Inhibition of tumor growth and metastasis of human breast cancer cells transfected with tissue inhibitor of metalloproteinase 4.
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.
Wang
M
M
Department of Pediatrics, Long Island Jewish Medical Center, The Long Island Campus for the Albert Einstein College of Medicine, New Hyde Park, New York 11040, USA.
Liu
Y E
YE
Greene
J
J
Sheng
S
S
Fuchs
A
A
Rosen
E M
EM
Shi
Y E
YE
D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000473:pathology*; D003001:Cloning, Molecular; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D006801:Humans; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors*; D051379:Mice; D008819:Mice, Nude; D008969:Molecular Sequence Data; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D011506:Proteins / Q000235:genetics* / Q000494:pharmacology; D019714:Tissue Inhibitor of Metalloproteinases; D014162:Transfection; D014407:Tumor Cells, Cultured; D000097792:Tissue Inhibitor of Metalloproteinase-4
D004791:Enzyme Inhibitors; D008666:Metalloendopeptidases; D011506:Proteins; D019714:Tissue Inhibitor of Metalloproteinases; D000097792:Tissue Inhibitor of Metalloproteinase-4