Estrogen plays an important role in the expression of genes that regulate hormone levels, normal prostate developments and prostate diseases 
. Aberrant expressions or mutations of hormone receptors in cancer cells were also found to be associated with prostate cancer aggressiveness 
. Additionally, inherited variants in sex hormonal receptor genes may perhaps interact with other variants in the steroidogenic and metabolic pathways cooperatively 
. Therefore, hormonal status is clearly an important factor in prostate cancer biology. Estrogen exerts its effects on prostatic tissues by binding to and activating estrogen receptors (ESR1 and ESR2). Estrogen receptor (ESR1) is involved in sex steroid metabolism and functions in carrying out the proper cellular responses 
. Accumulating evidences also indicate that estrogen and estrogen receptors play crucial roles in prostate cancer development and progression 
. ESR1 is expressed in prostate stromal cells and is thought to stimulate growth factor release and cause epithelial cell proliferation. Ricke et al suggested that it is likely an imbalance of their expression may be critical in determining the effects that estrogen ultimately has on prostate cancer cells 
. However, a recent genetic study showed that mutations in ESR1 were independent risk factors 
Human ESR1 encoding gene is located on chromosome 6q24–27, consists of eight exons and seven introns, and is about 140 kb in length with two promoter regions and five functional domains, designated as A/B–F, in two differing transcripts at the 5′ region 
. The protein itself has 595 amino acids and weights a molecular weight of 66,182 Da 
. In the normal prostate, ESR1 is expressed in stromal cells but not in epithelial cells. In contrast, it has been discovered that ESR1 is expressed in the epithelium in malignant prostate tissues 
. ESR1 gene mutations may alter the concentration of reactive estrogens in the prostate 
. Several polymorphisms in ESR1 gene, such as PvuII (rs9340799 A>G) and XbaI (rs2234693 C>T), have been studied to a assess their causal relationships with prostate cancer 
. It appears that inherited alterations of the ESR1 gene can possibly explain interpopulation differences in the incidences associated with estrogen-related diseases 
. Many investigations have demonstrated that prostate cancer risk was associated with the ESR1 gene polymorphism 
To explore the association between ESR1 gene polymorphisms and prostate cancer risk, we performed a meta-analysis on 2,165 prostate cancer cases and 3,361 controls. This is the first meta-analysis exploring the relationship between prostate cancer and the ESR1 gene polymorphisms. When all the eligible studies were pooled into the meta-analysis, the results showed that ESR1 PvuII (C>T) and XbaI (A>G) polymorphisms were not associated with the risk of prostate cancer, yet many studies have inferred that ESR1 gene polymorphisms were related to the onset and develop of prostate cancer 
. A possible reason for the controversy is that a considerable degree of heterogeneity existed among the other studies due to differences in sample sizes, exposure estimates, ethnicity, source of controls and other potential confounding variables. Therefore, we performed a stratified analysis based on ethnicity and country. The results showed that ESR1 PvuII (C>T) polymorphism might increase the risk of prostate cancer among Asian populations, especially among Indian population. ESR1 XbaI (A>G) polymorphism was confirmed to be associated with increased risk of prostate cancer among American population under the allele model, but not among Japanese and Indian populations. However, pooled estimates for Indian population was slightly higher than that for American population, and only pooled OR under the allele model was significant and might lead to unacceptably low levels of statistical power. Therefore, this result should be verified by large, well-designed epidemiologic population-based studies. Ethnic differences in prostate cancer susceptibility are probably the results of both genetic and epidemiological factors, which may mainly be the results of genetic factors including mutations in rare genes that confer high risks and/or mutations in specific genes that confer modestly increased risks 
. Furthermore, we also performed a pooled analysis for all eligible case-control studies to explore the role of codon 10 (T>C), codon 325 (C>G), codon 594 (G>A) and +261G>C polymorphisms in prostate cancer risk. However, no significant associations between these SNPs and prostate cancer risk were observed.
In interpreting the results of the current meta-analysis, some limitations need to be addressed. First, the sample size is still relatively small and may not provide sufficient power to estimate the association between ESR1 gene polymorphisms and prostate cancer risk. Second, heterogeneity across studies was obvious, which might be a result of the difference in ethnicity, country, source of controls and genotype methods. Third, the selection bias may exist because only articles published in English or Chinese were included. Besides, our meta-analysis was also based on unadjusted ORs estimates because not all published studies presented adjusted ORs, or when they were, the ORs were not adjusted by the same potential confounders, such as ethnicity, age, gender, geographic distribution, etc. Although no obvious publication bias was identified, potential bias cannot be completely ruled out. Nonetheless, it is well acknowledged that many other factors, such as gene-gene or gene-environment interactions may affect the risk of gastrointestinal cancer. Finally, although all cases and controls of each study were well defined with similar inclusion criteria, there may be potential factors that were not taken into account that could have influenced our results.
In spite of these limitations, our meta-analysis still had some merits and values. To the best of our knowledge, this is the first meta-analysis on the relationship of ESR1 gene polymorphisms and prostate cancer risk. It is worthwhile to mention that we also established an efficient searching strategy based on computer-assisted programs and manual searches, which allowed us to include as many studies as possible. According to our selection criteria, the quality of studies included in this meta-analysis is sufficient. Explicit methods for study selection, data extraction, and data analysis were well designed before initiating. Finally, there was no evidence of publication bias in this meta-analysis and the sensitivity analysis indicated that the results are statistically robust.
In summary, this meta-analysis suggested that ESR1 PvuII (C>T) polymorphism may be a potential risk factor for prostate cancer among Asian populations, especially among Indian population; while ESR1 XbaI (A>G) polymorphism may increase the risk of prostate cancer among American population. Such relationship can provide a more comprehensive mechanism of how ESR1 mutations function in the development of prostate cancer, as well as promise a more effective treatment for prostate cancer. However, further studies are still needed to warrant and validate the association between ESR1 gene polymorphism with other genetic polymorphisms and prostate cancer risk.