title: Tenascin-C upregulates matrix metalloproteinase-9 in breast cancer cells: direct and synergistic effects with transforming growth factor beta1.
abstract: 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.
authors.affiliation: Department of Pathology, Mie University School of Medicine, Tsu, Mie, Japan.
authors.forename: Ilunga
authors.initials: I
authors.lastname: Kalembeyi
authors.forename: Hiroyasu
authors.initials: H
authors.lastname: Inada
authors.forename: Rika
authors.initials: R
authors.lastname: Nishiura
authors.forename: Kyoko
authors.initials: K
authors.lastname: Imanaka-Yoshida
authors.forename: Teruyo
authors.initials: T
authors.lastname: Sakakura
authors.forename: Toshimichi
authors.initials: T
authors.lastname: Yoshida
mesh_terms: D000818:Animals; D017077:Culture Media, Conditioned / Q000494:pharmacology; D016895:Culture Media, Serum-Free / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D004797:Enzyme-Linked Immunosorbent Assay; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism; D005353:Fibronectins / Q000378:metabolism; D007797:Laminin / Q000378:metabolism; D015674:Mammary Neoplasms, Animal / Q000201:enzymology* / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D051379:Mice; D010766:Phosphorylation; D012313:RNA / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019063:Tenascin / Q000494:pharmacology*; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D053773:Transforming Growth Factor beta1; D014407:Tumor Cells, Cultured; D015854:Up-Regulation
chemical_list: D017077:Culture Media, Conditioned; D016895:Culture Media, Serum-Free; D005353:Fibronectins; D007797:Laminin; D012333:RNA, Messenger; C508960:TGFB1 protein, human; D019063:Tenascin; C508961:Tgfb1 protein, mouse; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D016222:Fibroblast Growth Factor 2; D012313:RNA; D020780:Matrix Metalloproteinase 9