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Transforming growth factor‐β1 enhances the invasiveness of human MDA‐MB‐231 breast cancer cells by up‐regulating urokinase activity
Author(s) -
Farina Antonietta R.,
Coppa Anna,
Tiberio Antonella,
Tacconelli Antonella,
Turco Alessandra,
Colletta Gulia,
Gulino Alberto,
Mackay Andrew R.
Publication year - 1998
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/(sici)1097-0215(19980302)75:5<721::aid-ijc10>3.0.co;2-9
Subject(s) - plasmin , matrix metalloproteinase , plasminogen activator , urokinase receptor , urokinase , transforming growth factor , cancer research , secretion , biology , cell culture , growth factor , cancer cell , chemistry , endocrinology , medicine , cancer , receptor , biochemistry , enzyme , genetics
Transforming growth factor‐beta (TGFβ1) 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, TGFβ1 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. TGFβ1 does not induce MMP‐2 expression. Our data indicate that TGFβ1 can promote the malignant behaviour of MDA‐MB‐231 cells refractory to TGFβ1‐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. Int. J. Cancer 75:721–730, 1998.© 1998 Wiley‐Liss, Inc.