Beta-catenin/TCF Pathway and Castrate Resistant Progression in Osteoblastic Bone Metastases

Abstract : In this project, we are studying the role of D32G-mutant beta-catenin in the expression of secretory genes by prostate cancer cells. We believe that D32G-mutant beta-catenin potently activates a subset of beta-catenin/wnt downstream target genes, thus providing a tool for identifying bone progression factors activated by this pathway in prostate cancer. Results from the studies performed during this period indicate that activation of beta-catenin in prostate cancer cells stimulates a subset of betacatenin target genes and suggest that beta-catenin expression in prostate cancer cells mediates the prostate cancer induced new bone formation in vitro and in vivo. These results provide confidence that our gene-expression studies will be informative for identifying the beta-catenin downstream target genes that mediate the osteoblastic phenotype induced by prostate cancer cells. Immunohistochemical studies performed in human bone metastases of prostate cancer identified 4 groups based on beta-catenin intracellular distribution and expression and androgen receptor expression. It will be interesting to assess how the selected factors induced by beta-catenin in prostate cancer cells are expressed in the different groups. Although these results would only be correlative, they would provide the basis for prioritization in future studies.