Transforming growth factor-beta1 enhances the invasiveness of human MDA-MB-231 breast cancer cells by up-regulating urokinase activity

Int J Cancer. 1998 Mar 2;75(5):721-30. doi: 10.1002/(sici)1097-0215(19980302)75:5<721::aid-ijc10>3.0.co;2-9.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Breast Neoplasms / enzymology
  • Breast Neoplasms / pathology*
  • Caseins / metabolism
  • Collagen / metabolism
  • Drug Combinations
  • Humans
  • Laminin
  • Matrix Metalloproteinase 3 / metabolism
  • Neoplasm Invasiveness*
  • Plasminogen Activator Inhibitor 1 / metabolism
  • Proteoglycans
  • Receptors, Transforming Growth Factor beta / metabolism
  • Tissue Inhibitor of Metalloproteinase-1 / metabolism
  • Transforming Growth Factor beta / pharmacology*
  • Up-Regulation
  • Urokinase-Type Plasminogen Activator / metabolism*

Substances

  • Caseins
  • Drug Combinations
  • Laminin
  • Plasminogen Activator Inhibitor 1
  • Proteoglycans
  • Receptors, Transforming Growth Factor beta
  • Tissue Inhibitor of Metalloproteinase-1
  • Transforming Growth Factor beta
  • matrigel
  • Collagen
  • Urokinase-Type Plasminogen Activator
  • Matrix Metalloproteinase 3