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

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 while the activation of both Tag and the Wnt/β-Catenin pathway resulted in invasive prostate adenocarcinoma. Also, 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 (D.A.) β-Catenin prostates, MMP7, a Wnt/β-Catenin target gene, was up-regulated. Furthermore, we also assessed AR and AR signaling pathway in these LPB-Tag/D.A. 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 down-regulated in the prostate of LPB-Tag/D.A. β-Catenin mice. Histological analysis shows that prostate sections derived from the LPB-Tag/D.A. β-Catenin mice display neuroendocrine differentiation (NED) but NE cancer does not develop. Together, our findings indicate that Wnt/β-Catenin signaling plays an important role in the progression of mPIN to prostate adenocarcinoma.

Prostate Cancer Progression to Androgen Independent Disease: The Role of the Wnt/β-Catenin Pathway

“…Last but not least, the activation of Wnt signals in LNCaP cells resulted in expression of neuroendocrine (NE) markers, NSE and Chr.A, signifying Wnt/ -catenin in the development of neuroendocrine differentiation (NED) . This is confirmed by in vivo studies, which have revealed areas of NED in mouse prostates expressing dominant active -catenin and T-antigen (Yu et al, 2011). While -catenin is the point of interest in terms of Wnt signaling and cancer progression, dysfunction of other components within the Wnt pathway can be equally detrimental.…”

“…This suggests that aberrant expression of -catenin is likely responsible for late CaP tumorigenesis. For instance, in mouse prostate expressing SV40-large T-antigen (LPB-Tag), a powerful deactivator of p53 and retinoblastoma (Rb) family of tumor suppressors, the integration of a non-degradable -catenin gene provided additional morphological changes by transforming areas of benign HGPIN into invasive adenocarcinoma, along with an elevated expression of matrix metalloproteinase (MMP)-7 (Yu et al, 2011). MMPs are proteases known to facilitate membrane invasion by catalyzing the breakdown of the extracellular matrix (Bonfil et al, 2007).…”

A basal stem cell signature identifies aggressive prostate cancer phenotypes

“…Murine models overexpressing key components of developmental signaling pathways alone or with other genetic alterations can drive a phenotype reminiscent of late-stage prostate cancer (19)(20)(21)(22). Although these studies provide evidence of a relationship between stem-like qualities and an aggressive phenotype, no studies to our knowledge have shown a molecular relationship between aggressive prostate cancer and uncultured stem-like cells from the human prostate.…”

Increased androgen receptor transcription: a cause of castration-resistant prostate cancer and a possible therapeutic target

“…Synchronous activation of K-ras and b-catenin significantly reduced survival in a mouse model, associated with accelerated tumorigenesis and the development of invasive carcinoma (Pearson et al 2009). In addition, Wnt/b-catenin activation promoted PCa progression in another mouse model (Yu et al 2010), and the small molecule inhibitor of Wnt/b-catenin signaling, PKF118-310, has recently been shown to inhibit the proliferation of PCa cells (Lu et al 2009). …”