Hormone-dependent cancers depend largely on folding and regulation by a chaperone-steroid receptor complex. The final stage of the receptor-chaperone complex consists of a receptor, a heat shock protein 90 (Hsp90) dimer, p23, and an immunophilin. Hormone-dependent prostate cancer progresses due to key interactions between the androgen receptor complex and the ligand dihydrotestosterone. While current treatments block androgen receptor-ligand interactions, these therapies are no longer effective in advanced stage, hormone independent prostate cancer (HRPC), when the receptor is activated even in miniscule levels of hormone. Therefore, we are interested in targeting other members of the androgen receptor complex and signaling cascade, namely the immunophilin FK506 binding protein (FKBP52) and the Wnt cell signaling protein β-catenin. FKBP52 has the ability to potentiate activity of the androgen, progesterone, and glucocorticoid receptors and is a prostate cancer biomarker. β-catenin is a member of the cellular adhesion complex with E-cadherin in healthy cells, but in aberrant situations, β-catenin actively promotes progression and invasion in a number of cancers. Our data from FKBP52 knockout mouse embryonic fibroblast cell lines suggests that FKBP52 and β-catenin work in tandem to synergize androgen receptor (AR) transcriptional activity with the probasin promoter. When AR, FKBP52, and β-catenin are co-transfected, a synergistic up-regulation of AR signaling is observed, as assessed by luciferase reporter assays. According to pull down assays, FKBP52 and β-catenin can interact in the absence of other proteins. Luciferase assays of mutant FKBP52 proteins suggest that FKBP52's binding to β-catenin involves the FKBP52 proline-rich loop and may act independently of Hsp90 binding. Interestingly, it appears that this synergistic effect is promoter-specific, suggesting that regulation by these proteins occurs at the transcriptional level. We have successfully abrogated the synergism of these proteins using the FKBP52-specific inhibitor MJC13, a small molecule developed for use in our laboratory. According to surface plasmon resonance studies, this molecule binds the androgen receptor at the BF-3 regulatory surface, the interaction surface for FKBP52 regulation of receptor. According to recent findings, AR, Wnt, and Human Epidermal Growth Factor Receptor 2 signaling pathways are linked in molecular apocrine breast cancer progression. We therefore hypothesize that our findings could be relevant to breast cancer as well as prostate cancer.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P5-07-02.

2012