Polymorphisms in tissue inhibitors of metalloproteinases-2 and -3 and breast cancer susceptibility and survival.

Tissue inhibitors of metalloproteinases (TIMPs) are endogenous inhibitors of matrix metalloproteinases which are involved in normal cellular processes and also in cancer development and progression. The purpose of this study was to evaluate polymorphisms in the TIMP-2 and TIMP-3 genes for their associations with breast cancer susceptibility and survival. Using data from the Shanghai Breast Cancer Study, 19 SNPs for each gene were evaluated for associations with breast cancer risk among 1,062 cases and 1,069 controls; associations with disease-free and overall survival were evaluated among the cases. For TIMP-2, women with the rs7501477 TT genotype were 3 times more likely to be breast cancer cases than women with the CC genotype (OR: 2.9, 95% CI: 1.2-7.0). For TIMP-3, women with the rs9609643 AA genotype were 60% less likely to be breast cancer cases than women with the GG genotype (OR: 0.4, 95% CI: 0.2-1.0), whereas women with the rs8136803 TT genotype were 5 times more likely to be cases than women with the GG genotype (OR: 5.1, 95% CI: 1.1-24.3). Further, breast cancer cases with rs8136803 TT were almost 4 times more likely to have decreased disease-free survival (HR: 3.9, 95% CI: 1.4-10.6) and had a trend toward decreased overall survival (HR: 1.9, 95% CI: 0.6-6.1). An important study limitation was that these 3 SNPs (rs7501477, rs9609643, rs8136803) had low minor allele frequencies which resulted in small numbers of homozygote individuals. Genetic variation in the TIMP-2 and TIMP-3 genes may contribute to individual differences in breast cancer susceptibility and survival.