In vitro evidence for complex modes of nuclear β-catenin signaling during prostate growth and tumorigenesis - Oncogene

Abstract

Understanding the molecular etiology of prostate cancer (CaP) progression is paramount for broadening current diagnostic and therapeutic modalities. Current interest in the role of wnt pathway signaling in prostate tumorigenesis was generated with the finding of β-catenin mutation and corresponding nuclear localization in primary lesions. The recent finding of β-catenin-induced enhancement of androgen receptor (AR) function potentially ties β-catenin to key regulatory steps of prostate cell growth, differentiation, and transformation. By immunohistological analysis of metastatic tumors, we detected nuclear β-catenin in 20% of lethal CaP cases, suggesting a more common role for β-catenin in advanced disease than would be predicted by its mutation rate. Interestingly, β-catenin nuclear localization was found to occur concomitantly with androgen-induced regrowth of normal rat prostate. These in vivo observations likely implicate β-catenin involvement in both normal and neoplastic prostate physiology, thus prompting our interest in further characterizing modes of β-catenin signaling in prostate cells. Extending our previous findings, we demonstrate that transient β-catenin over-expression stimulates T cell factor (TCF) signaling in most CaP cell lines. Further, this activity is not subject to cross-regulation by phosphoinositide-3-kinase (PI3-K)/Akt signaling, a stimulatory pathway often upregulated in CaP upon PTEN inactivation. Consistent with a previous report, we observed that transient β-catenin over-expression enhances AR-mediated transcription off two natural target gene promoters. However, we were unable to recapitulate β-catenin-induced stimulation of ectopically expressed AR in AR-negative cells, suggesting that other AR-associated factors are required for this activity. Although LNCaP cells are capable of this mode of AR co-stimulation, stable expression of mutant β-catenin did not alter their proliferative response to androgen. In total, our characterization of β-catenin signaling in CaP reveals the complex nature of its activity in prostate tissue, indicating that β-catenin potentially contributes to multiple stimulatory inputs required for disease progression.