The major goal for this project is to understand the mechanism for the paradoxical effects of exogenous and endogenous TIMP-1 on the growth of breast carcinomas. TIMP-1 transgene expression targeted to the liver by using an albumin promoter (Alb/TIMP-1), resulted in elevated levels of biologically active hTIMP-1 in the systemic circulation. Alb/TIMP-1 transgenic mice represent an important model to study the effects of sustained elevated levels of exogenous TIMP-1 on mammary tumor development and progression. A DMBA-induced mammary carcinogenesis study in the Alb/TIMP-1 transgenic mice showed markedly decreased tumor incidence, tumor multiplicity and tumor angiogenesis. Mammary carcinoma induction through breeding the Alb/TIMP-1 mice with Middle T antigen transgenic mice which develop spontaneously metastatic mammary carcinomas, resulted in decreased tumor growth and fewer spontaneous lung metastses. These findings show that sustained elevated TIMP-1 levels suppress the development and progression of mammary carcinomas. Studies are ongoing, using MMTV/TIMP-1 transgenic mice to examine the effects of high endogenous TIMP-1 levels on mammary tumor development. We have evidence from TIMP-1 transfected rat mammary carcinoma xenografts that high endogenous TIMP-1 promotes tumor growth through up-regulation of VEGF and the basement membrane type IV collagen and laminin expression. There is also an association between high levels of TIMP-1 and VEGF expression in human breast carcinoma cell lines. Data showing translocation of a chimeric EGFP-TIMP-1 protein into the nucleus of MCF-7 cells raises the question if TIMP-1 may affect transcription. - angiogenesis, Breast, Cancer, TIMP-1, transgenics, - Human Tissues, Fluids, Cells, etc.