Common MMP-7 polymorphisms and breast cancer susceptibility: a multistage study of association and functionality.
Common MMP-7 polymorphisms and breast cancer susceptibility: a multistage study of association and functionality.
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DOI：
10.1158/0008-5472.can-08-0636
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发表时间：
2008-08-01
期刊：
影响因子：
11.2
通讯作者：
Zheng W
中科院分区：
文献类型：
--
作者：
Beeghly-Fadiel A;Long JR;Gao YT;Li C;Qu S;Cai Q;Zheng Y;Ruan ZX;Levy SE;Deming SL;Snoddy JR;Shu XO;Lu W;Zheng W
基质金属蛋白酶-7（MMP-7）是一种分泌型蛋白水解酶，对细胞外基质（ECM）和非ECM成分具有广泛的底物特异性。已知对于肿瘤侵袭和转移至关重要，越来越多的证据也暗示MMP-7在癌症发展中。利用上海乳腺癌研究（SBCS）的数据，我们进行了一项两阶段研究，以评估MMP-7单核苷酸多态性（SNPs）与乳腺癌风险的关联。此外，通过实验室测定来表征相关SNP。在第1阶段，使用Affysses基因分型系统对1，079例事件病例和1，082例社区对照中的11个SNP进行基因分型。在一组独立的1,911例病例和1,811例对照中，选择有希望的SNP进行第2阶段评估，并通过TaqMan等位基因鉴别试验进行基因分型。选择三个SNP用于第2阶段验证（rs 880197、rs 10895304和rs 12184413）;其中一个在研究的两个阶段之间具有高度一致的结果。在联合分析中，与常见C等位基因相比，rs 12184413变异T等位基因的纯合性与0.7（95%CI：0.6-0.9）的比值比相关。绝经后女性（OR：0.6，95% CI：0.4-0.8）中的这一效应略高于绝经前女性（OR：0.8，95% CI：0.6-1.1）。该SNP位于MMP-7基因的3′端，位于富含CTCF结合位点的区域。计算机模拟分析表明，该区域的调节作用，我们在体外试验证明了核蛋白结合能力的等位基因差异。我们的研究结果表明，常见的MMP-7基因多态性可能有助于乳腺癌的易感性。
Matrix metalloproteinase-7 (MMP-7) is a small secreted proteolytic enzyme with broad substrate specificity against extracellular matrix (ECM) and non-ECM components. Known to be vital for tumor invasion and metastasis, accumulating evidence also implicates MMP-7 in cancer development. Using data from the Shanghai Breast Cancer Study (SBCS), we conducted a two-stage study to evaluate the association of MMP-7 single nucleotide polymorphisms (SNPs) with breast cancer risk. Additionally, associated SNPs were characterized by laboratory assays. In Stage 1, 11 SNPs were genotyped among 1,079 incident cases and 1,082 community controls using an Affymetrix Genotyping System. Promising SNPs were selected for Stage 2 evaluation and genotyped by TaqMan allelic discrimination assays in an independent set of 1,911 cases and 1,811 controls. Three SNPs were selected for Stage 2 validation (rs880197, rs10895304, and rs12184413); one had highly consistent results between the two stages of the study. In combined analysis, homozygosity for the variant T allele for rs12184413 was associated with an odds ratio of 0.7 (95% CI: 0.6–0.9) compared to the common C allele. This effect was slightly more pronounced in postmenopausal women (OR: 0.6, 95% CI: 0.4–0.8) than in pre-menopausal women (OR: 0.8, 95% CI: 0.6–1.1). This SNP is located 3′ of the MMP-7 gene, in an area enriched with CTCF binding sites. In silico analysis suggested a regulatory role for this region, and our in vitro assays demonstrated an allelic difference in nuclear protein binding capacity. Results from our study suggest that common MMP-7 genetic polymorphisms may contribute to breast cancer susceptibility.