title: Pleiotropic functions of the tumor- and metastasis-suppressing matrix metalloproteinase-8 in mammary cancer in MMTV-PyMT transgenic mice.
abstract: BACKGROUND
  Matrix metalloproteinase-8 (MMP-8; neutrophil collagenase) is an important regulator of innate immunity that has oncosuppressive actions in numerous tumor types.
  
  
  METHODS
  We have intercrossed Mmp8-null mice with the Polyoma virus middle T oncogene-driven (MMTV-PyMT) mouse model of mammary cancer to explore the effects of loss of MMP-8 on the incidence and progression of mammary carcinomas.
  
  
  RESULTS
  In this aggressive mouse model of breast cancer, loss of MMP-8 accelerated tumor onset even further, such that 90% of MMTV-PyMT; Mmp8-null female mice were tumor-bearing at the time of weaning. Throughout the 14 weeks of the model, tumor burden increased in homozygous Mmp8-null mice compared to Mmp8-wild-type and -heterozygote animals. Likewise, lung metastasis dramatically increased in the MMTV-PyMT; Mmp8-null mice. Immunohistochemistry revealed that tumors in wild-type, Mmp8-heterozygotes and -null animals had similar vascular density at 8 weeks, but at 10 weeks Mmp8-wild-type tumors had a lower vascularity than their heterozygote and null counterparts. No differences in macrophage infiltration were apparent throughout primary tumor development, though at 10 weeks a drop in neutrophil infiltrates was observed in Mmp8-wild-type tumors. Using quantitative real-time RT-PCR, we tracked the expression of the entire Mmp and Timp gene families, observing a significant decrease in Mmp3 expression in Mmp8-null tumors compared to wild-type and heterozygotes throughout the time course of the model, which was confirmed at the protein level.
  
  
  CONCLUSIONS
  These findings provide novel insight into the suppressive action of MMP-8 on mammary tumorigenesis and metastasis, and indicate that the loss of MMP-8 likely has pleiotropic effects on innate immunity and angiogenesis that are reflected in changes in the protease web.
authors.forename: Julie
authors.initials: J
authors.lastname: Decock
authors.forename: Wouter
authors.initials: W
authors.lastname: Hendrickx
authors.forename: Sally
authors.initials: S
authors.lastname: Thirkettle
authors.forename: Ana
authors.initials: A
authors.lastname: Gutiérrez-Fernández
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Robinson
authors.forename: Dylan R
authors.initials: DR
authors.lastname: Edwards
mesh_terms: D000818:Animals; D000957:Antigens, Viral, Tumor / Q000235:genetics*; D002471:Cell Transformation, Neoplastic; D018450:Disease Progression; D005260:Female; D018836:Inflammation Mediators / Q000378:metabolism; D008175:Lung Neoplasms / Q000556:secondary; D008325:Mammary Neoplasms, Experimental / Q000209:etiology* / Q000473:pathology*; D008324:Mammary Tumor Virus, Mouse / Q000235:genetics*; D020784:Matrix Metalloproteinase 8 / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D005810:Multigene Family; D009362:Neoplasm Metastasis; D009389:Neovascularization, Pathologic / Q000235:genetics; D020556:Neutrophil Infiltration; D012192:Retroviridae Infections / Q000150:complications*; D014412:Tumor Virus Infections / Q000150:complications*
chemical_list: D000957:Antigens, Viral, Tumor; D018836:Inflammation Mediators; D020784:Matrix Metalloproteinase 8
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