Present efforts are on methylbenzanthracene (DMBA)-induced mammary carcinogenesis in trangenic mice overexpressing tissue inhibitor of metalloproteinases-1 (TIMP-1)in mammary epithelial cells under the control of the mouse mammary tumor virus (MMTV). Induction of mammary carcinomas in double transgenic MMTV-Middle T/ MMTV-TIMP-1 mice showed no inhibition of tumor growth, compared with the wildtype littermates. High circulating TIMP-1 levels were observed in these mice due to the release of large amount of transgenic TIMP-1 protein from the mammary tumors. Lower levels of circulating TIMP-1 in our Albumin-TIMP-1 transgenic mice were associated with 30% inhibition of Middle T-induced mammary tumor burden. Analysis of mammary carcinomas in the MMTV/TIMP-1 mice showed increased proliferative activity of the tumor cells. These findings support our hypothesis that high endogenous TIMP-1 in mammary epithelial cells leads to increased malignant behavior, which is not overcome by the high circulating TIMP-1 levels. To further characterize the effects of high mammary TIMP-1 expression on tumor development, we use DMBA to induce mammary carcinomas, which are less aggressive than the metastatic Middle T-induced carcinomas. Preliminary data show accelerated mammary tumor development in the DMBA treated MMTV-TIMP-1 mice. The second part of the TIMP-1 project focuses on its function as an inhibitor of angiogenesis. Previos findings showed that TIMP-1 inhibits endothelial cell migration and causes F-actin cytoskeletal changes. We are following up on cDNA microarray data, which showed that TIMP-1 down-regulates angiopoientin-1, a stimulator of endothelial sprouting that acts at focal adhesion points. The findings show that TIMP-1 causes disorganization of focal adhesion points and inhibits phosphorylation of focal adhesion kinase (FAK). Collectively, the data suggest that TIMP-1 acts by suppressing angiopoietin-1 to inhibit endothelial cell migration. Halting endothelial migration may be the main mechanism by which TIMP-1 inhibits angiogenesis in experimental models.
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