Breast Cancer Research and Treatment

, Volume 126, Issue 1, pp 37–45 | Cite as

A systematic review of the relationship between polymorphic sites in the estrogen receptor-beta (ESR2) gene and breast cancer risk

  • Ke-Da Yu
  • Nan-Yan Rao
  • Ao-Xiang Chen
  • Lei Fan
  • Chen Yang
  • Zhi-Ming Shao
Preclinical study


The estrogen signal is mediated by the estrogen receptor (ER). The specific role of ER-beta, a second ER, in breast carcinogenesis is not known. A number of association studies have been carried out to investigate the relationship between polymorphic sites in the ESR2 gene and breast cancer risk, however, the results are inconsistent. We searched PubMed, Medline, and Web of Science database (updated to 10 January 2010) and identified 13 relevant case–control studies, and approximately 28 single-nucleotide polymorphisms (SNPs) and one micro-satellite marker were reported in the literature. The median number of study subjects was 776 (range 158–13,550). Three genetic variants [(CA)n, rs2987983, and rs4986938] showed significant overall associations with breast cancer, and rs4986938 was reported twice. Because rs4986938 and rs1256049 were the most extensively studied polymorphisms, we subsequently conducted a meta-analysis to evaluate their relationship with breast cancer risk (9 studies of 10,837 cases and 16,021 controls for rs4986938; 8 studies of 11,652 cases and 15,726 controls for rs1256049). For rs4986938, the women harboring variant allele seemed to be associated with a decreased risk either in the dominant model [pooled OR = 0.944, 95% confidence interval (95% CI) 0.897–0.993, fixed-effects] or in the co-dominant model (AG vs. GG) (OR = 0.944, 95% CI 0.895–0.997, fixed-effects). rs1256049 was not associated with breast cancer risk in any model. Five studies had investigated the effect of haplotypes in the ESR2 gene on breast cancer risk, and four of them had positive outcomes. In summary, the present systematic review suggests that SNP rs4986938 as well as haplotypes in the ESR2 gene might be associated with breast cancer. The need for additional studies examining these issues seems of vital importance.


ESR2 Polymorphism Breast cancer Systematic review Meta-analysis 



This research is supported by grants from the National Basic Research Program of China (2006CB910501), 2009 Youth Foundation of Shanghai Public Health Bureau, 2009 Youth Foundation of Shanghai Medical College, and the National Natural Science Foundation of China (30971143, 30972936).

Conflict of interest statement

All authors declared no potential conflicts of interest.


  1. 1.
    Yager JD, Davidson NE (2006) Estrogen carcinogenesis in breast cancer. N Engl J Med 354:270–282CrossRefPubMedGoogle Scholar
  2. 2.
    Mosselman S, Polman J, Dijkema R (1996) ER beta: identification and characterization of a novel human estrogen receptor. FEBS Lett 392:49–53CrossRefPubMedGoogle Scholar
  3. 3.
    Fox EM, Davis RJ, Shupnik MA (2008) ERbeta in breast cancer-onlooker, passive player, or active protector? Steroids 73:1039–1051CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Fuqua SA, Schiff R, Parra I, Friedrichs WE, Su JL, McKee DD, Slentz-Kesler K, Moore LB, Willson TM, Moore JT (1999) Expression of wild-type estrogen receptor beta and variant isoforms in human breast cancer. Cancer Res 59:5425–5428PubMedGoogle Scholar
  5. 5.
    Saji S, Hirose M, Toi M (2005) Clinical significance of estrogen receptor beta in breast cancer. Cancer Chemother Pharmacol 56(1):21–26CrossRefPubMedGoogle Scholar
  6. 6.
    Omoto Y, Eguchi H, Yamamoto-Yamaguchi Y, Hayashi S (2003) Estrogen receptor (ER) beta1 and ERbetacx/beta2 inhibit ERalpha function differently in breast cancer cell line MCF7. Oncogene 22:5011–5020CrossRefPubMedGoogle Scholar
  7. 7.
    Goulart AC, Zee RY, Rexrode KM (2009) Association of estrogen receptor 2 gene polymorphisms with obesity in women (obesity and estrogen receptor 2 gene). Maturitas 62:179–183CrossRefPubMedGoogle Scholar
  8. 8.
    Huo L, Straub RE, Roca C, Schmidt PJ, Shi K, Vakkalanka R, Weinberger DR, Rubinow DR (2007) Risk for premenstrual dysphoric disorder is associated with genetic variation in ESR1, the estrogen receptor alpha gene. Biol Psychiatry 62:925–933CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Eastwood H, Brown KM, Markovic D, Pieri LF (2002) Variation in the ESR1 and ESR2 genes and genetic susceptibility to anorexia nervosa. Mol Psychiatry 7:86–89CrossRefPubMedGoogle Scholar
  10. 10.
    Pirskanen M, Hiltunen M, Mannermaa A, Helisalmi S, Lehtovirta M, Hanninen T, Soininen H (2005) Estrogen receptor beta gene variants are associated with increased risk of Alzheimer’s disease in women. Eur J Hum Genet 13:1000–1006CrossRefPubMedGoogle Scholar
  11. 11.
    Chen YC, Kraft P, Bretsky P, Ketkar S, Hunter DJ, Albanes D, Altshuler D, Andriole G, Berg CD, Boeing H, Burtt N, Bueno-de-Mesquita B, Cann H, Canzian F, Chanock S, Dunning A, Feigelson HS, Freedman M, Gaziano JM, Giovannucci E, Sanchez MJ, Haiman CA, Hallmans G, Hayes RB, Henderson BE, Hirschhorn J, Kaaks R, Key TJ, Kolonel LN, LeMarchand L, Ma J, Overvad K, Palli D, Pharaoh P, Pike M, Riboli E, Rodriguez C, Setiawan VW, Stampfer M, Stram DO, Thomas G, Thun MJ, Travis RC, Virtamo J, Trichopoulou A, Wacholder S, Weinstein SJ (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 16:1973–1981CrossRefPubMedGoogle Scholar
  12. 12.
    Wittke-Thompson JK, Pluzhnikov A, Cox NJ (2005) Rational inferences about departures from Hardy–Weinberg equilibrium. Am J Hum Genet 76:967–986CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Yu KD, Di GH, Fan L, Shao ZM (2009) Test of Hardy–Weinberg equilibrium in breast cancer case-control studies: an issue may influence the conclusions. Breast Cancer Res Treat 117:675–677CrossRefPubMedGoogle Scholar
  14. 14.
    Yu KD, Chen AX, Yang C, Qiu LX, Fan L, Xu WH, Shao ZM (2009) Current evidence on the relationship between polymorphisms in the COX-2 gene and breast cancer risk: a meta-analysis. Breast Cancer Res Treat (in press). doi: 10.1007/s10549-009-0688-3
  15. 15.
    Yu KD, Di GH, Fan L, Wu J, Hu Z, Shen ZZ, Huang W, Shao ZM (2009) A functional polymorphism in the promoter region of GSTM1 implies a complex role for GSTM1 in breast cancer. FASEB J 23:2274–2287CrossRefPubMedGoogle Scholar
  16. 16.
    Forsti A, Zhao C, Israelsson E, Dahlman-Wright K, Gustafsson JA, Hemminki K (2003) Polymorphisms in the estrogen receptor beta gene and risk of breast cancer: no association. Breast Cancer Res Treat 79:409–413CrossRefPubMedGoogle Scholar
  17. 17.
    Zheng SL, Zheng W, Chang BL, Shu XO, Cai Q, Yu H, Dai Q, Xu J, Gao YT (2003) Joint effect of estrogen receptor beta sequence variants and endogenous estrogen exposure on breast cancer risk in Chinese women. Cancer Res 63:7624–7629PubMedGoogle Scholar
  18. 18.
    Gold B, Kalush F, Bergeron J, Scott K, Mitra N, Wilson K, Ellis N, Huang H, Chen M, Lippert R, Halldorsson BV, Woodworth B, White T, Clark AG, Parl FF, Broder S, Dean M, Offit K (2004) Estrogen receptor genotypes and haplotypes associated with breast cancer risk. Cancer Res 64:8891–8900CrossRefPubMedGoogle Scholar
  19. 19.
    Maguire P, Margolin S, Skoglund J, Sun XF, Gustafsson JA, Borresen-Dale AL, Lindblom A (2005) Estrogen receptor beta (ESR2) polymorphisms in familial and sporadic breast cancer. Breast Cancer Res Treat 94:145–152CrossRefPubMedGoogle Scholar
  20. 20.
    Gallicchio L, Berndt SI, McSorley MA, Newschaffer CJ, Thuita LW, Argani P, Hoffman SC, Helzlsouer KJ (2006) Polymorphisms in estrogen-metabolizing and estrogen receptor genes and the risk of developing breast cancer among a cohort of women with benign breast disease. BMC Cancer 6:173CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Iobagiu C, Lambert C, Normand M, Genin C (2006) Microsatellite profile in hormonal receptor genes associated with breast cancer. Breast Cancer Res Treat 95:153–159CrossRefPubMedGoogle Scholar
  22. 22.
    Tsezou A, Tzetis M, Gennatas C, Giannatou E, Pampanos A, Malamis G, Kanavakis E, Kitsiou S (2008) Association of repeat polymorphisms in the estrogen receptors alpha, beta (ESR1, ESR2) and androgen receptor (AR) genes with the occurrence of breast cancer. Breast 17:159–166CrossRefPubMedGoogle Scholar
  23. 23.
    Cox DG, Bretsky P, Kraft P, Pharoah P, Albanes D, Altshuler D, Amiano P, Berglund G, Boeing H, Buring J, Burtt N, Calle EE, Canzian F, Chanock S, Clavel-Chapelon F, Colditz GA, Feigelson HS, Haiman CA, Hankinson SE, Hirschhorn J, Henderson BE, Hoover R, Hunter DJ, Kaaks R, Kolonel L, LeMarchand L, Lund E, Palli D, Peeters PH, Pike MC, Riboli E, Stram DO, Thun M, Tjonneland A, Travis RC, Trichopoulos D, Yeager M (2008) Haplotypes of the estrogen receptor beta gene and breast cancer risk. Int J Cancer 122:387–392CrossRefPubMedGoogle Scholar
  24. 24.
    Treeck O, Elemenler E, Kriener C, Horn F, Springwald A, Hartmann A, Ortmann O (2009) Polymorphisms in the promoter region of ESR2 gene and breast cancer susceptibility. J Steroid Biochem Mol Biol 114:207–211CrossRefPubMedGoogle Scholar
  25. 25.
    Sonestedt E, Ivarsson MI, Harlid S, Ericson U, Gullberg B, Carlson J, Olsson H, Adlercreutz H, Wirfalt E (2009) The protective association of high plasma enterolactone with breast cancer is reasonably robust in women with polymorphisms in the estrogen receptor alpha and beta genes. J Nutr 139:993–1001CrossRefPubMedGoogle Scholar
  26. 26.
    Surekha D, Sailaja K, Rao DN, Raghunadharao D, Vishnupriya S (2009) Oestrogen receptor beta (ERbeta) polymorphism and its influence on breast cancer risk. J Genet 88:261–266CrossRefPubMedGoogle Scholar
  27. 27.
    Abbas S, Brauch H, Chang-Claude J, Dunnebier T, Flesch-Janys D, Hamann U, Hein R, Justenhoven C and Salazar R (2009) Polymorphisms in genes of the steroid receptor superfamily modify postmenopausal breast cancer risk associated with menopausal hormone therapy. Int J Cancer (in press)Google Scholar
  28. 28.
    Iwasaki M, Hamada GS, Nishimoto IN, Netto MM, Motola J Jr, Laginha FM, Kasuga Y, Yokoyama S, Onuma H, Nishimura H, Kusama R, Kobayashi M, Ishihara J, Yamamoto S, Hanaoka T, Tsugane S (2009) Isoflavone, polymorphisms in estrogen receptor genes and breast cancer risk in case-control studies in Japanese, Japanese Brazilians and non-Japanese Brazilians. Cancer Sci 100:927–933CrossRefPubMedGoogle Scholar
  29. 29.
    Putnik M, Zhao C, Gustafsson JA, Dahlman-Wright K (2009) Effects of two common polymorphisms in the 3′ untranslated regions of estrogen receptor beta on mRNA stability and translatability. BMC Genet 10:55CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Dunning AM, Healey CS, Pharoah PD, Teare MD, Ponder BA, Easton DF (1999) A systematic review of genetic polymorphisms and breast cancer risk. Cancer Epidemiol Biomarkers Prev 8:843–854PubMedGoogle Scholar
  31. 31.
    Hartmann LC, Sellers TA, Frost MH, Lingle WL, Degnim AC, Ghosh K, Vierkant RA, Maloney SD, Pankratz VS, Hillman DW, Suman VJ, Johnson J, Blake C, Tlsty T, Vachon CM, Melton LJ 3rd, Visscher DW (2005) Benign breast disease and the risk of breast cancer. N Engl J Med 353:229–237CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC. 2010

Authors and Affiliations

  • Ke-Da Yu
    • 1
    • 2
  • Nan-Yan Rao
    • 3
  • Ao-Xiang Chen
    • 1
    • 2
  • Lei Fan
    • 1
    • 2
  • Chen Yang
    • 1
    • 2
  • Zhi-Ming Shao
    • 1
    • 2
    • 4
  1. 1.Department of Breast Surgery, Cancer Hospital/Cancer Institute, Breast Cancer InstituteFudan UniversityShanghaiPeople’s Republic of China
  2. 2.Department of Oncology, Shanghai Medical CollegeFudan UniversityShanghaiPeople’s Republic of China
  3. 3.Department of Breast SurgerySecond Affiliated Hospital of Sun Yat-sen UniversityGuangzhouPeople’s Republic of China
  4. 4.Institutes of Biomedical ScienceFudan UniversityShanghaiPeople’s Republic of China

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