Institute for Cell and Molecular Biosciences, Newcastle University, Newcastle-upon-Tyne, United Kingdom ; Human Nutrition Research Centre, Newcastle University, Newcastle-upon-Tyne, United Kingdom.
PLoS One. 2013 Sep 10;8(9):e73316. doi: 10.1371/journal.pone.0073316. eCollection 2013.
Breast cancer (BC) is one of the most common cancers in women. Evidence suggests that genetic variation in antioxidant enzymes could influence BC risk, but to date the relationship between selenoproteins and BC risk remains unclear. In this report, a study population including 975 Danish cases and 975 controls matched for age and hormone replacement therapy (HRT) use was genotyped for five functional single nucleotide polymorphisms (SNPs) in SEPP1, GPX1, GPX4 and the antioxidant enzyme SOD2 genes. The influence of genetic polymorphisms on breast cancer risk was assessed using conditional logistic regression. Additionally pre-diagnosis erythrocyte GPx (eGPx) activity was measured in a sub-group of the population. A 60% reduction in risk of developing overall BC and ductal BC was observed in women who were homozygous Thr carriers for SEPP1 rs3877899. Additionally, Leu carriers for GPX1 Pro198Leu polymorphism (rs1050450) were at ∼2 fold increased risk of developing a non-ductal BC. Pre-diagnosis eGPx activity was found to depend on genotype for rs713041 (GPX4), rs3877899 (SEPP1), and rs1050450 (GPX1) and on HRT use. Moreover, depending on genotype and HRT use, eGPx activity was significantly lower in women who developed BC later in life compared with controls. Furthermore, GPx1 protein levels increased in human breast adenocarcinoma MCF7 cells exposed to β-estradiol and sodium selenite.In conclusion, our data provide evidence that SNPs in SEPP1 and GPX1 modulate risk of BC and that eGPx activity is modified by SNPs in SEPP1, GPX4 and GPX1 and by estrogens. Our data thus suggest a role of selenoproteins in BC development.
乳腺癌（BC）是女性最常见的癌症之一。有证据表明，抗氧化酶的遗传变异可能影响 BC 的风险，但迄今为止，硒蛋白与 BC 风险之间的关系仍不清楚。在本报告中，研究人群包括 975 例丹麦病例和 975 例年龄和激素替代疗法（HRT）相匹配的对照，对 SEPP1、GPX1、GPX4 和抗氧化酶 SOD2 基因中的 5 个功能性单核苷酸多态性（SNP）进行了基因分型。使用条件逻辑回归评估遗传多态性对乳腺癌风险的影响。此外，在人群的亚组中测量了预诊断红细胞 GPx（eGPx）活性。SEPP1 rs3877899 纯合 Thr 携带者的女性患总体 BC 和导管性 BC 的风险降低了 60%。此外，GPX1 Pro198Leu 多态性（rs1050450）的 Leu 携带者患非导管性 BC 的风险增加了约 2 倍。发现 rs713041（GPX4）、rs3877899（SEPP1）和 rs1050450（GPX1）的基因型以及 HRT 的使用依赖于 rs713041（GPX4）、rs3877899（SEPP1）和 rs1050450（GPX1）的基因型，eGPx 活性与 HRT 的使用有关。此外，根据基因型和 HRT 的使用情况，与对照组相比，生命后期发生 BC 的女性的 eGPx 活性显著降低。此外，暴露于β-雌二醇和亚硒酸钠的人乳腺癌 MCF7 细胞中 GPx1 蛋白水平升高。总之，我们的数据提供了证据表明 SEPP1 和 GPX1 中的 SNP 调节 BC 的风险，并且 eGPx 活性受 SEPP1、GPX4 和 GPX1 中的 SNP 以及雌激素的修饰。因此，我们的数据表明硒蛋白在 BC 的发生中起作用。
