Common MMP-7 polymorphisms and breast cancer susceptibility: a multistage study of association and functionality.
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.
Beeghly-Fadiel
Alicia
A
Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee 37203-1738, USA.
Long
Ji-Rong
JR
Gao
Yu-Tang
YT
Li
Chun
C
Qu
Shimian
S
Cai
Qiuyin
Q
Zheng
Ying
Y
Ruan
Zhi-Xian
ZX
Levy
Shawn E
SE
Deming
Sandra L
SL
Snoddy
Jay R
JR
Shu
Xiao-Ou
XO
Lu
Wei
W
Zheng
Wei
W
D000328:Adult; D001483:Base Sequence; D001943:Breast Neoplasms / Q000235:genetics*; D016022:Case-Control Studies; D017931:DNA Primers; D024202:Electrophoretic Mobility Shift Assay; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D020783:Matrix Metalloproteinase 7 / Q000235:genetics*; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide
D017931:DNA Primers; D020783:Matrix Metalloproteinase 7