Stimulatory effect of endogenous tissue inhibitor of metalloproteinases-1 (TIMP-1) overexpression on type IV collagen and laminin gene expression in rat mammary carcinoma cells.

We recently reported enhanced tumor growth and stimulation of vascular endothelial growth factor (VEGF) expression in rat mammary carcinoma cells transfected with a human tissue inhibitor of metalloproteinases-1 (hTIMP-1) cDNA (1). In the present study, we examined if the composition of the stroma was altered in the tumors with the highest hTIMP-1 production. Immunohistological examination revealed increased amounts of the basement membrane (BM) components, type IV collagen and laminin, in the hTIMP-1 overexpressing tumors compared to that of the control. In vitro studies also revealed upregulation of type IV collagen and laminin gene expression associated with the hTIMP-1 overexpression. Endogenous RNA levels of rat TIMP-1 and the rat matrix metalloproteinases (MMPs), MMP-2, MMP-3, and MMP-9, were not affected by the hTIMP-1 transfection, suggesting that the increase in BM deposition was not a result of decreased collagenolytic activity. This is the first report to show an association between overexpression of TIMP-1 and increased tumor BM matrix production through stimulation of type IV collagen and laminin gene expression.