Dai et al. Cancer Cell Int (2019) 19:11 https://doi.org/10.1186/s12935-019-0727-z Cancer Cell International PRIMARY RESEARCH Open Access Genetic polymorphisms of estrogen receptor genes are associated with breast cancer susceptibility in Chinese women Zhijun Dai1,2*† , Tian Tian1,2†, Meng Wang2†, Tielin Yang3, Hongtao Li4, Shuai Lin2, Qian Hao1,2, Peng Xu1, Yujiao Deng1,2, Linghui Zhou1,2, Na Li1,2 and Yan Diao2* Abstract Background: Estrogen exposure is a widely known risk factor for BC. And the interaction of estrogen with estrogen receptor (ER) plays an important role in breast cancer development. This case–control study aims to assess the association of genetic polymorphisms in the estrogen receptor genes with breast cancer (BC) susceptibility in Chinese Han women. Methods: Four polymorphisms (rs2881766, rs9383951, rs9340799 in ESR1 and rs3020449 in ESR2) were genotyped in 459 patients and 549 healthy controls using the Sequenom MassARRAY method. Odds ratio (OR) and 95% confdence intervals (95% CI) were calculated to evaluate the associations. False-positive report probability (FPRP) was utilized to examine the noteworthiness of signifcant fndings. Results: We observed that rs2881766 was associated with a decreased BC risk (GG vs. TT: OR 0.63, 95% CI 0.44– 0.91; GG vs. TT/GT: OR 0.68, 95% CI 0.49–0.95), while rs3020449 was associated with an increased= risk of BC= (CT vs. TT: OR 1.58, 95% CI = 1.21–2.06; CT/CC= vs. TT: OR 1.54, 95% CI 1.20–1.98; TT/CC vs. CT: OR 1.48, 95% CI 1.15– 1.90). The= other two polymorphisms= have no relation= with BC susceptibility.= In addition, rs2881766= was correlated= with lymph node metastasis and ER expression, and rs3020449 was related to tumor size, histological grade and ER expression. The values of false-positive report probability indicated that the signifcant associations of BC risk with both rs2881766 and rs3020449 were noteworthy. Conclusions: Our study suggests that polymorphisms rs2881766 and rs3020449 in estrogen receptor genes were associated with BC susceptibility as well as clinical features in Chinese women. These fndings need further validation in a large population. Keywords: Estrogen receptor genes, Polymorphism, Breast cancer, Susceptibility Background for 15% of all new cancers and 7% malignancy deaths [2]. Breast cancer (BC), which had approximately 1.7 million BC is a complex heterogeneous disease. Both genetic and new cases and 0.5 million deaths in 2012, has become environmental factors are involved in the occurrence of the most common cancer type and the leading cause BC [3]. of global cancer death among females [1]. In Chinese Estrogen exposure is a widely known risk factor for women, BC also holds the highest incidence, accounting BC. And the interaction of estrogen with estrogen recep- tor (ER), which can alter the expression of downstream *Correspondence: [email protected]; [email protected] genes, plays an important role in breast cancer develop- † Zhijun Dai, Tian Tian and Meng Wang contributed equally to this work ment [4]. ER alpha (ERα) and beta (ERβ) are the main 1 Department of Breast Surgery, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou 510623, forms of ER. Tey were encoded by the gene estrogen Guangdong, China receptor 1 (ESR1) and estrogen receptor 2 (ESR2) respec- 2 Department of Oncology, The Second Afliated Hospital of Xi’an tively. And evidence showed that genetic variants in these Jiaotong University, Xi’an 710004, China Full list of author information is available at the end of the article two genes were associated with BC susceptibility [5–8]. © The Author(s) 2019. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creat​iveco​mmons​.org/licen​ses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creat​iveco​mmons​.org/ publi​cdoma​in/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Dai et al. Cancer Cell Int (2019) 19:11 Page 2 of 7 Polymorphisms in ESR1 have been investigated in a num- of the selected SNPs were listed in Additional fle 1: ber of studies. Te pooled results demonstrated that the Table S1. Data was analyzed with Sequenom Typer Soft- AA genotype of rs2228480 was correlated with a lower ware (version 4.0, USA). risk of BC in Caucasians. Te C allele of the rs3798577 decreased BC risk in Asians while increased BC risk in Statistical analysis Caucasians [5]. Te TT/TC genotype of rs2234693 was Te Student t test and χ2-test were adopted to compare related to high risk of BC [8]. In addition, meta-analysis the diferences in basic characteristics between cases of the relationship between ESR2 polymorphisms and BC and controls. Hardy–Weinberg equilibrium (HWE) for susceptibility showed that the polymorphism rs4986938 selected SNPs in controls and the diferences in geno- was associated with reduced BC risk in overall popula- types distribution between cases and controls were tion under both dominant and heterozygous models [6]. examined by χ2-test. We evaluated the associations of In the present study, four single nucleotide poly- the four SNPs with BC risk in codominant, dominant, morphisms (SNPs) in the two estrogen receptor genes recessive, and overdominant models. Odds ratios (ORs) were selected to be studied. Te efects of these SNPs with 95% confdence intervals (CIs) were calculated by (rs2881766, rs9383951, rs9340799 in ESR1 and rs3020449 multivariate logistic regression, with adjustment for age in ESR2) in BC risk in Chinese population were either and body mass index (BMI). All the tests were two-tailed seldom being explored or the conclusions were still con- and P-value < 0.05 was considered statistically signifcant. troversial. Terefore, we conducted a hospital-based Akaike’s information criterion (AIC) and Bayesian infor- case–control study to explore the association of the four mation criterion (BIC) values were used to determine the polymorphisms with BC susceptibility in Chinese Han best-ft model for each SNP. We then conducted False- women. positive report probability (FPRP) analysis to examine whether the signifcant results were noteworthy. Te Methods prior probability of 0.1 was set to detect the noteworthi- Study population ness for OR of 1.50/0.67 and 0.25 was determined as a BC patients treated at the Department of Oncology, FPRP cut-of value as described in previous studies [12, the Second Afliated Hospital of Xi’an Jiaotong Univer- 13]. All data were analyzed using SPSS software (version sity (Xi’an, China) were enrolled as cases [9]. Women 22.0, IBM Corporation, USA). who came to the hospital for a checkup during the same period of time were recruited to form the control group. Results Te cases were newly diagnosed and confrmed by histol- Basic information of the study population and SNPs ogy or pathology. None of them had received chemother- A total of 1008 subjects including 459 BC patients and apy, endocrinotherapy or radiotherapy before surgery. 549 healthy individuals were enrolled in this study. As Patients with other types of cancer were excluded. Te shown in Table 1, no signifcant diference was observed controls were healthy individuals without any history of between the case and control groups in the distribution a tumor or chronic diseases. All of the participants were of age, menopausal status, procreative times and BMI. It Han population from Northwest China and have no rela- suggested that the cases and controls in this study were tion to each other. Clinical information was collected matched adequately on basic characteristics. Te basic from the medical records of the study subjects. information of the four SNPs was presented in Table 2. Te genotypic frequencies of all the selected SNPs in Sample collection and genotyping Peripheral blood samples were collected in tubes coated Table 1 The basic characteristics of cases and controls with EDTA and were stored at − 80 °C. Genomic DNA was extracted from whole blood using the Universal Characteristics Cases (459) Controls (549) P-value Genomic DNA Extraction Kit (TaKaRa Bio Inc., Japan). Age (mean SD) 49.09 11.02 48.80 8.28 0.610 DNA concentration was measured with the UV/VIS ± ± ± Menopausal status 0.376 spectrophotometer (DU530, Beckman Instruments, Premenopausal 237 267 USA). Four tag-SNPs (rs2881766, rs9383951, rs9340799 Postmenopausal 222 282 and rs3020449) were selected from Te Single Nucleo- tide Polymorphism database (dbSNP). A multiplexed Procreative times 0.657 SNP MassEXTEND assay was designed by Sequenom < 2 242 298 2 217 251 MassARRAY Assay Design V3.0 Software (Agena Biosci- ≥ BMI (kg/m2, mean SD) 23.06 2.92 22.45 2.53 0.274 ence Inc., USA). And SNP genotypes was detected using ± ± ± Sequenom MassARRAY RS1000 [10, 11]. Te primers BMI body mass index Dai et al. Cancer Cell Int (2019) 19:11 Page 3 of 7 Table 2 The basic information of selected SNPs status (GG vs.TT: OR = 0.52, 95% CI = 0.29–0.91; GG vs.TT/GT: OR 0.53, 95% CI 0.32–0.90) (Table 5). Rs number Gene symbol Allele Chromosome MAF PHWE = = position Te rs3020449 was related to a larger tumor size rs2881766 ESR1 G/T Chr6:151797984 0.452 0.556 under heterozygous and dominant model (CT vs. rs9383951 ESR1 C/G Chr6:151974478 0.068 0.662 TT: OR = 1.60, 95% CI = 1.06–2.43; CT/CC vs. TT: rs9340799 ESR1 A/G Chr6:151842246 0.281 0.797 OR = 1.55, 95% CI = 1.05–2.31).