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

• Published in: Oncogene Vol. 14; no. 23; pp. 2767 - 2774
• Main Authors: WANG, M, LIU, Y. E, GREENE, J, SHENG, S, FUCHS, A, ROSEN, E. M, SHI, Y. E
• Format: Journal Article
• Language: English
• Published: Basingstoke Nature Publishing 12.06.1997; Nature Publishing Group
• Subjects: Animals; Biological and medical sciences; Breast cancer; Breast Neoplasms - genetics; Breast Neoplasms - pathology; Cell physiology; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes; Cloning, Molecular; Enzyme Inhibitors - pharmacology; Female; Fundamental and applied biological sciences. Psychology; Humans; Lymph nodes; Metalloendopeptidases - antagonists & inhibitors; Metalloproteinase; Metastases; Metastasis; Mice; Mice, Nude; Molecular and cellular biology; Molecular Sequence Data; mRNA; Neoplasm Invasiveness; Neoplasm Metastasis; Proteins - genetics; Proteins - pharmacology; Tissue Inhibitor of Metalloproteinase-4; Tissue Inhibitor of Metalloproteinases; Transfection; Tumor Cells, Cultured; Tumors; Human; Enzyme; Rodentia; Enzyme inhibitor; Metalloendopeptidases; Metastasis; Mammary gland diseases; Peptidases; Vertebrata; Regulation(control); Mammalia; Cell line; Mouse; Tumor progression; Hydrolases; Tumor; Mammary gland; Inhibition
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/sj.onc.1201245

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.