Tissue Inhibitor of Matrix Metalloproteinase-1 (TIMP-1) is commonly believed to function as an inhibitor of the malignant phenotype by blocking the degradative activity of Matrix Metalloproteinases (MMPs). However, recent clinical observations have demonstrated that TIMP-1 is overexpressed in a majority of tumors and is often associated with a poor prognosis, suggesting that TIMPs may possess a pro-malignant function. TIMP-1 is able to induce Epithelial to Mesenchymal Transition (EMT) in MCF10A breast epithelial cells, an initial step leading to metastasis. The goals of these studies are to determine the mechanism by which TIMP-1 is able to induce EMT and provide important information about the alternative pro-malignant activity of TIMP-1. An inducible vector system will be used to overexpress TIMP-1 to assess its potential role in regulating TGF-Beta signaling, an important mediator of EMT. In addition, studies will be performed to assess the potential role and necessity of PAI-1 in TIMP-1 mediated EMT through siRNA techniques. Finally, these in vitro observations will be related to clinical data to assess potential correlations between TIMP-1, E-cadherin, Beta-catenin, PAI-1 and prognosis and mortality of breast carcinoma patients.
| Bigelow, Rebecca L H; Williams, Briana J; Carroll, Jennifer L et al. (2009) TIMP-1 overexpression promotes tumorigenesis of MDA-MB-231 breast cancer cells and alters expression of a subset of cancer promoting genes in vivo distinct from those observed in vitro. Breast Cancer Res Treat 117:31-44 |
