 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. (Cancer Sci 2005; 96: 645 – 652)
References
- 1 Parker SL, Tong T, Bolden S, Wingo PA. Cancer statistics. CA Cancer J Clin 1996; 46: 25–7.
- 2 Parazzini F, La Vecchia C, Bocciolone L, Francheschi S. The epidemiology of endometrial cancer. Gynecol Oncol 1991; 41: 1–16.
- 3
Silverberg SG,
Mullen D,
Faraci JA et al.
Clinical-pathologic comparison of cases in postmenopausal women receiving exogenous estrogens.
Cancer
1980; 45: 3018–26.
10.1002/1097-0142(19800615)45:12<3018::AID-CNCR2820451224>3.0.CO;2-3 CAS PubMed Web of Science® Google Scholar
- 4 Kelsey JL. A case control study of cancer of the endometrium. Am J Epidemiol 1982; 16: 333–42.
- 5 Lippman ME, Swain SA. Endocrine-responsive cancers of humans. In: JD Wilson, DW Foster, eds. Williams Textbook of Endocrinology. Philadelphia: Saunders, 1992; 1577–97.
- 6 Zanaria E, Muscatelli F, Bardoni B et al. An unusual member of the nuclear hormone receptor superfamily responsible for X-linked adrenal hypoplasia congenita. Nature 1994; 372: 635–45.
- 7 Swain A, Zanaria E, Hacker A, Lovell-Badge R, Camerino G. Mouse Dax1 expression is consistent with a role in sex determination as well as in adrenal and hypothalamus function. Nat Genet 1996; 12: 404–9.
- 8 Tamai KT, Monaco L, Alastalo TP, Lalli E, Prvinen M, Sassone-Corsi P. Hormonal and developmental regulation of DAX-1 expression in Sertoli cells. Mol Endocrinol 1996; 10: 1561–9.
- 9 Ikeda Y, Swain A, Weber TJ et al. Steroidogenic factor 1 and DAX-1 colocalization in multiple cell lineages: potential kinks in endocrine development. Mol Endocrinol 1996; 10: 1261–72.
- 10 Lalli E, Melner MH, Stocco DM, Sassone-Corsi P. DAX-1 blocks steroid production at multiple levels. Endocrinology 1998; 139: 4237–43.
- 11 Zazopoulos E, Lalli E, Stocco DM, Sassone-Corsi P. DNA binding and transcriptional repression by DAX-1 blocks steroidogenesis. Nature 1997; 390: 311–5.
- 12 Sugawara T, Lin D, Hoolt J et al. Structure of the human steroidogenic acute regulatory protein (StAR) gene: StAR stimulates mitochondrial cholesterol 27 hydroxylase activity. Biochemistry 1995; 34: 12506–12.
- 13 Stocco DM, Clark BJ. Regulation of acute production of steroid in steroidogenic tissue. Endocr Rev 1996; 17: 221–44.
- 14 Parker KL, Schimmer BP. Steroidogenic factor 1: a key determinant of endocrine development and function. Endocr Rev 1997; 18: 361–77.
- 15 Takayama K, Sasano H, Fukuya T et al. Immunohistochemical localization of Ad4-binding protein with correlation to steroidogenic enzyme expression in cycling human ovaries and sex cord stromal tumors. J Clin Endocrinol Metab 1995; 80: 2815–21.
- 16 Crawford PA, Dorn C, Sadovsky Y, Milbrandt J. Nuclear receptor DAX-1 recruits nuclear receptor corepressor N-CoR to steroidogenic factor 1. Mol Cell Biol 1998; 18: 2949–56.
- 17 Hanley NA, Rainey WE, Wilson DI, Ball SG, Parker KL. Expression profiles of SF-1, DAX1, and CYP17 in the human fetal adrenal gland: potential interactions in gene regulation. Mol Endocrinol 2001; 15: 57–68.
- 18 Wang ZJ, Jeffs B, Ito M et al. Aromatase (Cyp19) expression is up-regulated by targeted disruption of Dax1. Proc Natl Acad Sci USA 2001; 98: 7988–93.
- 19 Gurates B, Sebastian S, Yang S et al. WT1 and DAX-1 inhibit aromatase P450 expression in human endometrial and endometriotic stromal cells. J Clin Endocrinol Metab 2002; 87: 4369–77.
- 20 Lalli E, Ohe K, Hindelang C, Sassone-Corsi P. Orphan receptor DAX-1 is a shuttling RNA binding protein associated with polyribosomes via mRNA. Mol Cell Biol 2000; 20: 4910–21.
- 21 Zhang H, Thomsen JS, Johansson L, Gustafsson JA, Treuter E. DAX-1 functions as an LXXLL-containing corepressor for activated estrogen receptors. J Biol Chem 2000; 275: 39855–9.
- 22
Creasman WT.
FIGO Stages: 1988 revision.
Gynecol Oncol
1989; 35: 125–7.
10.1016/0090-8258(89)90027-9 Google Scholar
- 23 Patel MV, Mckay IA, Burrin JM. Transcriptional regulators of steroidogenesis, DAX-1 and SF-1, are expressed in human skin. J Invest Dermatol 2001; 117: 1559–65.
- 24 Aylwin SJ, Welch JP, Davey CL et al. The relationship between steroidogenic factor 1 and DAX-1 expression and in vitro gonadotropin secretion in human pituitary adenomas. J Clin Endocrinol Metab 2001; 86: 2476–83.
- 25 Holter E, Kotaja N, Makela S et al. Inhibition of androgen receptor (AR) function by the reproductive orphan nuclear receptor DAX-1. Mol Endocrinol 2002; 16: 515–28.
- 26 Agoulnik IU, Krause WC, Bingman WE 3rd et al. Repressors of androgen and progesterone receptor action. J Biol Chem 2003; 278: 31136–48.
- 27 Sato Y, Suzuki T, Hidaka K et al. Immuno-localizaion of nuclear transcription factor, DAX-1 and COUP-TF in the normal human ovary: correlation with Ad4BP/SF-1 immuno-localization during the menstrual cycle. J Clin Endocrinol Metab 2002; 87: 4369–77.
- 28 Manar A-E, Akahira J, Moriya T, Suzuki T, Yaegashi N, Sasano H. Nuclear receptor DAX-1 in human common epithelial ovarian carcinoma: An independent prognostic factor of clinical outcome. Cancer Sci 2003; 94: 980–5.
- 29 Honda S, Morohashi K, Nomura M, Takeya H, Kitajima M, Omura T. Ad4BP regulating steroidogenic P-450 gene is a member of steroid hormone receptor superfamily. J Biol Chem 1993; 268: 7494–502.
- 30 Suzuki T, Sasano H, Kimura N et al. Immunohistochemical distribution of progesterone, androgen and oestrogen receptors in the human ovary during the menstrual cycle: relationship to expression of steroidogenic enzymes. Hum Reprod 1994; 9: 1589–95.
- 31 Sasano H, Shizawa S, Suzuki T et al. Ad4BP in the human adrenal cortex and its disorder. J Clin Endocrinol Metab 1995; 80: 2378–80.
- 32 Layfield LJ, Gupta D, Mooney EE. Assessment of tissue estrogen and progesterone receptor levels: a survey of current practice, techniques, and quantitation methods. Breast J 2000; 6: 189–96.
- 33 Wittwer CT, Ririe KM, Andrew RV, David DA, Gundry RA, Balis UJ. The LightCycler: a microvolume multisame fluorimeter with rapid temperature control. Biotechniques 1997; 22: 176–81.
- 34 Read SJ. Recovery efficiencies on nuclei acid extraction kits as measured by quantitative LightCycler PCR. Mol Pathol 2001; 54: 86–90.
- 35 Dumoulin FL, Nischalke HD, Leifeld L et al. Semi-quantification of human C-C chemokine mRNAs with reverse transcription/real time PCR using multi-specific standards. J Immunol Methods 2000; 241: 109–19.
- 36 Saruta M, Takahashi K, Suzuki T, Torii A, Kawakami M, Sasano H. Ucrocorin 1 in colonic mucosa in patients with ulcerative colitis. J Clin Endocrinol Metab 2004; 89: 5352–61.
- 37 Watanabe K, Sasano H, Harada N et al. Aromatase in human endometrial carcinoma and hyperplasia: Immunohistochemical in situ hybridization, and biochemical studies. Am J Pathol 1995; 146: 491–500.
- 38 Utsunomiya H, Suzuki T, Kaneko C et al. The analyses of 17β-hydroxysteroid dehydrogenase isozyme in human endometrial hyperplasia and carcinoma. J Clin Endocrinol Metab 2001; 86: 3436–43.
- 39 Jongen VH, Sluijmer AV, Heineman MJ. The postmenopausal ovary as an androgen-producing gland; hypothesis on the etiology of endometrial cancer. Maturitas 2002; 43: 77–85.
- 40 Utsunomiya H, Ito K, Suzuki T et al. Steroid sulfatase and estrogen sulfotransferase in human endometrial carcinoma. Clin Cancer Res 2004; 10: 5850–6.
- 41 Hinshelwood MM, Repa JJ, Shelton JM, Richardson JA, Mangelsdorf DJ, Mendelson CR. Expression of LRH-1 and SF-1 in the mouse ovary: localization in different cell types correlates with differing function. Mol Cell Endocrinol 2003; 207: 39–45.
- 42 Clyne CD, Speed CJ, Zhou J, Simpson ER. Liver Receptor Homologue-1 (LRH-1) regulates expression of aromatase in preadipocytes. J Biol Chem 2002; 277: 20591–7.
- 43 Matsuzaki S, Fukaya T, Suzuki T, Murakami T, Sasano H, Yajima A. Oestrogen receptor γ and β mRNA expression in human endometrium throughout the menstrual cycle. Mol Human Reprod 1999; 5: 559–64.
- 44 Baak JPA, Wisse-Brekelmans ECM, Fleege JC, van Der Putten HWHM, Bezemer PD. Assessment of the risk of endometrial cancer in hyperplasia by means of morphological and morphometrical features. Path Res Pract 1992; 188: 856–9.
- 45
Kurman RJ,
Kaminski PF,
Norris HJ.
The behavior of endometrial hyperplasia. A long-term study of ‘untreated’ hyperplasia in 170 patients.
Cancer
1985; 56: 403–12.
10.1002/1097-0142(19850715)56:2<403::AID-CNCR2820560233>3.0.CO;2-X CAS PubMed Web of Science® Google Scholar
- 46 Maxwell GL, Risinger JI, Gumbs C et al. Mutation of the PTEN tumor suppressor gene in endometrial hyperplasia. Cancer Res 1998; 58: 2500–3.
- 47 Sasaki H, Nishii H, Takahashi H et al. Mutation of the Ki-ras protooncogene in human endometrial hyperplasia and carcinoma. Cancer Res 1993; 53: 1906–10.
- 48 Ngan ES, Hashimoto Y, Ma ZQ, Tsai MJ, Tsai SY. Overexpression of Cdc25B, an androgen receptor coactivator, in prostate cancer. Oncogene 2003; 22: 734–9.
