Inhibition of tumor growth and metastasis of human breast cancer cells transfected with tissue inhibitor of metalloproteinase 4

Oncogene. 1997 Jun 12;14(23):2767-74. doi: 10.1038/sj.onc.1201245.

Abstract

We recently identified, cloned, and characterized a novel human tissue inhibitor of metalloproteinases-4, TIMP-4 (Greene et al., 1996). To determine if TIMP-4 can modulate the in vivo growth of human breast cancers, we transfected a full-length TIMP-4 cDNA into MDA-MB-435 human breast cancer cells and studied the orthotopic growth of TIMP-4-transfected (TIMP4-435) versus control (neo-435) clones in the mammary fat pad of athymic nude mice. TIMP4-435 clones expressed TIMP-4 mRNA and produced anti-metalloproteinase (MMP) activity, while neo-435 clones did not express TIMP-4 mRNA or produce detectable anti-MMP activity. Overexpression of TIMP-4 inhibited the invasion potential of the cells in the in vitro invasion assay. When injected orthotopically into nude mice, TIMP-4 transfectants were significantly inhibited in tumor growth by 4-10-fold in primary tumor volumes; and in an axillary lymph node and lung metastasis as compared with controls. These results suggest the therapeutic potential of TIMP-4 in treating cancer malignant progression.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Breast Neoplasms / genetics
  • Breast Neoplasms / pathology*
  • Cloning, Molecular
  • Enzyme Inhibitors / pharmacology*
  • Female
  • Humans
  • Metalloendopeptidases / antagonists & inhibitors*
  • Mice
  • Mice, Nude
  • Molecular Sequence Data
  • Neoplasm Invasiveness
  • Neoplasm Metastasis
  • Proteins / genetics*
  • Proteins / pharmacology
  • Tissue Inhibitor of Metalloproteinase-4
  • Tissue Inhibitor of Metalloproteinases*
  • Transfection
  • Tumor Cells, Cultured

Substances

  • Enzyme Inhibitors
  • Proteins
  • Tissue Inhibitor of Metalloproteinases
  • Metalloendopeptidases

Associated data

  • GENBANK/U76456