Genetic polymorphisms of estrogen receptor genes are associated with breast cancer susceptibility in Chinese women

Breast cancer (BC), which had approximately 1.7 million new cases and 0.5 million deaths in 2012, has become the most common cancer type and the leading cause of global cancer death among females [1]. In Chinese women, BC also holds the highest incidence, accounting for 15% of all new cancers and 7% malignancy deaths [2]. BC is a complex heterogeneous disease. Both genetic and environmental factors are involved in the occurrence of BC [3].

Estrogen exposure is a widely known risk factor for BC. And the interaction of estrogen with estrogen receptor (ER), which can alter the expression of downstream genes, plays an important role in breast cancer development [4]. ER alpha (ERα) and beta (ERβ) are the main forms of ER. They were encoded by the gene estrogen receptor 1 (ESR1) and estrogen receptor 2 (ESR2) respectively. And evidence showed that genetic variants in these two genes were associated with BC susceptibility [5‐8]. Polymorphisms in ESR1 have been investigated in a number of studies. The pooled results demonstrated that the AA genotype of rs2228480 was correlated with a lower risk of BC in Caucasians. The C allele of the rs3798577 decreased BC risk in Asians while increased BC risk in Caucasians [5]. The TT/TC genotype of rs2234693 was related to high risk of BC [8]. In addition, meta-analysis of the relationship between ESR2 polymorphisms and BC susceptibility showed that the polymorphism rs4986938 was associated with reduced BC risk in overall population under both dominant and heterozygous models [6].

In the present study, four single nucleotide polymorphisms (SNPs) in the two estrogen receptor genes were selected to be studied. The effects of these SNPs (rs2881766, rs9383951, rs9340799 in ESR1 and rs3020449 in ESR2) in BC risk in Chinese population were either seldom being explored or the conclusions were still controversial. Therefore, we conducted a hospital-based case–control study to explore the association of the four polymorphisms with BC susceptibility in Chinese Han women.

Genetic variation is an important risk factor for BC [14]. Single nucleotide polymorphism is the most frequent variation in the genome. Genome-wide association study (GWAS) has identified numerous BC susceptibility loci in tumor-related genes such as FGFR2, TOX3, TP53, PTEN, MAP3K1, c-MYC, LSP1, and CASP8 [14, 15]. Estrogen plays a critical role in the development of breast cancer [4]. Its effect on the breast epithelium is mediated by ER. The two major forms of ER (ERα and ERβ) are encoded by two separate genes, ESR1 located on Chr6 and ESR2 located on Chr14. And genetic polymorphisms in these two genes were reported to associate with BC susceptibility, including the extensively studied SNPs such as rs2228480, rs3798577, rs2077647, rs2234693 in ESR1 and rs4986938, rs1256049 in ESR2 as well as less common SNPs such as rs3020314, rs1514348, rs1062577, rs1271572, rs1256054 and rs2987983 [5‐8, 16‐19].

In this study, we investigated the associations of BC risk with four SNPs in the estrogen receptor genes ESR1 and ESR2. SNP rs2881766 is located in the promoter region of ESR1. This polymorphism was reported to increase BC risk in Korean women in a previously [20]. However, another study conducted in Chinese population showed that the GG genotype of this SNP decreases BC risk in menarche > 13-year-old while increases BC risk in menarche ≤ 13-year-old subgroup [21]. Our results indicated that the carriers of rs2881766 GG genotype had a lower risk of BC compared with the TT and GT genotype carriers. The discrepancy between our results and previous studies may caused by different sample sizes and the effects of confounding factors such as age, ethnicity and environmental effects. Moreover, the GG genotype may be a protective factor of lymph node metastasis for BC patients. And patients with rs2881766 GG genotype are more likely to have less expression of ER. SNP rs9340799 and rs9383951 are located in the first and fifth intron of ESR1 respectively [8, 22]. The association between rs9340799 (also known as Xbal) and BC risk has been evaluated in several studies before, but the conclusions were debatable. A few studies suggested this polymorphism can affect BC risk [23‐25], whereas others did not find any relationship between this polymorphism and BC susceptibility [8, 18, 26, 27]. There is only one previous study of rs9383951and BC risk, but no significant association was found. Our study indicated that neither rs9340799 nor rs9383951 were related to BC risk, which is in line with most of previous studies. SNP rs3020449 is located in the promoter region of the ESR2 gene [7]. Two previous studies investigated the effect of this SNP on BC risk, but neither one observed significant association [19, 28]. In contrast, our results suggested that the CT genotype of rs3020449 increased the risk of BC. In addition, BC patients with CT genotype tend to have a larger tumor size compared with TT genotype carriers. Furthermore, patients with CC genotype may have a greater tumor grade and higher expression of ER.

FPRP analysis is an effective approach to verify the noteworthiness of significant findings. In this study, we adopted a relatively stringent cut-off value for FPRP. The FPRP value of the significant association between ESR2 rs3020449 and BC risk was much lower than the threshold, suggesting that our findings of this SNP were noteworthy and authentic. The significant association of ESR1 rs2881766 with BC risk was noteworthy only in homozygous model. But actually, FPRP value of significant association in another model was still quite small (< 0.3). Hence, we believe our findings for this polymorphism were credible to some extent.

In conclusion, the current study suggests that the ESR1 rs2881766 decreases BC risk while ESR2 rs3020449 increases BC risk in Chinese women. Future large studies are required to validate these findings. The possible mechanisms underlying the associations also need to be explored.