Cancer Causes & Control

, Volume 20, Issue 1, pp 47–55 | Cite as

Genetic polymorphisms in the estrogen receptor beta (ESR2) gene and the risk of epithelial ovarian carcinoma

  • Galina LurieEmail author
  • Lynne R. Wilkens
  • Pamela J. Thompson
  • Katharine E. McDuffie
  • Michael E. Carney
  • Keith Y. Terada
  • Marc T. Goodman
Original Paper


Ovarian cancer is influenced by exogenous and endogenous estrogens as suggested by experimental and epidemiological evidence. Estrogen receptor beta is a predominant estrogen receptor in the normal ovary. Polymorphisms in the estrogen receptor beta gene (ESR2) might influence epithelial ovarian risk through regulation of cell proliferation and apoptosis. This population-based case–control study included 313 women with epithelial ovarian carcinoma and 574 controls, frequency-matched on age and ethnicity. Unconditional logistic regression was used to test associations of rs1271572, rs1256030, rs1256031, and rs3020450 ESR2 genotypes with ovarian cancer risk. Compared to homozygous common allele carriers, homozygous carriers of variant alleles for rs1271572 [odds ratio (OR) = 1.79, 95% confidence interval (CI):1.15–2.79, p global = 0.01] and rs1256030 [OR = 1.67, CI: 1.08–2.59, p global = 0.04], and women with haplotypes, including variant alleles of rs1271572, rs1256030, and rs1256031 SNPs [OR = 1.75, CI: 1.17–2.63, p global = 0.007], had significantly increased risk of ovarian carcinoma. The association of the rs1271572 genotype was strongest among women who had never used contraceptive steroids (p for interaction = 0.04). Our data suggest that ESR2 might be a susceptibility marker for epithelial ovarian cancer.


Epithelial ovarian cancer ESR2 Single nucleotide polymorphisms Case–control study 



This study was supported in part by Public Health Service grant R01-CA-58598 and by contracts N01-CN-67001 and NO1-CN-25403 from the Department of Health and Human Services, National Institutes of Health.


  1. 1.
    Parkin DM, Whelan SL, Ferlay J, Teppo L (2002) Cancer incidence in five continents. IARC, Lyon, FranceGoogle Scholar
  2. 2.
    Langdon SP, Hirst GL, Miller EP et al (1994) The regulation of growth and protein expression by estrogen in vitro: a study of 8 human ovarian carcinoma cell lines. J Steroid Biochem Mol Biol 50:131–135. doi: 10.1016/0960-0760(94)90019-1 PubMedCrossRefGoogle Scholar
  3. 3.
    Galtier-Dereure F, Capony F, Maudelonde T, Rochefort H (1992) Estradiol stimulates cell growth and secretion of procathepsin D and a 120-kilodalton protein in the human ovarian cancer cell line BG-1. J Clin Endocrinol Metab 75:1497–1502. doi: 10.1210/jc.75.6.1497 PubMedCrossRefGoogle Scholar
  4. 4.
    Riman T, Nilsson S, Persson IR (2004) Review of epidemiological evidence for reproductive and hormonal factors in relation to the risk of epithelial ovarian malignancies. Acta Obstet Gynecol Scand 83:783–795. doi: 10.1111/j.0001-6349.2004.00550.x PubMedCrossRefGoogle Scholar
  5. 5.
    Risch HA (1998) Hormonal etiology of epithelial ovarian cancer, with a hypothesis concerning the role of androgens and progesterone. J Natl Cancer Inst 90:1774–1786. doi: 10.1093/jnci/90.23.1774 PubMedCrossRefGoogle Scholar
  6. 6.
    Enmark E, Gustafsson JA (1999) Oestrogen receptors—an overview. J Intern Med 246:133–138. doi: 10.1046/j.1365-2796.1999.00545.x PubMedCrossRefGoogle Scholar
  7. 7.
    Hillier SG, Anderson RA, Williams AR, Tetsuka M (1998) Expression of oestrogen receptor alpha and beta in cultured human ovarian surface epithelial cells. Mol Hum Reprod 4:811–815. doi: 10.1093/molehr/4.8.811 PubMedCrossRefGoogle Scholar
  8. 8.
    Byers M, Kuiper GG, Gustafsson JA, Park-Sarge OK (1997) Estrogen receptor-beta mRNA expression in rat ovary: down-regulation by gonadotropins. Mol Endocrinol 11:172–182. doi: 10.1210/me.11.2.172 PubMedCrossRefGoogle Scholar
  9. 9.
    Rutherford T, Brown WD, Sapi E, Aschkenazi S, Munoz A, Mor G (2000) Absence of estrogen receptor-beta expression in metastatic ovarian cancer. Obstet Gynecol 96:417–421. doi: 10.1016/S0029-7844(00)00917-0 PubMedCrossRefGoogle Scholar
  10. 10.
    Brandenberger AW, Tee MK, Jaffe RB (1998) Estrogen receptor alpha (ER-alpha) and beta (ER-beta) mRNAs in normal ovary, ovarian serous cystadenocarcinoma and ovarian cancer cell lines: down-regulation of ER-beta in neoplastic tissues. J Clin Endocrinol Metab 83:1025–1028. doi: 10.1210/jc.83.3.1025 PubMedCrossRefGoogle Scholar
  11. 11.
    Pujol P, Rey JM, Nirde P et al (1998) Differential expression of estrogen receptor-alpha and -beta messenger RNAs as a potential marker of ovarian carcinogenesis. Cancer Res 58:5367–5373PubMedGoogle Scholar
  12. 12.
    Li AJ, Baldwin RL, Karlan BY (2003) Estrogen and progesterone receptor subtype expression in normal and malignant ovarian epithelial cell cultures. Am J Obstet Gynecol 189:22–27. doi: 10.1067/mob.2003.328 PubMedCrossRefGoogle Scholar
  13. 13.
    Bardin A, Hoffmann P, Boulle N et al (2004) Involvement of estrogen receptor beta in ovarian carcinogenesis. Cancer Res 64:5861–5869. doi: 10.1158/0008-5472.CAN-04-0552 PubMedCrossRefGoogle Scholar
  14. 14.
    Park BW, Kim KS, Heo MK et al (2003) Expression of estrogen receptor-beta in normal mammary and tumor tissues: is it protective in breast carcinogenesis? Breast Cancer Res Treat 80:79–85. doi: 10.1023/A:1024406223619 PubMedCrossRefGoogle Scholar
  15. 15.
    Fixemer T, Remberger K, Bonkhoff H (2003) Differential expression of the estrogen receptor beta (ERbeta) in human prostate tissue, premalignant changes, and in primary, metastatic, and recurrent prostatic adenocarcinoma. Prostate 54:79–87. doi: 10.1002/pros.10171 PubMedCrossRefGoogle Scholar
  16. 16.
    Foley EF, Jazaeri AA, Shupnik MA, Jazaeri O, Rice LW (2000) Selective loss of estrogen receptor beta in malignant human colon. Cancer Res 60:245–248PubMedGoogle Scholar
  17. 17.
    Tung KH, Goodman MT, Wu AH et al (2004) Aggregation of ovarian cancer with breast, ovarian, colorectal, and prostate cancer in first-degree relatives. Am J Epidemiol 159:750–758. doi: 10.1093/aje/kwh103 PubMedCrossRefGoogle Scholar
  18. 18.
    Sowers MR, Jannausch ML, McConnell DS, Kardia SR, Randolph JF Jr (2006) Menstrual cycle markers of ovarian aging and sex steroid hormone genotypes. Am J Med 119:S31–S43. doi: 10.1016/j.amjmed.2006.07.004 PubMedCrossRefGoogle Scholar
  19. 19.
    Peter I, Shearman AM, Vasan RS et al (2005) Association of estrogen receptor beta gene polymorphisms with left ventricular mass and wall thickness in women. Am J Hypertens 18:1388–1395. doi: 10.1016/j.amjhyper.2005.05.023 PubMedCrossRefGoogle Scholar
  20. 20.
    Sun YH, Yang B, Wang XH et al (2005) Association between single-nucleotide polymorphisms in estrogen receptor beta gene and risk of prostate cancer. Zhonghua Wai Ke Za Zhi 43:948–951PubMedGoogle Scholar
  21. 21.
    Rexrode KM, Ridker PM, Hegener HH, Buring JE, Manson JE, Zee RY (2007) Polymorphisms and haplotypes of the estrogen receptor-beta gene (ESR2) and cardiovascular disease in men and women. Clin Chem 53:1749–1756. doi: 10.1373/clinchem.2007.091454 PubMedCrossRefGoogle Scholar
  22. 22.
    Anonymous (1986) Surveillance, epidemiology, and end results program. Summary staging guide for the cancer surveillance, epidemiology, and end results reporting (SEER) Program. U.S. Department of Health and Human Services, Public Health Services, National Institute of Health, Bethesda, MDGoogle Scholar
  23. 23.
    Oyama N, Johnson DB (1986) Hawaii health surveillance program survey methods and procedures. R & S Report No 54. State Department of Health Research and Statistics Office, Honolulu, HawaiiGoogle Scholar
  24. 24.
    Tung KH, Goodman MT, Wu AH et al (2003) Reproductive factors and epithelial ovarian cancer risk by histologic type: a multiethnic case–control study. Am J Epidemiol 158:629–638. doi: 10.1093/aje/kwg177 PubMedCrossRefGoogle Scholar
  25. 25.
    Barrett JC, Fry B, Maller J, Daly MJ (2005) Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 21:263–265. doi: 10.1093/bioinformatics/bth457 PubMedCrossRefGoogle Scholar
  26. 26.
    Chen YC, Kraft P, Bretsky P et al (2007) Sequence variants of estrogen receptor beta and risk of prostate cancer in the National Cancer Institute Breast and Prostate Cancer Cohort Consortium. Cancer Epidemiol Biomarkers Prev 16:1973–1981. doi: 10.1158/1055-9965.EPI-07-0431 PubMedCrossRefGoogle Scholar
  27. 27.
    Cox DG, Bretsky P, Kraft P et al (2008) Haplotypes of the estrogen receptor beta gene and breast cancer risk. Int J Cancer 122:387–392. doi: 10.1002/ijc.23127 PubMedCrossRefGoogle Scholar
  28. 28.
    Pearce CL, Near AM, Butler JL et al (2008) Comprehensive evaluation of ESR2 variation and ovarian cancer risk. Cancer Epidemiol Biomarkers Prev 17:393–396. doi: 10.1158/1055-9965.EPI-07-2512 CrossRefGoogle Scholar
  29. 29.
    Yaffe K, Lindquist K, Sen S et al (2007) Estrogen receptor genotype and risk of cognitive impairment in elders: findings from the Health ABC study. Neurobiol Aging. doi: 10.1016/j.neurobiolaging.2007.08.003 [Available online 21 September 2007]Google Scholar
  30. 30.
    Bardin A, Boulle N, Lazennec G, Vignon F, Pujol P (2004) Loss of ERbeta expression as a common step in estrogen-dependent tumor progression. Endocr Relat Cancer 11:537–551. doi: 10.1677/erc.1.00800 PubMedCrossRefGoogle Scholar
  31. 31.
    Cheng J, Lee EJ, Madison LD, Lazennec G (2004) Expression of estrogen receptor beta in prostate carcinoma cells inhibits invasion and proliferation and triggers apoptosis. FEBS Lett 566:169–172. doi: 10.1016/j.febslet.2004.04.025 PubMedCrossRefGoogle Scholar
  32. 32.
    Kuiper GG, Enmark E, Pelto-Huikko M, Nilsson S, Gustafsson JA (1996) Cloning of a novel receptor expressed in rat prostate and ovary. Proc Natl Acad Sci USA 93:5925–5930. doi: 10.1073/pnas.93.12.5925 PubMedCrossRefGoogle Scholar
  33. 33.
    Roger P, Sahla ME, Makela S, Gustafsson JA, Baldet P, Rochefort H (2001) Decreased expression of estrogen receptor beta protein in proliferative preinvasive mammary tumors. Cancer Res 61:2537–2541PubMedGoogle Scholar
  34. 34.
    Campbell-Thompson M, Lynch IJ, Bhardwaj B (2001) Expression of estrogen receptor (ER) subtypes and ERbeta isoforms in colon cancer. Cancer Res 61:632–640PubMedGoogle Scholar
  35. 35.
    Sapi E, Brown WD, Aschkenazi S et al (2002) Regulation of Fas ligand expression by estrogen in normal ovary. J Soc Gynecol Investig 9:243–250. doi: 10.1016/S1071-5576(02)00162-4 PubMedCrossRefGoogle Scholar
  36. 36.
    Treeck O, Pfeiler G, Mitter D, Lattrich C, Piendl G, Ortmann O (2007) Estrogen receptor {beta}1 exerts antitumoral effects on SK-OV-3 ovarian cancer cells. J Endocrinol 193:421–433. doi: 10.1677/JOE-07-0087 PubMedCrossRefGoogle Scholar
  37. 37.
    Vendrell JA, Magnino F, Danis E et al (2004) Estrogen regulation in human breast cancer cells of new downstream gene targets involved in estrogen metabolism, cell proliferation and cell transformation. J Mol Endocrinol 32:397–414. doi: 10.1677/jme.0.0320397 PubMedCrossRefGoogle Scholar
  38. 38.
    Li LC, Yeh CC, Nojima D, Dahiya R (2000) Cloning and characterization of human estrogen receptor beta promoter. Biochem Biophys Res Commun 275:682–689. doi: 10.1006/bbrc.2000.3363 PubMedCrossRefGoogle Scholar
  39. 39.
    Hu YF, Luscher B, Admon A, Mermod N, Tjian R (1990) Transcription factor AP-4 contains multiple dimerization domains that regulate dimer specificity. Genes Dev 4:1741–1752. doi: 10.1101/gad.4.10.1741 PubMedCrossRefGoogle Scholar
  40. 40.
    McDonnell DP (2005) The molecular pharmacology of estrogen receptor modulators: implications for the treatment of breast cancer. Clin Cancer Res 11:871s–877sPubMedGoogle Scholar
  41. 41.
    Alarid ET, Bakopoulos N, Solodin N (1999) Proteasome-mediated proteolysis of estrogen receptor: a novel component in autologous down-regulation. Mol Endocrinol 13:1522–1534. doi: 10.1210/me.13.9.1522 PubMedCrossRefGoogle Scholar
  42. 42.
    Bhavnani BR, Tam SP, Lu X (2008) Structure activity relationships and differential interactions and functional activity of various equine estrogens mediated via estrogen receptors ER{alpha} and ER{beta}. Endocrinology. doi: 10.1210/en.2008-0304 PubMedGoogle Scholar
  43. 43.
    Kuiper GG, Carlsson B, Grandien K et al (1997) Comparison of the ligand binding specificity and transcript tissue distribution of estrogen receptors alpha and beta. Endocrinology 138:863–870. doi: 10.1210/en.138.3.863 PubMedCrossRefGoogle Scholar
  44. 44.
    Kuiper GG, Lemmen JG, Carlsson B et al (1998) Interaction of estrogenic chemicals and phytoestrogens with estrogen receptor beta. Endocrinology 139:4252–4263. doi: 10.1210/en.139.10.4252 PubMedCrossRefGoogle Scholar
  45. 45.
    Harris HA, Bapat AR, Gonder DS, Frail DE (2002) The ligand binding profiles of estrogen receptors alpha and beta are species dependent. Steroids 67:379–384. doi: 10.1016/S0039-128X(01)00194-5 PubMedCrossRefGoogle Scholar
  46. 46.
    Katzenellenbogen BS, Montano MM, Ediger TR et al (2000) Estrogen receptors: selective ligands, partners, and distinctive pharmacology. Recent Prog Horm Res 55:163–193PubMedGoogle Scholar
  47. 47.
    Beral V, Bull D, Green J, Reeves G (2007) Ovarian cancer and hormone replacement therapy in the Million Women Study. Lancet 369:1703–1710. doi: 10.1016/S0140-6736(07)60534-0 PubMedCrossRefGoogle Scholar
  48. 48.
    Sit AS, Modugno F, Weissfeld JL, Berga SL, Ness RB (2002) Hormone replacement therapy formulations and risk of epithelial ovarian carcinoma. Gynecol Oncol 86:118–123. doi: 10.1006/gyno.2002.6746 PubMedCrossRefGoogle Scholar
  49. 49.
    Pike MC, Pearce CL, Peters R, Cozen W, Wan P, Wu AH (2004) Hormonal factors and the risk of invasive ovarian cancer: a population-based case-control study. Fertil Steril 82:186–195PubMedCrossRefGoogle Scholar
  50. 50.
    Rossing MA, Cushing-Haugen KL, Wicklund KG, Doherty JA, Weiss NS (2007) Menopausal hormone therapy and risk of epithelial ovarian cancer. Cancer Epidemiol Biomarkers Prev 16:2548–2556. doi: 10.1158/1055-9965.EPI-07-0550 PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media B.V. 2008

Authors and Affiliations

  • Galina Lurie
    • 1
    Email author
  • Lynne R. Wilkens
    • 1
  • Pamela J. Thompson
    • 1
  • Katharine E. McDuffie
    • 1
  • Michael E. Carney
    • 2
  • Keith Y. Terada
    • 2
  • Marc T. Goodman
    • 1
  1. 1.Cancer Epidemiology Program, Cancer Research Center of HawaiiUniversity of HawaiiHonoluluUSA
  2. 2.Department of Obstetrics and Gynecology, John A. Burns School of MedicineUniversity of HawaiiHonoluluUSA

Personalised recommendations