Wnt/Β-Catenin activation promotes prostate tumor progression in a mouse model

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Abstract

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. © 2011 Macmillan Publishers Limited All rights reserved.

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Yu, X., Wang, Y., Degraff, D. J., Wills, M. L., & Matusik, R. J. (2011). Wnt/Β-Catenin activation promotes prostate tumor progression in a mouse model. Oncogene, 30(16), 1868–1879. https://doi.org/10.1038/onc.2010.560

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