title: Concurrent Hepsin overexpression and adenomatous polyposis coli deletion causes invasive prostate carcinoma in mice.
abstract: BACKGROUND
  A clinical need to better categorize patients with prostate cancer exists. The Wnt/β-catenin signaling pathway plays important roles in human prostate cancer progression. Deletion of the endogenous Wnt antagonist adenomatous polyposis coli (Apc) in mice causes high grade prostate intraepithelial neoplasia, widely thought to be the precursor to prostate cancer. However, no metastasis occurrs in this model. New mouse models are needed to determine molecular causes of tumorigenesis, progression, and metastasis.
  
  
  METHODS
  To determine whether the overexpression of the prostate oncogene Hepsin could cause prostate cancer progression, we crossed a prostate-specific Hepsin overexpression model to a prostate-specific Apc-deletion model and classified the observed phenotype.
  
  
  RESULTS
  When Apc was deleted and Hepsin overexpressed concurrently, mice displayed invasive carcinoma, with loss of membrane characteristics and increase of fibrosis. These tumors had both luminal and basaloid characteristics. Though no metastasis was observed, there was evidence of adenomas and lung necrosis, inflammation, and chronic hemorrhage.
  
  
  CONCLUSIONS
  This work indicates that the Wnt/β-catenin pathway and the Hepsin pathway act in concert to promote prostate cancer progression. Both of these pathways are up-regulated in human prostate cancer and could represent chemotherapeutic targets.
authors.affiliation: Center for Cancer and Cell Biology, Van Andel Research Institute, Grand Rapids, Michigan.
authors.forename: Kenneth C
authors.initials: KC
authors.lastname: Valkenburg
authors.affiliation: Laboratory of Analytical Pathology, Van Andel Research Institute, Grand Rapids, Michigan.
authors.forename: Galen
authors.initials: G
authors.lastname: Hostetter
authors.affiliation: Center for Cancer and Cell Biology, Van Andel Research Institute, Grand Rapids, Michigan.
authors.forename: Bart O
authors.initials: BO
authors.lastname: Williams
mesh_terms: D011125:Adenomatous Polyposis Coli / Q000235:genetics; D000818:Animals; D014408:Biomarkers, Tumor / Q000096:biosynthesis*; D017353:Gene Deletion; D015972:Gene Expression Regulation, Neoplastic; D008297:Male; D008565:Membrane Proteins / Q000096:biosynthesis; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009361:Neoplasm Invasiveness / Q000235:genetics / Q000473:pathology; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D012697:Serine Endopeptidases / Q000096:biosynthesis*; D060449:Wnt Signaling Pathway / Q000502:physiology
chemical_list: D014408:Biomarkers, Tumor; D008565:Membrane Proteins; D012697:Serine Endopeptidases; C055645:hepsin
keywords: Apc; Wnt signaling; hepsin; mouse model; prostate cancer