Transforming growth factor-beta1 enhances the invasiveness of human MDA-MB-231 breast cancer cells by up-regulating urokinase activity.
Transforming growth factor-beta (TGFbeta1) enhances human MDA-MB-231 breast tumour cell invasion of reconstituted basement membrane in vitro but does not inhibit proliferation of this cell line. In contrast to basal invasion, which is plasmin-, urokinase (uPA)-, tissue-type plasminogen activator (t-PA)-, matrix metalloproteinase (MMP)-9- and TIMP-1-inhibitable MMP-dependent, TGFbeta1 enhanced-invasion is dependent upon plasmin and uPA activity but does not appear to involve t-PA-, MMP9- or TIMP-1-inhibitable MMPs, as judged by inhibitor studies. Enhanced 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 expression; 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 plasmin and APMA-activatable gelatinolytic, collagenolytic and caseinolytic MMP activity but no change in membrane-associated gelatinolytic activity, despite increased MT-MMP-1 expression and MMP-9 membrane association. TGFbeta1 does not induce MMP-2 expression. Our data indicate that TGFbeta1 can promote the malignant behaviour of MDA-MB-231 cells refractory to TGFbeta1-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 uPA expression, secretion and subsequent activity, despite elevated PAI-1 inhibitor levels.
Farina
A R
AR
Section of Molecular Pathology, Department of Experimental Medicine, University of L'Aquila, Italy. farina@aquila.infn.it
Coppa
A
A
Tiberio
A
A
Tacconelli
A
A
Turco
A
A
Colletta
G
G
Gulino
A
A
Mackay
A R
AR
D001943:Breast Neoplasms / Q000201:enzymology / Q000473:pathology*; D002364:Caseins / Q000378:metabolism; D003094:Collagen / Q000378:metabolism; D004338:Drug Combinations; D006801:Humans; D007797:Laminin; D019278:Matrix Metalloproteinase 3 / Q000378:metabolism; D009361:Neoplasm Invasiveness; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism; D011509:Proteoglycans; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D015854:Up-Regulation; D014568:Urokinase-Type Plasminogen Activator / Q000378:metabolism*
D002364:Caseins; D004338:Drug Combinations; D007797:Laminin; D017395:Plasminogen Activator Inhibitor 1; D011509:Proteoglycans; D018125:Receptors, Transforming Growth Factor beta; D019715:Tissue Inhibitor of Metalloproteinase-1; D016212:Transforming Growth Factor beta; C059485:matrigel; D003094:Collagen; D014568:Urokinase-Type Plasminogen Activator; D019278:Matrix Metalloproteinase 3