Novel Tissue Inhibitor of Metalloproteinase, TIMP-4, in Human Breast Cancer Growth and Metastasis
Annual rept. 1 Oct 1998-30 Sep 1999
LONG ISLAND JEWISH-HILLSIDE MEDICAL CENTER NEW HYDE PARK NY
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TIMP-4, a novel human tissue inhibitor of metalloproteinase, was identified and characterized. Enzymatic kinetic studies revealed IC50 values of 19, 3, 45, 8, and 83 nM for MMP-1, MMP-2, MMP-3, MMP-7, and MMP-9, respectively. TIMP-4 has a strong inhibitory effect on the invasion of human breast cancer cells across reconstituted basement membranes. To determine if TIMP-4 can modulate the in vivo growth of human breast cancers, we administrated TIMP-4 both locally by transfection of the gene into breast cancer cells and systemically by a gene therapy approach with intramuscular injection of TIMP-4 expression plasmid. 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.
- Medicine and Medical Research