Tissue inhibitor of metalloproteinases-1 (TIMP-1) is widely distributed in body fluids and interstitial tissues throughout the body. In addition to its role as a regulator of matrix metalloproteinases activity, TIMP-1 is emerging as a protein with diverse functions, including inhibition of angiogenesis and growth promoting activity. We have demonstrated increased TIMP-1 expression in human breast carcinoma samples and an association between high in vitro TIMP-1 production and more malignant phenotypes among human breast carcinoma cell lines. Enhanced tumor growth of TIMP-1 transfected breast carcinoma cells in nude mice was associated with up-regulation of VEGF expression and increased vascularization. This contradicts the angiogenesis inhibitory activity which was observed when TIMP-1 was administered exogenously. Ongoing studies to define the role of TIMP-1 in angiogenesis utilize a tetracycline-regulated gene expression system in which stimulation and suppression of TIMP-1 expression on endothelial capillary formation can be examined. Future studies will also utilize transgenic mice overexpressing TIMP-1. We recently generated several homozygous TIMP-1 transgenic lines, using an albumin promoter for targeting of the liver. The transgenic line with the highest TIMP-1 expression in the liver showed microscopic abnormalities at 4 months with diffuse cytoplasmic clearing of the hepatocytes. This preliminary finding may suggest that the high TIMP-1 production is interfering with normal hepatocyte function. In addition to the importance of this transgenic model in studying the biological effects of TIMP-1 on the liver, the exceptionally high circulating TIMP-1 levels in these mice are advantageous for testing its effects on tumor growth and neovascularization of transplanted tumor cells. Cell lines from these transgenic mice are being established for these studies. The most recent generation of two homozygous MMTV/TIMP-1 transgenic lines will provide an important experimental model to help define the role of TIMP-1 in breast cancer development.
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