Inhibition of human MDA-MB-231 breast cancer cell invasion by matrix metalloproteinase 3 involves degradation of plasminogen

Eur J Biochem. 2002 Sep;269(18):4476-83. doi: 10.1046/j.1432-1033.2002.03142.x.

Abstract

Matrix metalloproteinase (MMP)-3 inhibited human MDA-MB-231 breast cancer cell invasion through reconstituted basement membrane in vitro. Inhibition of invasion was dependent upon plasminogen and MMP-3 activation, was impaired by the peptide MMP-3 inhibitor Ac-Arg-Cys-Gly-Val-Pro-Asp-NH2 and was associated with: rapid MMP-3-mediated plasminogen degradation to microplasminogen and angiostatin-like fragments; the removal of single-chain urokinase plasminogen activator from MDA-MB-231 cell membranes; impaired membrane plasminogen association; reduced rate of tissue plasminogen activator (t-PA) and membrane-mediated plasminogen activation; and reduced laminin-degrading capacity. Purified human plasminogen lysine binding site-1 (kringles 1-3) exhibited a similar capacity to inhibit MDA-MB-231 invasion, impair t-PA and cell membrane-mediated plasminogen activation and impair laminin degradation by plasmin. Our data provide evidence that MMP-3 can inhibit breast tumour cell invasion in vitro by a mechanism involving plasminogen degradation to fragments that limit plasminogen activation and the degradation of laminin. This supports the hypothesis that MMP-3, under certain conditions, may protect against tumour invasion, which would help to explain why MMP-3 expression, associated with benign and early stage breast tumours, is frequently lost in advanced stage, aggressive, breast disease.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiostatins
  • Breast Neoplasms / drug therapy
  • Breast Neoplasms / enzymology*
  • Cell Membrane / metabolism
  • Female
  • Humans
  • Laminin / metabolism
  • Matrix Metalloproteinase 3 / metabolism*
  • Matrix Metalloproteinase 3 / pharmacology
  • Neoplasm Invasiveness / physiopathology
  • Peptide Fragments / metabolism
  • Plasminogen / metabolism*
  • Tumor Cells, Cultured

Substances

  • Laminin
  • Peptide Fragments
  • Angiostatins
  • Plasminogen
  • Matrix Metalloproteinase 3