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 me talloprotease-1 (hTIMP-1) is able to exert a growth factor-like effect on t wo clonal cell lines (BC-3A and BC-61), isolated from a parental line of hu man breast carcinoma cells (8701-BC), and endowed with different growth and invasive behaviour 'in vitro' and in nude mouse. The data obtained indicat e 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 transmembr ane protein of about 80 kDa able to bind hTIMP-1 'in vitro' and 'in vivo' w ith high affinity (K-d of 0.07 +/- 0.004 nM), and that treatment of BC-61 c ells with a proliferation-promoting concentration of hTIMP-1 is able to sti mulate tyrosine-targeted phosphorylation. The cumulative results obtained s trongly support the hypothesis that hTIMP-1, 'classically' regarded as a co llagenase inhibitor, may be a crucial element of the extracellular signalli ng network during breast cancer development by controlling cell growth phen otype in autocrine and paracrine manner, and that intratumoural heterogenei ty for the biological response to TIMP-1 may exist within the composite cel l population of the primary tumour site.