TRANSFORMING GROWTH-FACTOR-BETA-1 ENHANCES THE INVASIVENESS OF HUMAN MDA-MB-231 BREAST-CANCER CELLS BY UP-REGULATING UROKINASE ACTIVITY

Transforming growth factor-beta (TGF beta 1) enhances human MDA-MB-231 breast tumour cell invasion of reconstituted basement membrane in vit ro but does not inhibit proliferation of this cell line. In contrast t o basal invasion, which is plasmin-, urokinase (uPA)-, tissue-type pla sminogen activator (t-PA)-, matrix metalloproteinase (MMP)-9- and TIMP -I-inhibitable MMP-dependent, TGF beta 1 enhanced-invasion is dependen t upon plasmin and uPA activity but does not appear to involve t-PA-, MMP9- or TIMP-1-inhibitable MMPs, as judged by inhibitor studies. Enha nced invasion is associated with increased u-PA, UPAR, PAI-1, MT-MMP-1 , MMP-9 and TIMP-1 expression; with reduced t-PA, MMP-1 and MMP-3 expr ession; and with the induction of membrane MMP-9 association. The net result of these changes includes increased secreted, but not membrane- associated, uPA levels and activity and reduced secreted levels of pla smin and APMA-activatable gelatinolytic, collagenolytic and caseinolyt ic MMP activity but no change in membrane-associated gelatinolytic act ivity, despite increased MT-MMP-1 expression and MMP-9 membrane associ ation. TGF beta 1 does not induce MMP-2 expression. Our data indicate that TGF beta 1 can promote the malignant behaviour of MDA-MB-231 cell s refractory to TGF beta 1-mediated proliferation control by enhancing their invasive capacity. We suggest that this results from the action of a uPA/plasmin-dependent mechanism resulting from stimulation of uP A expression, secretion and subsequent activity, despite elevated PAI- I inhibitor levels. (C) 1998 Wiley-Liss, Inc.