Genetic polymorphism of ESR1 rs2881766 increases breast cancer risk in Korean women

  • Byung Ho Son
  • Mi Kyung Kim
  • Young Mi Yun
  • Hee Jeong Kim
  • Jong Han Yu
  • Beom Seok Ko
  • Hanna Kim
  • Sei Hyun Ahn
Original Article - Cancer Research



We performed a case–control study to evaluate the association of genetic polymorphisms of estrogen-metabolizing enzyme genes and estrogen receptor genes with breast cancer risk according to age group and subtypes in Korean women.


Breast cancer patients (n = 830) and the hospital healthy controls (n = 390) with both clinical information and SNP data were included in the study. Age was divided into three groups: premenopausal under 35 years (n = 64), premenopausal over 35 years (n = 456), and postmenopausal women (n = 310), respectively. Tumor subtype was classified into four subtypes: luminal A, luminal B, HER2-overexpressing, and triple-negative, respectively. Genotyping of the selected SNPs in ESR1, ESR2, CYP1A1, CYP1B1, and COMT was conducted using the VeraCode Golden Gate Genotyping Assay Technology. Multiple logistic regression models (dominant, recessive, and additive) were applied to determine the odds ratio, 95 % confidence interval, and p value.


ESR1, rs2881766, rs2077647, rs926778, and rs2273206 polymorphisms increased breast cancer risk, and rs3798377 decreased the risk in overall patients. The association between SNP genotype and breast cancer risk was varied according to age groups and tumor subtypes. For age subgroups, rs2881766 increased breast cancer risk in the all three age groups, and rs926778 increased the risk in premenopausal over 35 years women and in postmenopausal women. For the tumor subtypes, rs2881766 increased breast cancer risk manly in luminal A, HER2-overexpressing, and triple-negative subtypes except for luminal B subtype, and rs926778 increased the risk in luminal A and triple-negative subtypes. Rs3798577 decreased the risk in luminal B and triple-negative subtypes.


The results showed that ESR1 rs2881766 polymorphism increased breast cancer risk and rs3798377 decreased the risk in Korean women. Because of wide variation of the association between SNP genotype and breast cancer risk according to age group and tumor subtypes, further studies such as a large-scale cohort study need for validation and test of biologic significance.


Breast cancer Genetic polymorphism Estrogen-metabolizing enzyme Estrogen receptor gene Age Subtype 



This study was supported by a Grant (2009-022) from the Asan Institute for Life Sciences, Seoul, Korea.

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

432_2014_1849_MOESM1_ESM.docx (63 kb)
Supplementary material 1 (DOCX 62 kb)


  1. Ahn SH, Son BH, Kim SW, Kim SI, Jeong J, Ko SS, Han W, Korean Breast Cancer S (2007) Poor outcome of hormone receptor-positive breast cancer at very young age is due to tamoxifen resistance: nationwide survival data in Korea–a report from the Korean Breast Cancer Society. J Clin Oncol 25:2360–2368CrossRefPubMedGoogle Scholar
  2. Andersen TI, Heimdal KR, Skrede M, Tveit K, Berg K, Borresen AL (1994) Oestrogen receptor (ESR) polymorphisms and breast cancer susceptibility. Hum Genet 94:665–670PubMedGoogle Scholar
  3. Anghel A, Raica M, Narita D, Seclaman E, Nicola T, Ursoniu S, Anghel M, Popovici E (2010) Estrogen receptor alpha polymorphisms: correlation with clinicopathological parameters in breast cancer. Neoplasma 57:306–315CrossRefPubMedGoogle Scholar
  4. Blows FM, Driver KE, Schmidt MK, Broeks A, van Leeuwen FE, Wesseling J, Cheang MC, Gelmon K, Nielsen TO, Blomqvist C, Heikkila P, Heikkinen T, Nevanlinna H, Akslen LA, Begin LR, Foulkes WD, Couch FJ, Wang X, Cafourek V, Olson JE, Baglietto L, Giles GG, Severi G, McLean CA, Southey MC, Rakha E, Green AR, Ellis IO, Sherman ME, Lissowska J, Anderson WF, Cox A, Cross SS, Reed MW, Provenzano E, Dawson SJ, Dunning AM, Humphreys M, Easton DF, Garcia-Closas M, Caldas C, Pharoah PD, Huntsman D (2010) Subtyping of breast cancer by immunohistochemistry to investigate a relationship between subtype and short and long term survival: a collaborative analysis of data for 10,159 cases from 12 studies. PLoS Med 7:e1000279CrossRefPubMedCentralPubMedGoogle Scholar
  5. Cai Q, Shu XO, Jin F, Dai Q, Wen W, Cheng JR, Gao YT, Zheng W (2003) Genetic polymorphisms in the estrogen receptor alpha gene and risk of breast cancer: results from the Shanghai Breast Cancer Study. Cancer Epidemiol Biomark Prev 12:853–859Google Scholar
  6. Carey LA, Perou CM, Livasy CA, Dressler LG, Cowan D, Conway K, Karaca G, Troester MA, Tse CK, Edmiston S, Deming SL, Geradts J, Cheang MC, Nielsen TO, Moorman PG, Earp HS, Millikan RC (2006) Race, breast cancer subtypes, and survival in the Carolina Breast Cancer Study. JAMA 295:2492–2502CrossRefPubMedGoogle Scholar
  7. Feigelson HS, Cox DG, Cann HM, Wacholder S, Kaaks R, Henderson BE, Albanes D, Altshuler D, Berglund G, Berrino F, Bingham S, Buring JE, Burtt NP, Calle EE, Chanock SJ, Clavel-Chapelon F, Colditz G, Diver WR, Freedman ML, Haiman CA, Hankinson SE, Hayes RB, Hirschhorn JN, Hunter D, Kolonel LN, Kraft P, LeMarchand L, Linseisen J, Modi W, Navarro C, Peeters PH, Pike MC, Riboli E, Setiawan VW, Stram DO, Thomas G, Thun MJ, Tjonneland A, Trichopoulos D (2006) Haplotype analysis of the HSD17B1 gene and risk of breast cancer: a comprehensive approach to multicenter analyses of prospective cohort studies. Cancer Res 66:2468–2475CrossRefPubMedGoogle Scholar
  8. Figueroa JD, Garcia-Closas M, Humphreys M, Platte R, Hopper JL, Southey MC, Apicella C, Hammet F, Schmidt MK, Broeks A, Tollenaar RA, Van’t Veer LJ, Fasching PA, Beckmann MW, Ekici AB, Strick R, Peto J, dos Santos Silva I, Fletcher O, Johnson N, Sawyer E, Tomlinson I, Kerin M, Burwinkel B, Marme F, Schneeweiss A, Sohn C, Bojesen S, Flyger H, Nordestgaard BG, Benitez J, Milne RL, Ignacio Arias J, Zamora MP, Brenner H, Muller H, Arndt V, Rahman N, Turnbull C, Seal S, Renwick A, Brauch H, Justenhoven C, Bruning T, Network G, Chang-Claude J, Hein R, Wang-Gohrke S, Dork T, Schurmann P, Bremer M, Hillemanns P, Nevanlinna H, Heikkinen T, Aittomaki K, Blomqvist C, Bogdanova N, Antonenkova N, Rogov YI, Karstens JH, Bermisheva M, Prokofieva D, Gantcev SH, Khusnutdinova E, Lindblom A, Margolin S, Chenevix-Trench G, Beesley J, Chen X, kConFab AMG, Mannermaa A, Kosma VM, Soini Y, Kataja V, Lambrechts D, Yesilyurt BT, Chrisiaens MR, Peeters S, Radice P, Peterlongo P, Manoukian S, Barile M, Couch F, Lee AM, Diasio R, Wang X, Giles GG, Severi G, Baglietto L, Maclean C, Offit K, Robson M, Joseph V, Gaudet M, John EM, Winqvist R, Pylkas K, Jukkola-Vuorinen A, Grip M, Andrulis I, Knight JA, Mulligan AM, O’Malley FP, Brinton LA, Sherman ME, Lissowska J, Chanock SJ, Hooning M, Martens JW, van den Ouweland AM, Collee JM, Hall P, Czene K, Cox A, Brock IW, Reed MW, Cross SS, Pharoah P, Dunning AM, Kang D, Yoo KY, Noh DY, Ahn SH, Jakubowska A, Lubinski J, Jaworska K, Durda K, Sangrajrang S, Gaborieau V, Brennan P, McKay J, Shen CY, Ding SL, Hsu HM, Yu JC, Anton-Culver H, Ziogas A, Ashworth A, Swerdlow A, Jones M, Orr N, Trentham-Dietz A, Egan K, Newcomb P, Titus-Ernstoff L, Easton D, Spurdle AB (2011) Associations of common variants at 1p11.2 and 14q24.1 (RAD51L1) with breast cancer risk and heterogeneity by tumor subtype: findings from the Breast Cancer Association Consortium. Hum Mol Genet 20:4693–4706Google Scholar
  9. 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
  10. 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
  11. Goldhirsch A, Wood WC, Coates AS, Gelber RD, Thurlimann B, Senn HJ, Panel m (2011) Strategies for subtypes–dealing with the diversity of breast cancer: highlights of the St. Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2011. Ann Oncol 22:1736–1747CrossRefPubMedCentralPubMedGoogle Scholar
  12. Han W, Woo JH, Yu JH, Lee MJ, Moon HG, Kang D, Noh DY (2011) Common genetic variants associated with breast cancer in Korean women and differential susceptibility according to intrinsic subtype. Cancer Epidemiol Biomark Prev 20:793–798CrossRefGoogle Scholar
  13. Jung YS, Na KY, Kim KS, Ahn SH, Lee SJ, Park HK, Cho YU (2011) Nation-wide Korean breast cancer data from 2008 using the breast cancer registration program. J Breast Cancer 14:229–236CrossRefPubMedCentralPubMedGoogle Scholar
  14. Kang D (2003) Genetic polymorphisms and cancer susceptibility of breast cancer in Korean women. J Biochem Mol Biol 36:28–34CrossRefPubMedGoogle Scholar
  15. Kang HJ, Kim SW, Kim HJ, Ahn SJ, Bae JY, Park SK, Kang D, Hirvonen A, Choe KJ, Noh DY (2002) Polymorphisms in the estrogen receptor-alpha gene and breast cancer risk. Cancer Lett 178:175–180CrossRefPubMedGoogle Scholar
  16. Kang HS, Ahn SH, Mishra SK, Hong KM, Lee ES, Shin KH, Ro J, Lee KS, Kim MK (2014) Association of polymorphisms and haplotypes in the insulin-like growth factor 1 receptor (IGF1R) gene with the risk of breast cancer in Korean women. PLoS One 9:e84532CrossRefPubMedCentralPubMedGoogle Scholar
  17. Kim JY, Lee CS, Kim HO, Jo YH, Lee J, Jung MH, Baik HH, Choe W, Kang I, Yoon KS (2009) The association between genetic polymorphisms in CYP19 and breast cancer risk in Korean women. Oncol Rep 22:487–492PubMedGoogle Scholar
  18. Ko SS, Korean Breast Cancer S (2008) Chronological changing patterns of clinical characteristics of Korean breast cancer patients during 10 years (1996-2006) using nationwide breast cancer registration on-line program: biannual update. J Surg Oncol 98:318–323CrossRefPubMedGoogle Scholar
  19. Lee KM, Abel J, Ko Y, Harth V, Park WY, Seo JS, Yoo KY, Choi JY, Shin A, Ahn SH, Noh DY, Hirvonen A, Kang D (2003) Genetic polymorphisms of cytochrome P450 19 and 1B1, alcohol use, and breast cancer risk in Korean women. Br J Cancer 88:675–678CrossRefPubMedCentralPubMedGoogle Scholar
  20. Li N, Dong J, Hu Z, Shen H, Dai M (2010) Potentially functional polymorphisms in ESR1 and breast cancer risk: a meta-analysis. Breast Cancer Res Treat 121:177–184CrossRefPubMedGoogle Scholar
  21. Mitrunen K, Hirvonen A (2003) Molecular epidemiology of sporadic breast cancer. The role of polymorphic genes involved in oestrogen biosynthesis and metabolism. Mutat Res 544:9–41CrossRefPubMedGoogle Scholar
  22. Miyoshi Y, Noguchi S (2003) Polymorphisms of estrogen synthesizing and metabolizing genes and breast cancer risk in Japanese women. Biomed Pharmacother 57:471–481CrossRefPubMedGoogle Scholar
  23. Paracchini V, Raimondi S, Gram IT, Kang D, Kocabas NA, Kristensen VN, Li D, Parl FF, Rylander-Rudqvist T, Soucek P, Zheng W, Wedren S, Taioli E (2007) Meta- and pooled analyses of the cytochrome P-450 1B1 Val432Leu polymorphism and breast cancer: a HuGE-GSEC review. Am J Epidemiol 165:115–125CrossRefPubMedGoogle Scholar
  24. Perou CM, Sorlie T, Eisen MB, van de Rijn M, Jeffrey SS, Rees CA, Pollack JR, Ross DT, Johnsen H, Akslen LA, Fluge O, Pergamenschikov A, Williams C, Zhu SX, Lonning PE, Borresen-Dale AL, Brown PO, Botstein D (2000) Molecular portraits of human breast tumours. Nature 406:747–752CrossRefPubMedGoogle Scholar
  25. Rebbeck TR, Troxel AB, Walker AH, Panossian S, Gallagher S, Shatalova EG, Blanchard R, Norman S, Bunin G, DeMichele A, Berlin M, Schinnar R, Berlin JA, Strom BL (2007) Pairwise combinations of estrogen metabolism genotypes in postmenopausal breast cancer etiology. Cancer Epidemiol Biomark Prev 16:444–450CrossRefGoogle Scholar
  26. Schiff R, Massarweh SA, Shou J, Bharwani L, Mohsin SK, Osborne CK (2004) Cross-talk between estrogen receptor and growth factor pathways as a molecular target for overcoming endocrine resistance. Clin Cancer Res 10:331S–336SCrossRefPubMedGoogle Scholar
  27. Schubert EL, Lee MK, Newman B, King MC (1999) Single nucleotide polymorphisms (SNPs) in the estrogen receptor gene and breast cancer susceptibility. J Steroid Biochem Mol Biol 71:21–27CrossRefPubMedGoogle Scholar
  28. Shin A, Kang D, Nishio H, Lee MJ, Park SK, Kim SU, Noh DY, Choe KJ, Ahn SH, Hirvonen A, Kim JH, Yoo KY (2003) Estrogen receptor alpha gene polymorphisms and breast cancer risk. Breast Cancer Res Treat 80:127–131CrossRefPubMedGoogle Scholar
  29. Shin A, Kang D, Choi JY, Lee KM, Park SK, Noh DY, Ahn SH, Yoo KY (2007) Cytochrome P450 1A1 (CYP1A1) polymorphisms and breast cancer risk in Korean women. Exp Mol Med 39:361–366CrossRefPubMedGoogle Scholar
  30. Sorlie T, Perou CM, Tibshirani R, Aas T, Geisler S, Johnsen H, Hastie T, Eisen MB, van de Rijn M, Jeffrey SS, Thorsen T, Quist H, Matese JC, Brown PO, Botstein D, Lonning PE, Borresen-Dale AL (2001) Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci USA 98:10869–10874CrossRefPubMedCentralPubMedGoogle Scholar
  31. Sowers MR, Jannausch ML, McConnell DS, Kardia SR, Randolph JF Jr (2006) Endogenous estradiol and its association with estrogen receptor gene polymorphisms. Am J Med 119(9 Suppl 1):S16–S22CrossRefPubMedGoogle Scholar
  32. Stacey SN, Manolescu A, Sulem P, Thorlacius S, Gudjonsson SA, Jonsson GF, Jakobsdottir M, Bergthorsson JT, Gudmundsson J, Aben KK, Strobbe LJ, Swinkels DW, van Engelenburg KC, Henderson BE, Kolonel LN, Le Marchand L, Millastre E, Andres R, Saez B, Lambea J, Godino J, Polo E, Tres A, Picelli S, Rantala J, Margolin S, Jonsson T, Sigurdsson H, Jonsdottir T, Hrafnkelsson J, Johannsson J, Sveinsson T, Myrdal G, Grimsson HN, Sveinsdottir SG, Alexiusdottir K, Saemundsdottir J, Sigurdsson A, Kostic J, Gudmundsson L, Kristjansson K, Masson G, Fackenthal JD, Adebamowo C, Ogundiran T, Olopade OI, Haiman CA, Lindblom A, Mayordomo JI, Kiemeney LA, Gulcher JR, Rafnar T, Thorsteinsdottir U, Johannsson OT, Kong A, Stefansson K (2008) Common variants on chromosome 5p12 confer susceptibility to estrogen receptor-positive breast cancer. Nat Genet 40:703–706CrossRefPubMedGoogle Scholar
  33. Yim DS, Park SK, Yoo KY, Yoon KS, Chung HH, Kang HL, Ahn SH, Noh DY, Choe KJ, Jang IJ, Shin SG, Strickland PT, Hirvonen A, Kang D (2001) Relationship between the Val158Met polymorphism of catechol O-methyl transferase and breast cancer. Pharmacogenetics 11:279–286CrossRefPubMedGoogle Scholar
  34. Zhang L, Gu L, Qian B, Hao X, Zhang W, Wei Q, Chen K (2009) Association of genetic polymorphisms of ER-alpha and the estradiol-synthesizing enzyme genes CYP17 and CYP19 with breast cancer risk in Chinese women. Breast Cancer Res Treat 114:327–338CrossRefPubMedGoogle Scholar
  35. 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

Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Byung Ho Son
    • 1
  • Mi Kyung Kim
    • 2
  • Young Mi Yun
    • 1
  • Hee Jeong Kim
    • 1
  • Jong Han Yu
    • 1
  • Beom Seok Ko
    • 1
  • Hanna Kim
    • 1
  • Sei Hyun Ahn
    • 1
    • 3
  1. 1.Department of Surgery, College of Medicine, Asan Medical CenterUniversity of UlsanSeoulKorea
  2. 2.Cancer Epidemiology Branch, Division of Cancer Epidemiology and Management, Research InstituteNational Cancer CenterGoyangKorea
  3. 3.Division of Breast and Endocrine Surgery, Department of Surgery, Asan Medical Center, College of MedicineUniversity of UlsanSeoulKorea

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