Tissue Inhibitor of Metalloprotease (TIMP)-1 and Proliferative Behaviour of Clonal Breast Cancer Cells

In the present paper, we have examined whether human tissue inhibitor of metalloprotease-1 (hTIMP-1) is able to exert a growth factor-like effect on two clonal cell lines (BC-3A and BC-61), isolated from a parental line of human breast carcinoma cells (8701-BC), and endowed with different growth and invasive behaviour 'in vitro' and in nude mouse. The data obtained indicate that only the more tumorigenic clonal cell line (BC-61) is responsive to hTIMP-1 treatment by increasing its proliferative rate in a dose-dependent manner. It was also found that BC-61 cells selectively express a transmembrane protein of about 80 kDa able to bind hTIMP-1 'in vitro' and 'in vivo' with high affinity (Kd of 0.07 +/- 0.004 nM), and that treatment of BC-61 cells with a proliferation-promoting concentration of hTIMP-1 is able to stimulate tyrosine-targeted phosphorylation. The cumulative results obtained strongly support the hypothesis that hTIMP-1, 'classically' regarded as a collagenase inhibitor, may be a crucial element of the extracellular signalling network during breast cancer development by controlling cell growth phenotype in autocrine and paracrine manner, and that intratumoural heterogeneity for the biological response to TIMP-1 may exist within the composite cell population of the primary tumour site.