The main goal of this project is to characterize the significance of tissue inhibitor of metalloproteinases-1 (TIMP-1) in mammary carcinogenesis. We have developed transgenic mouse lines to examine the effects of circulating TIMP-1, as well as endogenous mammary TIMP-1, on different stages of mammary carcinogenesis. To generate chronically elevated TIMP-1 levels in the circulation, the transgene was targeted to the liver under the control of the albumin (Alb) promoter.The mouse mammary tumor virus (MMTV) promoter was used to target the TIMP-1 transgene to mammary epithelial cells. In Alb/TIMP-1 mice, the transgenic TIMP-1 protein in the liver and in the circulation showed matrix metalloproteinase (MMP) inhibitory activity. Mammary carcinomas were induced by crossing the Alb/TIMP-1 mice and the MMTV/TIMP-1 mice to polyomavirus Middle T transgenic mice (Middle T) mice, which develop spontaneous metastatic mammary carcinomas within the first 4-5 months of life. Results from the crosses of the Alb-TIMP-1 mice or the wildtype littermates with the Middle T mice showed 30% decrease in the total mammary tumor burden in the mice with high circulating TIMP-1 levels, but no effect on the number or size of lung metastases. Results from the MMTV-TIMP-1 mice and the wildtype littermates crossed with the Middle T mice showed no effect of the high endogenous mammary TIMP-1 on the mammary tumor burden or metastases. Preliminary results from ongoing dimethylbenz[a]antracene (DMBA)-induced chemical carcinogenesis studies in the Alb-TIMP-1 mice showed that the high circulating TIMP-1 did not inhibit the development of the DMBA-induced hyperplastic and early neoplastic lesions in the mammary gland. Studies of early DMBA-induced lesions in the MMTV-TIMP-1 model are ongoing, using mammary glands in organ culture. TIMP-1 has been shown to inhibit neovascularization in angiogenesis assays but the mechansim is incompletely understood. Our data show that TIMP-1-mediated inhibition of endothelial cell migration is associated with disorganization of the cytoskeletal F-actin filaments and down-regulation of angiopoientin-1 mRNA, which is known to stimulate endothelial sprouting, the first step in the neovascularization process. Ongoing efforts focus on the functional link between TIMP-1, angiopoientin-1, and the cytoskeleton during endothelial sprouting.
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