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

Abstract

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.

Estrogen metabolism and breast cancer

“…The only SNP that showed borderline significant association with reduced risk of breast cancer was rs2234693 (CC genotype vs. TT; OR=0.92; 95 % CI, 0.86–0.99; P =0.08 for heterogeneity test) [69]. Polymorphisms in the ERβ gene and breast cancer risk have also been studied in a recent systematic review [70] that reported that rs2987983, and rs4986938 SNPS are significantly associated with overall breast cancer risk…”

The role of estrogens and estrogen receptor signaling pathways in cancer and infertility: the case of schistosomes

“…Once estrogen binds to the inactive ER, the receptor is activated, a conformational change and homodimerization occurs, and two receptorligand monomers dimerize and bind to the ERE. Once bound to the ERE, the ER uses activation functions (AFs) (AF-1 and AF-2) to stimulate transcription from Homology rat ERα and ER β the promoter [20,30]. The ER contains two functional domain areas called AFs: AF-1 is located in the N-terminal region of the ER and AF-2 is located in the C-terminal region in the ligand-binding domain (LBD) of the ER.…”

“…The EREs are constituted by 13-bp palindromic sequences upstream the transcriptional start site. Binding of the ER to the corresponding ERE enhances the transcriptional rate of the gene in the target tissue, for example, breast [20,30]. ER mediates the biological effects of estrogens in a variety of target tissues.…”

Associations between estrogen receptor-beta polymorphisms and endometriosis risk: a meta-analysis

“…The former SNP located in exon 8 gives rise to a G-A exchange at nucleotide 1730 and introduces a recognition site for AluI , whereas the latter results in a G-A exchange at nucleotide 1082 in exon 5 and creates a recognition site for RsaI . In recent years, many meta-analyses have reported associations of these two SNPs in the ER-β gene with several diseases, including prostate cancer [10], male infertility [11], Parkinson’s disease [12], osteoarthritis [13], and breast cancer [14]. …”