Tenascin-C upregulates matrix metalloproteinase-9 in breast cancer cells: direct and synergistic effects with transforming growth factor beta1

Int J Cancer. 2003 May 20;105(1):53-60. doi: 10.1002/ijc.11037.


Tenascin-C (TN-C) and matrix metalloproteinases (MMPs) are highly expressed in cancer tissues and probably promote cell migration during cancer progression. TN-C and MMPs are often co-localized in areas of active tissue remodeling in pathologic conditions, suggesting reciprocal regulation. To investigate whether TN-C regulates MMPs expression in cancer cells, we first exposed mammary cancer cells derived from TN-C-deficient mice to TN-C and examined MMPs expression. TN-C was then compared with fibronectin (FN), laminin (LN), basic fibroblast growth factor (b-FGF) and transforming growth factor-beta1 (TGF-beta1). Results of endpoint RT-PCR, quantitative real-time RT-PCR and gelatin zymography demonstrated that TN-C, strongly and dose dependently, upregulates MMP-9 expression in murine mammary cancer cells. TN-C weakly induced MMP-2, MMP-3 and MMP-13. FN and LN induced MMP-9 to lesser extents compared with TN-C. b-FGF had no effect on MMP-9 expression. TGF-beta1 induced MMP-9 expression in a dose-dependent manner, and this induction was significantly enhanced by addition of TN-C. TN-C and TGF-beta1 also upregulated MMP-9 expression in the human breast cancer cell line MDA-MB-231. Neutralization with specific anti-TGF-beta1 antibody showed decreased expression of MMP-9, indicating that TGF-beta controls the baseline MMP-9 expression by a direct autocrine mechanism. Under neutralization of TGF-beta, addition of TN-C still upregulated MMP-9. Conversely, neutralization of endogenous TN-C (in a TN-C-positive mammary cancer cell line) downregulated TGF-beta-induced MMP-9 expression. Thus, TN-C induces MMP-9 expression directly and by collaboration with TGF-beta. These findings reveal a novel role of TN-C in breast cancer progression.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Culture Media, Conditioned / pharmacology
  • Culture Media, Serum-Free / pharmacology
  • Dose-Response Relationship, Drug
  • Down-Regulation
  • Enzyme-Linked Immunosorbent Assay
  • Fibroblast Growth Factor 2 / metabolism
  • Fibronectins / metabolism
  • Laminin / metabolism
  • Mammary Neoplasms, Animal / enzymology*
  • Mammary Neoplasms, Animal / metabolism
  • Matrix Metalloproteinase 9 / metabolism*
  • Mice
  • Phosphorylation
  • RNA / metabolism
  • RNA, Messenger / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Tenascin / pharmacology*
  • Transforming Growth Factor beta / metabolism*
  • Transforming Growth Factor beta1
  • Tumor Cells, Cultured
  • Up-Regulation*


  • Culture Media, Conditioned
  • Culture Media, Serum-Free
  • Fibronectins
  • Laminin
  • RNA, Messenger
  • TGFB1 protein, human
  • Tenascin
  • Tgfb1 protein, mouse
  • Transforming Growth Factor beta
  • Transforming Growth Factor beta1
  • Fibroblast Growth Factor 2
  • RNA
  • Matrix Metalloproteinase 9