Mammary carcinoma cells over-expressing tissue inhibitor of metalloproteinases-1 show enhanced vascular endothelial growth factor expression

Int J Cancer. 1998 Jan 5;75(1):81-7. doi: 10.1002/(sici)1097-0215(19980105)75:1<81::aid-ijc13>;2-g.


The tissue inhibitor of metalloproteinases-1 (TIMP-1) has at least 2 independent functions, i.e., regulation of matrix metalloproteinases and 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 did 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 larger than the control. TIMP-1 over-expression was associated with increased vascular endothelial growth factor (VEGF) expression, vascularization and proliferative activity of the s.c. tumors. Similar to the rat breast carcinoma cells, transfection of TIMP-1 cDNA into the human breast carcinoma cell line MCF-7 resulted in up-regulation of VEGF, with a linear relationship between TIMP-1 and VEGF production in 9 cell clones examined. There was, however, no change in VEGF expression when the 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 TIMP-1-mediated, growth-stimulating effect.

MeSH terms

  • Animals
  • Cell Division
  • Endothelial Growth Factors / metabolism*
  • Female
  • Genetic Vectors / genetics
  • Humans
  • Lymphokines / metabolism*
  • Mammary Neoplasms, Experimental / blood supply
  • Mammary Neoplasms, Experimental / genetics
  • Mammary Neoplasms, Experimental / metabolism*
  • Mammary Neoplasms, Experimental / pathology*
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / metabolism*
  • Neovascularization, Pathologic / pathology
  • Rats
  • Tissue Inhibitor of Metalloproteinase-1 / genetics
  • Tissue Inhibitor of Metalloproteinase-1 / metabolism*
  • Transfection
  • Tumor Cells, Cultured
  • Vascular Endothelial Growth Factor A
  • Vascular Endothelial Growth Factors


  • Endothelial Growth Factors
  • Lymphokines
  • Neoplasm Proteins
  • Tissue Inhibitor of Metalloproteinase-1
  • Vascular Endothelial Growth Factor A
  • Vascular Endothelial Growth Factors