Estrogen receptor alpha haplotypes and breast cancer risk in older Caucasian women
Life-long exposure to estrogen is an established risk factor for breast cancer development. The underlying mechanism has been suggested to be the binding of estrogen-to-estrogen receptors in mammary tissue, which in turn promotes the proliferation and differentiation of breast tissue. Polymorphisms and haplotypes in estrogen receptor alpha (ESR1) have been reportedly associated with breast cancer risk; however, the results are not fully consistent. In this study, we investigated breast cancer risk associated with genotypes and haplotypes resulting from four ESR1 single nucleotide polymorphisms (SNPs), rs746432, rs2234693, rs9340799, and rs1801132. Genotyping has been performed on 393 breast cancer cases and 790 randomly selected controls in 1,183 Caucasian women over age 65 from the Study of Osteoporotic Fractures (SOF). We observed an allelic protective effect for SNP rs9340799 with an estimated odds ratio (OR) of 0.82 (95% CI = 0.68–1.00; P = 0.04) after adjustment for age, BMI and hip BMD. A protective effect of this SNP has been reported before in several different studies. We did not replicate the previously reported C–C–A–G haplotype association to breast cancer—the C–C–A–G haplotype from these SNPs was rare in this study (estimated frequency below 0.001% in cases and controls). No other statistically significant associations were observed between ESR1 haplotypes from the same four SNPs and the risk of breast cancer in older Caucasian women.
KeywordsEstrogen receptor alpha Haplotype Single nucleotide polymorphism Association Breast cancer
The Study of Osteoporotic Fractures is supported by National Institutes of Health funding, under the following Grant Numbers: AG05407, AR35582, AG05394, AR35584, and AR35583.
- 16.Shin A, Kang D, Nishio H, Lee MJ, Park SK, Kim SU, Noh DY, Choe KJ, Ahn SH, Hirvonen A et al (2003) Estrogen receptor alpha gene polymorphisms and breast cancer risk. Breast Cancer Res Treat 80(1):127–131Google Scholar
- 18.Wedren S, Lovmar L, Humphreys K, Magnusson C, Melhus H, Syvanen AC, Kindmark A, Landegren U, Fermer ML, Stiger F et al (2004) Oestrogen receptor alpha gene haplotype and post-menopausal breast cancer risk: a case control study. Breast Cancer Res 6(4):R437–449Google Scholar
- 20.Gold B, Kalush F, Bergeron J, Scott K, Mitra N, Wilson K, Ellis N, Huang H, Chen M, Lippert R et al (2004) Estrogen receptor genotypes and haplotypes associated with breast cancer risk. Cancer Res 64(24):8891–8900Google Scholar
- 27.Agresti A (2002) Categorical data analysis. John Wiley & Sons, Inc., Hoboken, New JerseyGoogle Scholar
- 28.Cauley JA, Lucas FL, Kuller LH, Vogt MT, Browner WS, Cummings SR (1996) Bone mineral density and risk of breast cancer in older women: the study of osteoporotic fractures. Study of Osteoporotic Fractures Research Group. Jama 276(17):1404–1408Google Scholar
- 37.Tzukerman MT, Esty A, Santiso-Mere D, Danielian P, Parker MG, Stein RB, Pike JW, McDonnell DP (1994) Human estrogen receptor transactivational capacity is determined by both cellular and promoter context and mediated by two functionally distinct intramolecular regions. Mol Endocrinol 8(1):21–30PubMedCrossRefGoogle Scholar
- 38.Herrington DM, Howard TD, Brosnihan KB, McDonnell DP, Li X, Hawkins GA, Reboussin DM, Xu J, Zheng SL, Meyers DA et al (2002) Common estrogen receptor polymorphism augments effects of hormone replacement therapy on E-selectin but not C-reactive protein. Circulation 105(16):1879–1882Google Scholar
- 39.Schuit SC, Oei HH, Witteman JC, Geurts van Kessel CH, van Meurs JB, Nijhuis RL, van Leeuwen JP, de Jong FH, Zillikens MC, Hofman A et al (2004) Estrogen receptor alpha gene polymorphisms and risk of myocardial infarction. Jama 291(24):2969–2977Google Scholar