Association of estrogen receptor α polymorphisms with breast cancer risk in older Caucasian women

Abstract

Estrogens exert their effect on the breast through the estrogen receptor. We prospectively investigated breast cancer risk associated with 2 polymorphic sites in the estrogen receptor alpha gene (ESR1). A total of 4,248 Caucasian women from the Study of Osteoporotic Fractures were genotyped for the 2401 T/C and 2354 A/G polymorphisms in ESR1. Cox proportional hazards models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for the associations between genotypes and breast cancer. During a mean follow-up of 12.4 years, 252 (5.9%) women developed breast cancer. The HR (95% CI) for breast cancer were 0.928 (0.708, 1.22) and 0.834 (0.538, 1.29) for the 2354 A/ G and A/A genotypes, respectively. Interactions with 2354 variant were observed for smoking (HR 5 1.52 and 1.56 for A/G and A/A smokers, respectively; HR 5 0.74 and 0.60 for A/G and A/A nonsmokers, respectively; interaction p 5 0.03) and walking (HR 5 0.75 and 1.15 for A/G and A/A walkers, respectively; HR 5 0.18 and 0.49 for A/G and A/A non-walkers, respectively; interaction p 5 0.01). There were no differences in the HR for the 2401 T/C genotypes. An interaction between parity and carriage of the T allele was found (HR 5 0.60 vs. 1.12 for nulliparous vs. parous women; interaction p 5 0.03). ESR1 polymorphisms in combination with lifestyle factors may be associated with breast cancer risk in older Caucasian women. ' 2005 Wiley-Liss, Inc.Key words: breast neoplasms; estrogen receptor; genetic polymorphisms; epidemiology; prospective cohort study The actions of estrogen, believed to be a causal factor in postmenopausal breast cancer, 1-4 are mediated by the estrogen receptors (ER). The ER has 2 major forms, a and b. 5,6 The ER-a (ESR1) is of interest in breast cancer because its expression has been associated with the disease. In particular, breast cancer occurs more often when ESR1 is over-expressed in adjacent normal epithelium. 7 Moreover, increased ESR1 expression in normal epithelium is found in older women, 8 as well as in Caucasian women compared to non-Caucasian 9 and Asian 8 women, reflecting age and ethnic-associated patterns of breast cancer risk. In addition, estrogen receptor status is a prognostic factor in breast cancer and a strong predictor of response to endocrine therapy. 10 The ESR1 gene contains several single nucleotide polymorphisms (SNP) 8,11-14 whose functional significance remains unknown. Nonetheless, 2 of these SNP located in intron 1, the IVS1 2401 and IVS1 2354 A/G variants, have been associated with hormonally-related diseases including breast, [15][16][17][18][19] prostate 20 and endometrial 21 cancers. These same 2 SNP have also been associated with other estrogen-linked conditions, 22,23 as well as factors associated with increased breast cancer risk, such as age at menopause 24 and age at menarche. 25 In addition, increased bone mineral density, a potential surrogate marker of cumulative estrogen exposure and a predictor of breast cancer risk, 26 has also been associated with these SNP, 27,28 although...

Estrogen Receptor α Polymorphism and Risk of Cardiovascular Disease, Cancer, and Hip Fracture

“…Previous smaller studies 18 -21,23 and a recent large cohort study 24 (4248 women followed up for 12.4 years; 252 events) on the association between the ESR1 IVS1-397T/C polymorphism of the ESR1 and risk of breast cancer showed no association, whereas a Chinese case-control study of 1069 cases and 1166 controls, in accordance with our results, showed an increase in risk of breast cancer with age-adjusted odds ratios for IVS1-397T/C genotypes TT versus CC of 1.4 (95% CI, 1.1 to 1.8). 22 Furthermore, a combined odds ratio for 5 of the previous studies 17-20,22 was 1.23 (95% CI, 1.08 to 1.43) on risk of breast cancer for TT versus CC genotype of the ESR1 IVS1-397T/C polymorphism.…”

“…Postmenopausal women with ESR1 IVS1-397T/C CC versus TT genotype undergoing hormone replacement therapy (HRT) had an augmented response of high-density lipoprotein (HDL) cholesterol levels 3 and greater reductions in E-selectin, 2 both of which could influence risk of disease in estrogen-responsive organ systems. In addition, there have already been several studies of the ESR1 IVS1-397T/C polymorphism in relation to CVD, 4 -16 breast cancer, [17][18][19][20][21][22][23][24] endometrial cancer, 25,26 prostate cancer, [27][28][29][30][31] and hip fracture, 32,33 although the results have been conflicting. It is therefore biologically plausible that the ESR1 IVS1-397T/C polymorphism may modify the effect of endogenous estrogen on risk of CVD, cancer of reproductive organs, and osteoporotic fractures like hip fracture.…”

Estrogen and progesterone receptor gene polymorphisms and sporadic breast cancer risk: A Spanish case‐control study

“…Modugno et al 16 found a modest but nonsignificant decrease in breast cancer risk associated with 2 loci in ESR1 for a range of population subgroups defined by various life style factors in Caucasians (2354 A/G and -401 T/C). Gold et al 10 identified protective haplotypes (H4, H6, H13) in the ESR1 gene in a mixed population and one in particular (H6) when the European-American subset population was analyzed, while Hsiao et al, 11 found that the SNP S10S (rs2077647) was associated with reduced breast cancer risk in a Taiwanese population.…”

Active and passive smoking, IL6, ESR1, and breast cancer risk

“…The three most widely studied polymorphisms of the ESR1, the PvuII 397T > C, the XbaI (351A > G) restriction fragment length polymorphisms, both located in intron 1, and the TA repeat within the promoter region of the gene, are in linkage disequilibrium [18,19]. These polymorphisms have been examined with breast cancer risk [20][21][22][23] as well as with other conditions that have been linked to estrogen [19,24,25] with mixed results.…”