Wnt/β-catenin activation promotes prostate tumor progression in a mouse model.

Yu X, Wang Y, DeGraff DJ, Wills ML, Matusik RJ
Oncogene. 2011 30 (16): 1868-79

PMID: 21151173 · PMCID: PMC3081383 · DOI:10.1038/onc.2010.560

Our previous studies have found that activation of Wnt/β-catenin signaling resulted in mouse prostatic intraepithelial neoplasia (mPIN). In the large probasin promoter directed SV40-large T-antigen (LPB-Tag) expressing mouse prostate, mPIN forms with rare areas of adenocarcinoma. Combining expression of both Wnt-signaling and Tag expression in the mouse prostate, we have studied the role of Wnt/β-catenin signaling in the progression from mPIN to adenocarcinoma. Our results show that the prostates of mice expressing Tag alone or nuclear β-catenin alone developed mPIN, whereas the activation of both Tag and the Wnt/β-catenin pathway resulted in invasive prostate adenocarcinoma. Furthermore, Foxa2, a forkhead transcription factor, was induced by active Wnt/β-catenin signaling, and the expression of Foxa2 was associated with the invasive phenotype in the primary prostate cancer. In the LPB-Tag/dominant active (DA) β-catenin prostates, MMP7, a Wnt/β-catenin target gene, was upregulated. Furthermore, we also assessed AR and AR signaling pathway in these LPB-Tag/DA β-catenin mice. Although β-catenin is a well-known AR co-activator in vitro, our study provides strong in vivo evidences indicating that both AR protein and the AR pathway were downregulated in the prostate of LPB-Tag/DA β-catenin mice. Histological analysis shows that prostate sections derived from the LPB-Tag/DA β-catenin mice display neuroendocrine differentiation (NED), but NE cancer does not develop. Together, our findings indicate that Wnt/β-catenin signaling has an important role in the progression of mPIN to prostate adenocarcinoma.

MeSH Terms (10)

Adenocarcinoma Animals beta Catenin Disease Progression Male Mice Prostatic Neoplasms Receptors, Androgen Signal Transduction Wnt Proteins

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