Common MMP-7 Polymorphisms and Breast Cancer Susceptibility: A Multistage Study of Association and Functionality

^{1 1}Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine and ²Department of Biomedical Informatics, Vanderbilt University School of Medicine, Nashville, Tennessee; and ³Department of Epidemiology, Shanghai Cancer Institute and ⁴Shanghai Center for Disease Prevention and Control, Shanghai, China

^* To whom correspondence should be addressed. E-mail: wei.zheng{at}vanderbilt.edu.

	Abstract

Matrix metalloproteinase-7 (MMP-7) is a small secreted proteolytic enzyme with broad substrate specificity against 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, 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 (OR) of 0.7 [95% confidence interval (95% CI), 0.6–0.9] compared with the common C allele. This effect was slightly more pronounced in postmenopausal women (OR, 0.6; 95% CI, 0.4–0.8) than in premenopausal 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 showed 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. [Cancer Res 2008;68(15):6453–9]

Key Words: breast cancer, epidemiology, genetic susceptibility, MMP-7, polymorphisms, SNPs