MAMMARY-CARCINOMA CELLS OVER-EXPRESSING TISSUE INHIBITOR OF METALLOPROTEINASES-1 SHOW ENHANCED VASCULAR ENDOTHELIAL GROWTH-FACTOR EXPRESSION

The tissue inhibitor of metalloproteinases-1 (TIMP-1) has at least 2 i ndependent functions, i.e., regulation of matrix metalloproteinases an d erythroid-potentiating activity. We investigated the effects of TIMP -1 over-expression on tumor growth, using cloned lines derived from a TIMP-1-transfected rat breast carcinoma cell line. The in vitro growth rate of the TIMP-1-transfected clones was indistinguishable from that of the control. In contrast, the highest TIMP-1-producing clone (159. 0 ng/ml), designated as T-H, formed 4.6-fold larger s.c. tumors than d id the control after 14 days. Tumors derived from an intermediate TIMP -1-producing clone (45.4 ng/ml), designated as T-M, were 1.9-fold larg er than the control. TIMP-1 over-expression was associated with increa sed vascular endothelial growth factor OIEGF) expression, vascularizat ion and proliferative activity of the s.c. tumors. Similar to the rat breast carcinoma cells, transfection of TIMP-1 cDNA into the human bre ast carcinoma cell line MCF-7 resulted in up-regulation of VEGF, with a linear relationship between TIMP-1 and VEGF production in 9 cell clo nes examined. There was, however, no change in VEGF expression when th e rat and human breast carcinoma cell lines were exposed to exogenous recombinant TIMP-1. Our findings suggest that over-expression of TIMP- 1 confers growth advantage on breast carcinoma cells in vivo and that up-regulation of VEGF expression may play an important role in this TI MP-1 mediated, growth-stimulating effect. (C) 1998 Wiley-Liss, Inc.