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 d etermine if TIMP-4 can modulate the in vivo growth of human breast can cers, Ne transfected a full-length TIMP-4 cDNA into MDA-MB-435 human b reast cancer cells and studied the orthotopic growth of TIMP-4-transfe cted (TIMP4-435) versus control (neo-435) clones in the mammary fat pa d of athymic nude mice, TIMP4-435 clones expressed TIMP-4 mRNA and pro duced anti-metalloproteinase (MMP) activity, while neo-435 clones did not express TIMP-4 mRNA or produce detectable anti-MMP activity. Overe xpression of TIMP-4 inhibited the invasion potential of the cells in t he in vitro invasion assay, When injected orthotopically into nude mic e, TIMP-4 transfectants were significantly inhibited in tumor growth b y 4-10-fold in primary tumor volumes; and in an axillary lymph node an d lung metastasis as compared with controls. These results suggest the therapeutic potential of TIMP-4 in treating cancer malignant progress ion.