Tumor Biology

, Volume 35, Issue 6, pp 5921–5930 | Cite as

Estrogen receptor alpha gene polymorphisms and risk of prostate cancer: a meta-analysis involving 18 studies

  • Zhenwei Gu
  • Gang Wang
  • Weiguo Chen
Research Article


Genetic and epigenetic changes in the estrogen receptor alpha (ER-α) gene, according to multiple lines of evidence, might alter its expression and its downstream signaling thereby increasing the risk of developing prostate cancer. The purpose of this meta-analysis was to determine whether polymorphisms in two intronic restriction sites in the ER-α (PvuII and XbaI) gene contribute to prostate cancer. A literature search for eligible studies published before November 5, 2013 was conducted in the PubMed, Embase, China Biology Medicine (CBM), and CNKI databases. Pooled crude odds ratios (ORs) and their corresponding 95 % confidence intervals (CIs) were calculated. Eighteen case-control and cohort studies were included in this meta-analysis with a total 4,884 prostate cancer cases and 10,134 healthy controls. Two common ER-α polymorphisms were examined: IVS1-397 C > T (a.k.a. the PvuII restriction site, rs2234693) and IVS1-351 A > G (a.k.a. the XbaI restriction site, rs9340799). Results from this meta-analysis showed that the PvuII polymorphism was not significantly associated with prostate cancer risk in any of the racial subgroups, either by allelic or genotypic frequencies. However, this meta-analysis revealed that the G allele in the XbaI polymorphism was associated with a statistically significant increase in the risk of prostate cancer. In a stratified analysis based on ethnicity, the XbaI G allele remained significantly correlated with an increased risk of prostate cancer in Africans; this correlation, however, was not found in Caucasians or Asians. In summary, a positive association correlation was observed between frequencies of the XbaI (A > G) polymorphism and prostate cancer, especially in Africans, but not such correlation was found with regard to the frequency of the PvuII (C > T) polymorphism.


ER-α Prostate cancer Polymorphism Meta-analysis 


Conflict of interest



  1. 1.
    Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin. 2011;61:69–90. doi: 10.3322/caac.20107.CrossRefPubMedGoogle Scholar
  2. 2.
    Kimura T. East meets West: ethnic differences in prostate cancer epidemiology between East Asians and Caucasians. Chin J Cancer. 2012;31:421–9. doi: 10.5732/cjc.011.10324.PubMedCentralCrossRefPubMedGoogle Scholar
  3. 3.
    Delgado PO, Alves BC, Gehrke Fde S, Kuniyoshi RK, Wroclavski ML, Del Giglio A, et al. Characterization of cell-free circulating DNA in plasma in patients with prostate cancer. Tumour Biol. 2013;34:983–6. doi: 10.1007/s13277-012-0634-6.CrossRefPubMedGoogle Scholar
  4. 4.
    McDougall JA, Li CI. Trends in distant-stage breast, colorectal, and prostate cancer incidence rates from 1992 to 2004: potential influences of screening and hormonal factors. Horm Cancer. 2010;1:55–62. doi: 10.1007/s12672-009-0002-1.CrossRefPubMedGoogle Scholar
  5. 5.
    Huggins C, Hodges CV. Studies on prostatic cancer. I. The effect of castration, of estrogen and of androgen injection on serum phosphatases in metastatic carcinoma of the prostate. 1941. J Urol. 2002;167:948–51.CrossRefPubMedGoogle Scholar
  6. 6.
    Rhodes L, Ding VD, Kemp RK, Khan MS, Nakhla AM, Pikounis B, et al. Estradiol causes a dose-dependent stimulation of prostate growth in castrated beagle dogs. Prostate. 2000;44:8–18.CrossRefPubMedGoogle Scholar
  7. 7.
    Ho SM. Estrogens and anti-estrogens: key mediators of prostate carcinogenesis and new therapeutic candidates. J Cell Biochem. 2004;91:491–503. doi: 10.1002/jcb.10759.CrossRefPubMedGoogle Scholar
  8. 8.
    Prins GS, Korach KS. The role of estrogens and estrogen receptors in normal prostate growth and disease. Steroids. 2008;73:233–44. doi: 10.1016/j.steroids.2007.10.013.PubMedCentralCrossRefPubMedGoogle Scholar
  9. 9.
    Bonkhoff H, Berges R. The evolving role of oestrogens and their receptors in the development and progression of prostate cancer. Eur Urol. 2009;55:533–42. doi: 10.1016/j.eururo.2008.10.035.CrossRefPubMedGoogle Scholar
  10. 10.
    Ellem SJ, Risbridger GP. The dual, opposing roles of estrogen in the prostate. Ann N Y Acad Sci. 2009;1155:174–86. doi: 10.1111/j.1749-6632.2009.04360.x.CrossRefPubMedGoogle Scholar
  11. 11.
    Slater M, Brown D, Husband A. In the prostatic epithelium, dietary isoflavones from red clover significantly increase estrogen receptor beta and E-cadherin expression but decrease transforming growth factor beta1. Prostate Cancer Prostatic Dis. 2002;5:16–21. doi: 10.1038/sj.pcan.4500546.CrossRefPubMedGoogle Scholar
  12. 12.
    Harkonen PL, Makela SI. Role of estrogens in development of prostate cancer. J Steroid Biochem Mol Biol. 2004;92:297–305. doi: 10.1016/j.jsbmb.2004.10.016.CrossRefPubMedGoogle Scholar
  13. 13.
    Cowley SM, Hoare S, Mosselman S, Parker MG. Estrogen receptors alpha and beta form heterodimers on DNA. J Biol Chem. 1997;272:19858–62.CrossRefPubMedGoogle Scholar
  14. 14.
    Safarinejad MR, Safarinejad S, Shafiei N. Estrogen receptors alpha (rs2234693 and rs9340799), and beta (rs4986938 and rs1256049) genes polymorphism in prostate cancer: evidence for association with risk and histopathological tumor characteristics in Iranian men. Mol Carcinog. 2012;51 Suppl 1:E104–17. doi: 10.1002/mc.21870.CrossRefPubMedGoogle Scholar
  15. 15.
    Li N, Dong J, Hu Z, Shen H, Dai M. Potentially functional polymorphisms in ESR1 and breast cancer risk: a meta-analysis. Breast Cancer Res Treat. 2010;121:177–84. doi: 10.1007/s10549-009-0532-9.CrossRefPubMedGoogle Scholar
  16. 16.
    Guo H, Ming J, Liu C, Li Z, Zhang N, Cheng H, et al. A common polymorphism near the ESR1 gene is associated with risk of breast cancer: evidence from a case-control study and a meta-analysis. PLoS One. 2012;7:e52445. doi: 10.1371/journal.pone.0052445.PubMedCentralCrossRefPubMedGoogle Scholar
  17. 17.
    Leigh Pearce C, Near AM, Butler JL, Van Den Berg D, Bretsky P, Conti DV, et al. Comprehensive evaluation of ESR2 variation and ovarian cancer risk. Cancer Epidemiol Biomarkers Prev. 2008;17:393–6. doi: 10.1158/1055-9965.epi-07-2512.CrossRefPubMedGoogle Scholar
  18. 18.
    Einarsdottir K, Darabi H, Czene K, Li Y, Low YL, Li YQ, et al. Common genetic variability in ESR1 and EGF in relation to endometrial cancer risk and survival. Br J Cancer. 2009;100:1358–64. doi: 10.1038/sj.bjc.6604984.PubMedCentralCrossRefPubMedGoogle Scholar
  19. 19.
    Modugno F, Weissfeld JL, Trump DL, Zmuda JM, Shea P, Cauley JA, et al. Allelic variants of aromatase and the androgen and estrogen receptors: toward a multigenic model of prostate cancer risk. Clin Cancer Res. 2001;7:3092–6.PubMedGoogle Scholar
  20. 20.
    Berndt SI, Chatterjee N, Huang WY, Chanock SJ, Welch R, Crawford ED, et al. Variant in sex hormone-binding globulin gene and the risk of prostate cancer. Cancer Epidemiol Biomarkers Prev. 2007;16:165–8. doi: 10.1158/1055-9965.epi-06-0689.CrossRefPubMedGoogle Scholar
  21. 21.
    Sonoda T, Suzuki H, Mori M, Tsukamoto T, Yokomizo A, Naito S, et al. Polymorphisms in estrogen related genes may modify the protective effect of isoflavones against prostate cancer risk in Japanese men. Eur J Cancer Prev. 2010;19:131–7. doi: 10.1097/CEJ.0b013e328333fbe2.CrossRefPubMedGoogle Scholar
  22. 22.
    Jurecekova J, Sivonova MK, Evinova A, Kliment J, Dobrota D. The association between estrogen receptor alpha polymorphisms and the risk of prostate cancer in Slovak population. Mol Cell Biochem. 2013;381:201–7. doi: 10.1007/s11010-013-1703-x.CrossRefPubMedGoogle Scholar
  23. 23.
    Ding X, Cui FM, Xu ST, Pu JX, Huang YH, Zhang JL, et al. Variants on ESR1 and their association with prostate cancer risk: a meta-analysis. Asian Pac J Cancer Prev. 2012;13:3931–6.CrossRefPubMedGoogle Scholar
  24. 24.
    Chornokur G, Dalton K, Borysova ME, Kumar NB. Disparities at presentation, diagnosis, treatment, and survival in African American men, affected by prostate cancer. Prostate. 2011;71:985–97. doi: 10.1002/pros.21314.PubMedCentralCrossRefPubMedGoogle Scholar
  25. 25.
    Winters SJ, Brufsky A, Weissfeld J, Trump DL, Dyky MA, Hadeed V. Testosterone, sex hormone-binding globulin, and body composition in young adult African American and Caucasian men. Metabolism. 2001;50:1242–7. doi: 10.1053/meta.2001.26714.CrossRefPubMedGoogle Scholar
  26. 26.
    Rohrmann S, Sutcliffe CG, Bienstock JL, Monsegue D, Akereyeni F, Bradwin G, et al. Racial variation in sex steroid hormones and the insulin-like growth factor axis in umbilical cord blood of male neonates. Cancer Epidemiol Biomarkers Prev. 2009;18:1484–91. doi: 10.1158/1055-9965.EPI-08-0817.PubMedCentralCrossRefPubMedGoogle Scholar
  27. 27.
    Little J, Higgins JP, Ioannidis JP, Moher D, Gagnon F, von Elm E, et al. STrengthening the REporting of Genetic Association studies (STREGA)–an extension of the STROBE statement. Eur J Clin Invest. 2009;39:247–66.PubMedCentralCrossRefPubMedGoogle Scholar
  28. 28.
    Zintzaras E, Ioannidis JP. Heterogeneity testing in meta-analysis of genome searches. Genet Epidemiol. 2005;28:123–37. doi: 10.1002/gepi.20048.CrossRefPubMedGoogle Scholar
  29. 29.
    Sacks HS, Berrier J, Reitman D, Ancona-Berk VA, Chalmers TC. Meta-analyses of randomized controlled trials. N Engl J Med. 1987;316:450–5. doi: 10.1056/NEJM198702193160806.CrossRefPubMedGoogle Scholar
  30. 30.
    Egger M, Davey Smith G, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ. 1997;315:629–34.PubMedCentralCrossRefPubMedGoogle Scholar
  31. 31.
    Suzuki K, Nakazato H, Matsui H, Koike H, Okugi H, Kashiwagi B, et al. Genetic polymorphisms of estrogen receptor alpha, CYP19, catechol-O-methyltransferase are associated with familial prostate carcinoma risk in a Japanese population. Cancer. 2003;98:1411–6. doi: 10.1002/cncr.11639.CrossRefPubMedGoogle Scholar
  32. 32.
    Tanaka Y, Sasaki M, Kaneuchi M, Shiina H, Igawa M, Dahiya R. Polymorphisms of estrogen receptor alpha in prostate cancer. Mol Carcinog. 2003;37:202–8. doi: 10.1002/mc.10138.CrossRefPubMedGoogle Scholar
  33. 33.
    Fukatsu T, Hirokawa Y, Araki T, Hioki T, Murata T, Suzuki H, et al. Genetic polymorphisms of hormone-related genes and prostate cancer risk in the Japanese population. Anticancer Res. 2004;24:2431–7.PubMedGoogle Scholar
  34. 34.
    Hernandez J, Balic I, Johnson-Pais TL, Higgins BA, Torkko KC, Thompson IM, et al. Association between an estrogen receptor alpha gene polymorphism and the risk of prostate cancer in black men. J Urol. 2006;175:523–7. doi: 10.1016/s0022-5347(05)00240-5.CrossRefPubMedGoogle Scholar
  35. 35.
    Low YL, Taylor JI, Grace PB, Mulligan AA, Welch AA, Scollen S, et al. Phytoestrogen exposure, polymorphisms in COMT, CYP19, ESR1, and SHBG genes, and their associations with prostate cancer risk. Nutr Cancer. 2006;56:31–9. doi: 10.1207/s15327914nc5601_5.CrossRefPubMedGoogle Scholar
  36. 36.
    Cunningham JM, Hebbring SJ, McDonnell SK, Cicek MS, Christensen GB, Wang L, et al. Evaluation of genetic variations in the androgen and estrogen metabolic pathways as risk factors for sporadic and familial prostate cancer. Cancer Epidemiol Biomarkers Prev. 2007;16:969–78. doi: 10.1158/1055-9965.epi-06-0767.CrossRefPubMedGoogle Scholar
  37. 37.
    Kjaergaard AD, Ellervik C, Tybjaerg-Hansen A, Axelsson CK, Gronholdt ML, Grande P, et al. Estrogen receptor alpha polymorphism and risk of cardiovascular disease, cancer, and hip fracture: cross-sectional, cohort, and case-control studies and a meta-analysis. Circulation. 2007;115:861–71. doi: 10.1161/circulationaha.106.615567.CrossRefPubMedGoogle Scholar
  38. 38.
    Onsory K, Sobti RC, Al-Badran AI, Watanabe M, Shiraishi T, Krishan A, et al. Hormone receptor-related gene polymorphisms and prostate cancer risk in North Indian population. Mol Cell Biochem. 2008;314:25–35. doi: 10.1007/s11010-008-9761-1.CrossRefPubMedGoogle Scholar
  39. 39.
    Sobti RC, Gupta L, Singh SK, Seth A, Kaur P, Thakur H. Role of hormonal genes and risk of prostate cancer: gene-gene interactions in a North Indian population. Cancer Genet Cytogenet. 2008;185:78–85. doi: 10.1016/j.cancergencyto.2008.04.022.CrossRefPubMedGoogle Scholar
  40. 40.
    Beuten J, Gelfond JA, Franke JL, Weldon KS, Crandall AC, Johnson-Pais TL, et al. Single and multigenic analysis of the association between variants in 12 steroid hormone metabolism genes and risk of prostate cancer. Cancer Epidemiol Biomarkers Prev. 2009;18:1869–80. doi: 10.1158/1055-9965.epi-09-0076.CrossRefPubMedGoogle Scholar
  41. 41.
    Gupta L, Thakur H, Sobti RC, Seth A, Singh SK. Role of genetic polymorphism of estrogen receptor-alpha gene and risk of prostate cancer in north Indian population. Mol Cell Biochem. 2010;335:255–61. doi: 10.1007/s11010-009-0275-2.CrossRefPubMedGoogle Scholar
  42. 42.
    Sissung TM, Danesi R, Kirkland CT, Baum CE, Ockers SB, Stein EV, et al. Estrogen receptor alpha and aromatase polymorphisms affect risk, prognosis, and therapeutic outcome in men with castration-resistant prostate cancer treated with docetaxel-based therapy. J Clin Endocrinol Metab. 2011;96:E368–72. doi: 10.1210/jc.2010-2070.PubMedCentralCrossRefPubMedGoogle Scholar
  43. 43.
    Szendroi A, Speer G, Tabak A, Kosa JP, Nyirady P, Majoros A, et al. The role of vitamin D, estrogen, calcium sensing receptor genotypes and serum calcium in the pathogenesis of prostate cancer. Can J Urol. 2011;18:5710–6.PubMedGoogle Scholar
  44. 44.
    Henderson BE, Feigelson HS. Hormonal carcinogenesis. Carcinogenesis. 2000;21:427–33.CrossRefPubMedGoogle Scholar
  45. 45.
    Wigle DT, Turner MC, Gomes J, Parent ME. Role of hormonal and other factors in human prostate cancer. J Toxicol Environ Health B Crit Rev. 2008;11:242–59. doi: 10.1080/10937400701873548.CrossRefPubMedGoogle Scholar
  46. 46.
    Parnes HL, Thompson IM, Ford LG. Prevention of hormone-related cancers: prostate cancer. J Clin Oncol. 2005;23:368–77. doi: 10.1200/JCO.2005.08.027.CrossRefPubMedGoogle Scholar
  47. 47.
    Mononen N, Seppala EH, Duggal P, Autio V, Ikonen T, Ellonen P, et al. Profiling genetic variation along the androgen biosynthesis and metabolism pathways implicates several single nucleotide polymorphisms and their combinations as prostate cancer risk factors. Cancer Res. 2006;66:743–7. doi: 10.1158/0008-5472.CAN-05-1723.CrossRefPubMedGoogle Scholar
  48. 48.
    Shimada N, Iwasaki M, Kasuga Y, Yokoyama S, Onuma H, Nishimura H, et al. Genetic polymorphisms in estrogen metabolism and breast cancer risk in case-control studies in Japanese, Japanese Brazilians and non-Japanese Brazilians. J Hum Genet. 2009;54:209–15. doi: 10.1038/jhg.2009.13.CrossRefPubMedGoogle Scholar
  49. 49.
    Wang F, Zou YF, Feng XL, Su H, Huang F. CYP17 gene polymorphisms and prostate cancer risk: a meta-analysis based on 38 independent studies. Prostate. 2011;71:1167–77. doi: 10.1002/pros.21332.CrossRefPubMedGoogle Scholar
  50. 50.
    Li Q, Zhu Y, He J, Wang M, Zhu M, Shi T, et al. Steroid 5-alpha-reductase type 2 (SRD5A2) V89L and A49T polymorphisms and sporadic prostate cancer risk: a meta-analysis. Mol Biol Rep. 2013;40:3597–608. doi: 10.1007/s11033-012-2434-x.CrossRefPubMedGoogle Scholar
  51. 51.
    Cicek MS, Conti DV, Curran A, Neville PJ, Paris PL, Casey G, et al. Association of prostate cancer risk and aggressiveness to androgen pathway genes: SRD5A2, CYP17, and the AR. Prostate. 2004;59:69–76. doi: 10.1002/pros.10358.CrossRefPubMedGoogle Scholar
  52. 52.
    Ingles SA, Ross RK, Yu MC, Irvine RA, La Pera G, Haile RW, et al. Association of prostate cancer risk with genetic polymorphisms in vitamin D receptor and androgen receptor. J Natl Cancer Inst. 1997;89:166–70.CrossRefPubMedGoogle Scholar
  53. 53.
    Ross RK, Paganini-Hill A, Henderson BE. The etiology of prostate cancer: what does the epidemiology suggest? Prostate. 1983;4:333–44.CrossRefPubMedGoogle Scholar
  54. 54.
    Shin HR, Masuyer E, Ferlay J, Curado MP. Cancer in Asia—incidence rates based on data in cancer incidence in five continents IX (1998-2002). Asian Pac J Cancer Prev. 2010;11 Suppl 2:11–6.PubMedGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2014

Authors and Affiliations

  1. 1.Department of UrologyLuzhi People’s Hospital Department of UrologySuzhouChina
  2. 2.Department of UrologyThe First Affiliated Hospital of Soochow UniversitySuzhouChina

Personalised recommendations