title: Matrix metalloproteinase 8 (collagenase 2) induces the expression of interleukins 6 and 8 in breast cancer cells.
abstract: Matrix metalloproteinase 8 (MMP-8) is a tumor-suppressive protease that cleaves numerous substrates, including matrix proteins and chemokines. In particular, MMP-8 proteolytically activates IL-8 and, thereby, regulates neutrophil chemotaxis in vivo. We explored the effects of expression of either a WT or catalytically inactive (E198A) mutant version of MMP-8 in human breast cancer cell lines. Analysis of serum-free conditioned media from three breast cancer cell lines (MCF-7, SK-BR-3, and MDA-MB-231) expressing WT MMP-8 revealed elevated levels of IL-6 and IL-8. This increase was mirrored at the mRNA level and was dependent on MMP-8 catalytic activity. However, sustained expression of WT MMP-8 by breast cancer cells was non-permissive for long-term growth, as shown by reduced colony formation compared with cells expressing either control vector or E198A mutant MMP-8. In long-term culture of transfected MDA-MB-231 cells, expression of WT but not E198A mutant MMP-8 was lost, with IL-6 and IL-8 levels returning to base line. Rare clonal isolates of MDA-MB-231 cells expressing WT MMP-8 were generated, and these showed constitutively high levels of IL-6 and IL-8, although production of the interleukins was no longer dependent upon MMP-8 activity. These studies support a causal connection between MMP-8 activity and the IL-6/IL-8 network, with an acute response to MMP-8 involving induction of the proinflammatory mediators, which may in part serve to compensate for the deleterious effects of MMP-8 on breast cancer cell growth. This axis may be relevant to the recognized ability of MMP-8 to orchestrate the innate immune system in inflammation in vivo.
authors: School of Biological Sciences, University of East Anglia, Norwich Research Park, Norwich, NR4 7TJ, United Kingdom.
authors: Sally
authors: S
authors: Thirkettle
authors: School of Biological Sciences, University of East Anglia, Norwich Research Park, Norwich, NR4 7TJ, United Kingdom.
authors: Julie
authors: J
authors: Decock
authors: School of Biological Sciences, University of East Anglia, Norwich Research Park, Norwich, NR4 7TJ, United Kingdom.
authors: Hugh
authors: H
authors: Arnold
authors: School of Biological Sciences, University of East Anglia, Norwich Research Park, Norwich, NR4 7TJ, United Kingdom.
authors: Caroline J
authors: CJ
authors: Pennington
authors: Department of Neurological Sciences, University of Vermont College of Medicine, Burlington, Vermont 05405.
authors: Diane M
authors: DM
authors: Jaworski
authors: School of Biological Sciences, University of East Anglia, Norwich Research Park, Norwich, NR4 7TJ, United Kingdom. Electronic address: dylan.edwards@uea.ac.uk.
authors: Dylan R
authors: DR
authors: Edwards
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D015850:Interleukin-6 / Q000096:biosynthesis* / Q000235:genetics; D016209:Interleukin-8 / Q000096:biosynthesis* / Q000235:genetics; D020784:Matrix Metalloproteinase 8 / Q000096:biosynthesis* / Q000235:genetics; D009363:Neoplasm Proteins / Q000096:biosynthesis* / Q000235:genetics
chemical_list: C508606:CXCL8 protein, human; C508600:IL6 protein, human; D018836:Inflammation Mediators; D015850:Interleukin-6; D016209:Interleukin-8; D009363:Neoplasm Proteins; C488762:MMP8 protein, human; D020784:Matrix Metalloproteinase 8
keywords: Breast Cancer; Cancer Biology; Chemokines; Cytokine; Matrix Metalloproteinase (MMP); Neutrophil Collagenase
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