Daraei Abdolreza, Izadi Pantea, Khorasani Ghasemali, Nafissi Nahid, Naghizadeh Mohammad Mehdi, Younosi Nasim, Meysamie Alipasha, Mansoori Yaser, Bastami Milad, Tavakkoly-Bazzaz Javad
1 Department of Medical Genetics, School of Medicine, Tehran University of Medical Sciences , Tehran, Iran .
2 Division of Plastic and Reconstructive Surgery, Imam Khomeini Hospital Complex, Tehran University of Medical Sciences , Tehran, Iran .
Genet Test Mol Biomarkers. 2017 Aug;21(8):464-470. doi: 10.1089/gtmb.2017.0028. Epub 2017 Jul 14.
Reproductive history and obesity are among the well-recognized risk factors in the development of breast cancer, which are partially mediated by the increased exposure of breast tissues to estrogens. However, only a few studies have investigated the link between these risk factors and the pattern of methylation signatures in the breast tissue of healthy women. The role of the estrogen receptor 1 (ESR1) gene hypermethylation is reportedly important in the development of breast cancer. Thus, it is speculated that such ESR1 epigenetic changes may be influenced or shaped by obesity and reproductive history-related factors before and during breast carcinogenesis.
Breast samples were collected from 120 cancer-free women who had undergone cosmetic mammoplasty. DNA was extracted from the breast tissues and, then, the methylation levels at the promoter and exon 1 regions of the ESR1 gene CpG island were determined by using the methylated DNA immunoprecipitation-quantitative PCR assay.
The methylation level of the ESR1 promoter observed in women with a body mass index (BMI) ≥30 kg/m (p ≤ 0.001) was higher than in the subgroups of women of BMI <25 kg/m (p < 0.001) and BMI 25-29 kg/m (p < 0.001) and was also higher in postmenopausal women compared with that in premenopausal women (p = 0.046). Pearson correlation coefficient analyses also showed that the high methylation of the ESR1 promoter was correlated with increasing age (r = -0.246, p = 0.007) and BMI (r = -0.331, p ≤ 0.001). Finally, linear multivariate regression revealed a significant association between high methylation rates in the ESR1 gene promoter and increased BMI (β = -0.285, 95% CI = -0.457 to -0.113, p = 0.001). Furthermore, a higher methylation level at the ESR1 gene exon 1 was found in the BMI ≥ 30 kg/m subgroup compared to the BMI 25-29 kg/m subgroup (p = 0.023).
These findings provide new hints about the relationship between epigenetic changes within the ESR1 gene CpG island and postmenopausal obesity and aging in cancer-free women. In terms of lifestyle intervention opportunities, this study also highlights the significance and feasibility of such interventions for BMI as a modifiable risk factor.
生殖史和肥胖是乳腺癌发生过程中公认的风险因素，部分原因是乳腺组织暴露于雌激素的水平增加。然而，只有少数研究调查了这些风险因素与健康女性乳腺组织甲基化特征模式之间的联系。据报道，雌激素受体1（ESR1）基因高甲基化在乳腺癌发生中起重要作用。因此，推测这种ESR1表观遗传变化可能在乳腺癌发生之前及期间受到肥胖和生殖史相关因素的影响或塑造。
从120名接受了美容性乳房整形手术的无癌女性中采集乳房样本。从乳房组织中提取DNA，然后使用甲基化DNA免疫沉淀-定量PCR测定法确定ESR1基因CpG岛启动子和外显子1区域的甲基化水平。
体重指数（BMI）≥30 kg/m²的女性中观察到的ESR1启动子甲基化水平高于BMI<25 kg/m²（p≤0.001）和BMI 25-29 kg/m²（p<0.001）的女性亚组，并且绝经后女性的甲基化水平也高于绝经前女性（p=0.046）。Pearson相关系数分析还表明，ESR1启动子的高甲基化与年龄增长（r=-0.246，p=0.007）和BMI（r=-0.331，p≤0.001）相关。最后，线性多变量回归显示ESR1基因启动子的高甲基化率与BMI增加之间存在显著关联（β=-0.2,85，95%CI=-0.457至-0.113，p=0.001）。此外，与BMI 25-29 kg/m²亚组相比，BMI≥30 kg/m²亚组中ESR1基因外显子1的甲基化水平更高（p=0.023）。
这些发现为ESR1基因CpG岛内表观遗传变化与无癌女性绝经后肥胖和衰老之间的关系提供了新线索。就生活方式干预机会而言，本研究还强调了将BMI作为可改变风险因素进行此类干预的重要性和可行性。
