Concurrent Hepsin overexpression and adenomatous polyposis coli deletion causes invasive prostate carcinoma in mice.
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.
['Valkenburg|Kenneth C|KC|', 'Hostetter|Galen|G|', 'Williams|Bart O|BO|']
D011125:Adenomatous Polyposis Coli D000818:Animals D014408:Biomarkers, Tumor D017353:Gene Deletion D015972:Gene Expression Regulation, Neoplastic D008297:Male D008565:Membrane Proteins D051379:Mice D018345:Mice, Knockout D008822:Mice, Transgenic D009361:Neoplasm Invasiveness D011471:Prostatic Neoplasms D012697:Serine Endopeptidases D060449:Wnt Signaling Pathway
hepsin prostate cancer Apc mouse model Wnt signaling