Association Between Single Nucleotide Polymorphisms And Risk Of Breast Cancer

MMP-2 (also known as 72-kDa gelatinase or type IV collagenase) is a member of the MMP family that primarily hydrolyzes gelatine and type IV collagen, the major structural component of basement membrane. This enzyme also has activity toward a spectrum of other proteins, such as growth-factor-binding proteins and growth-factor receptors. These activities of MMP-2 are believed to play a role in both cancer development and progression.Because the human MMP2 promoter contains a number of as-acting regulatory elements, the constitutive and induced expression of this proteinase is likely to be subject to regulation by transcription factors. Although somatic mutation of the MMP2 gene in cancer has not been reported so far, several single nucleotide polymorphisms in the MMP2 promoter region have been identified. Among them, a C to T transition located at nucleotide -1306 abolishes the Sp1-binding site and consequently diminishes promoter activity. Transient transfection experiments showed that reporter gene expression driven by the C allelic MMP2 promoter was significantly greater than reporter gene expression driven by the T allelic counterpart both in epithelial cells and in macrophages, indicating the functional significance of this polymorphism.Besides transcriptional regulation, the activity of MMP-2, among other MMPs, is also regulated by endogenous factors including a family of antiproteinases known as tissue inhibitor of metalloproteinases (TIMPs). Of the four members in the TIMP family, TIMP-2 is particularly interested because of its dual functions in terms of regulating MMP-2 activity and its paradoxical effects on certain cancers. A single nucleotide polymorphism(-418G→C) has also been identified in the promoter of the TIMP2 gene. Although the functional significance of this germline polymorphism is currently unknown, down-regulation of the transcriptional activity due to the variant has been suggested because the G to C substitution is located within the consensus sequence for the Sp1-binding site in...