Genetic and epigenetic alterations of steroidogenic factor‑1 in ovarian tumors

Miller,Sarah; Bhasin,Nobel; Urrego,Heather; Moroz,Krzysztof; Rowan,Brian  G.; Ramayya,Meera S.; Makridakis,Nick  M.

doi:10.3892/ijo.2012.1758

Genetic and epigenetic alterations of steroidogenic factor‑1 in ovarian tumors

Authors:
- Sarah Miller
- Nobel Bhasin
- Heather Urrego
- Krzysztof Moroz
- Brian G. Rowan
- Meera S. Ramayya
- Nick M. Makridakis
View Affiliations

Affiliations: The Ohio Department of Health, Columbus, OH 43215, USA, Department of Epidemiology and Tulane Cancer Center, Tulane University, New Orleans, LA 70112, USA, Department of Pathology, Tulane University School of Medicine, New Orleans, LA 70112, USA, Department of Structural and Cellular Biology and Tulane Cancer Center, Tulane University School of Medicine, New Orleans, LA 70112, USA, Department of Pediatrics, John A. Burns School of Medicine, University of Hawaii, Honolulu, HI 96813, USA
Published online on: December 28, 2012 https://doi.org/10.3892/ijo.2012.1758
Pages: 627-634

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Steroidogenic factor-1 (SF‑1), the product of the NR5A1 gene, is an essential transcription factor that is known to regulate steroidogenesis in ovarian epithelia, including the synthesis of progesterone, a suppressor of ovarian cancer. Expression of the SF‑1 protein, a potential ovarian tumor suppressor, has been demonstrated in normal OSE cells, but is lost in most ovarian tumors and ovarian tumor cell lines. We examined loss of heterozygosity (LOH) and promoter methylation as potential mechanisms that may explain the loss of SF‑1 protein in ovarian tumor tissues. Genotyping of three NR5A1 SNPs in matched tumor/normal tissues identified LOH in 16/36 (44%) of the ovarian tumors successfully analyzed, and somatic mutations (gain of allele) in 10% of the tumors. Furthermore, a methylation-sensitive restriction enzyme method was used to demonstrate statistically significant (p<0.0001) increase in the frequency of NR5A1 gene methylation in ovarian tumors (36/46; 78%) versus normal ovaries (1/11; 9%). These data suggest that the SF‑1 encoding gene exhibits frequent genetic (LOH/base substitution) and epigenetic (methylation) somatic alterations in ovarian tumors. These data also present novel molecular mechanisms that may explain the loss of SF‑1 protein in ovarian tumors, and its potential role in ovarian carcinogenesis.

View Figures

View References

1.	Ozols RF: Treatment goals in ovarian cancer. Int J Gynecol Cancer. 15(Suppl 1): 3–11. 2005. View Article : Google Scholar : PubMed/NCBI
2.	Leung PC and Choi JH: Endocrine signaling in ovarian surface epithelium and cancer. Hum Reprod Update. 13:143–162. 2007. View Article : Google Scholar : PubMed/NCBI
3.	Rae MT, Niven D, Ross A, Forster T, Lathe R, Critchley HOD, Ghazal P and Hillier SG: Steroid signalling in human ovarian surface epithelial cells: the response to interleukin-1alpha determined by microarray analysis. J Endocrinol. 183:19–28. 2004. View Article : Google Scholar : PubMed/NCBI
4.	Papacleovoulou G, Hogg K, Fegan KS, Critchley HO, Hillier SG and Mason JI: Regulation of 3beta-hydroxysteroid dehydrogenase type 1 and type 2 gene expression and function in the human ovarian surface epithelium by cytokines. Mol Hum Reprod. 15:379–392. 2009. View Article : Google Scholar : PubMed/NCBI
5.	Ivarsson K, Sundfeldt K, Brannstrom M and Janson PO: Production of steroids by human ovarian surface epithelial cells in culture: possible role of progesterone as growth inhibitor. Gynecol Oncol. 82:116–121. 2001. View Article : Google Scholar : PubMed/NCBI
6.	Okamura H, Katabuchi H and Ohba T: What we have learned from isolated cells from human ovary? Mol Cell Endocrinol. 202:37–45. 2003. View Article : Google Scholar : PubMed/NCBI
7.	Nash DM, Hess SA, White BA and Peluso JJ: Steroidogenic factor-1 regulates the rate of proliferation of normal and neoplastic rat ovarian surface epithelial cells in vitro. Endocrinology. 139:4663–4671. 1998.PubMed/NCBI
8.	Batsche E, Desroches J, Bilodeau S, Gauthier Y and Drouin J: Rb enhances p160/SRC coactivator-dependent activity of nuclear receptors and hormone responsiveness. J Biol Chem. 280:19746–19756. 2005. View Article : Google Scholar : PubMed/NCBI
9.	Tran PV, Akana SF, Malkovska I, Dallman MF, Parada LF and Ingraham HA: Diminished hypothalamic bdnf expression and impaired VMH function are associated with reduced SF-1 gene dosage. J Comp Neurol. 498:637–648. 2006. View Article : Google Scholar : PubMed/NCBI
10.	Syed V, Ulinski G, Mok SC, Yiu GK and Ho SM: Expression of gonadotropin receptor and growth responses to key reproductive hormones in normal and malignant human ovarian surface epithelial cells. Cancer Res. 61:6768–6776. 2001.
11.	Hinkula M, Pukkala E, Kyyrönen P and Kauppila A: Incidence of ovarian cancer of grand multiparous women - A population-based study in Finland. Gynecol Oncol. 103:207–211. 2006. View Article : Google Scholar : PubMed/NCBI
12.	Sugawara T, Kiriakidou M, McAllister JM, Holt JA, Arakane F and Strauss JF III: Regulation of expression of the steroidogenic acute regulatory protein (StAR) gene: a central role for steroidogenic factor 1. Steroids. 62:5–9. 1997. View Article : Google Scholar : PubMed/NCBI
13.	Fujieda K, Tajima T, Nakae J, Sageshima S, Tachibana K, Suwa S, Sugawara T and Strauss JF III: Spontaneous puberty in 46,XX subjects with congenital lipoid adrenal hyperplasia. Ovarian steroidogenesis is spared to some extent despite inactivating mutations in the steroidogenic acute regulatory protein (StAR) gene. J Clin Invest. 99:1265–1271. 1997. View Article : Google Scholar
14.	Ramayya MS, Sheng M, Moroz K, Hill SM and Rowan BG: Human steroidogenic factor-1 (hSF-1) regulates progesterone biosynthesis and growth of ovarian surface epithelial cancer cells. J Steroid Biochem Mol Biol. 119:14–25. 2010. View Article : Google Scholar
15.	Abd-Elaziz M, Moriya T, Akahira J, Suzuki T and Sasano H: StAR and progesterone producing enzymes (3beta-hydroxysteroid dehydrogenase and cholesterol side-chain cleavage cytochromes P450) in human epithelial ovarian carcinoma: immunohistochemical and real-time PCR studies. Cancer Sci. 96:232–239. 2005. View Article : Google Scholar
16.	Taketo M, Parker KL, Howard TA, Tsukiyama T, Wong M, Niwa O, Morton CC, Miron PM and Seldin MF: Homologs of Drosophila Fushi-Tarazu factor 1 map to mouse chromosome 2 and human chromosome 9q33. Genomics. 25:565–567. 1995.
17.	Schultz DC, Vanderveer L, Buetow KH, Boente MP, Ozols RF, Hamilton TC and Godwin AK: Characterization of chromo-some 9 in human ovarian neoplasia identifies frequent genetic imbalance on 9q and rare alterations involving 9p, including CDKN2. Cancer Res. 55:2150–2157. 1995.
18.	Hoivik EA, Aumo L, Aesoy R, Lillefosse H, Lewis AE, Perrett RM, Stallings NR, Hanley NA and Bakke M: Deoxyribonucleic acid methylation controls cell type-specific expression of steroidogenic factor 1. Endocrinology. 149:5599–5609. 2008. View Article : Google Scholar : PubMed/NCBI
19.	Nakamura J, Kitajima Y, Kai K, Hashiguchi K, Hiraki M, Noshiro H and Miyazaki K: Expression of hypoxic marker CA IX is regulated by site-specific DNA methylation and is associated with the histology of gastric cancer. Am J Pathol. 178:515–524. 2011. View Article : Google Scholar : PubMed/NCBI
20.	Seidman JD, Russell P and Kurman RJ: Surface epithelial tumors of the ovary. Blausten’s pathology of the female genital tract. Kurman RJ: 5th ed. Springer; New York: pp. 791–904. 2002
21.	Despierre E, Lambrechts D, Neven P, Amant F, Lambrechts S and Vergote I: The molecular genetic basis of ovarian cancer and its roadmap towards a better treatment. Gynecol Oncol. 117:358–365. 2010. View Article : Google Scholar : PubMed/NCBI
22.	Chen JM, Cooper DN, Chuzhanova N, Férec C and Patrinos GP: Gene conversion: mechanisms, evolution and human disease. Nat Rev Genet. 8:762–775. 2007. View Article : Google Scholar : PubMed/NCBI
23.	Xue Q, Lin Z, Yin P, Milad MP, Cheng YH, Confino E, Reierstad S and Bulun SE: Transcriptional activation of steroidogenic factor-1 by hypomethylation of the 5′ CpG island in endometriosis. J Clin Endocrinol Metab. 92:3261–3267. 2007.PubMed/NCBI
24.	Balch C, Fang F, Matei DE, Huang TH and Nephew KP: Minireview: epigenetic changes in ovarian cancer. Endocrinology. 150:4003–4011. 2009. View Article : Google Scholar : PubMed/NCBI
25.	Barton CA, Hacker NF, Clark SJ and O’Brien PM: DNA methylation changes in ovarian cancer: implications for early diagnosis, prognosis and treatment. Gynecol Oncol. 109:129–139. 2008. View Article : Google Scholar : PubMed/NCBI