Regulation of Hormone Responses in Prostate Cancer by BAGIL
Abstract
Androgen ablation therapy represents the principal treatment for metastatic prostate cancer. However, nearly all tumors eventually relapse as hormone-refractory disease, indicating a need to better understand how the androgen receptor (AR) functions. In this project, we studied the expression and function of an AR-binding protein discovered in our laboratory, BAG1L. We showed that BAG1L becomes over-expressed in many prostate cancers. We determined that BAG1L potentiates the actions of AR, lowering concentrations of dihydrotestosterone needed to activate AR and rendering the AR resistant to anti-androgen drugs. We mapped the domains in BAG1L required for this activity, and generated transgenic mice over-expressing BAG1L in the prostate for future use in studying effects of BAG1L on AR in vivo. Finally, we performed work showing that BAG1L also interacts with the Vitamin D Receptor (VDR) and potentiates the growth suppressive and pro-apoptotic effects of VDR- ligands in prostate cancer cell lines in culture. Taken together, these observations suggest that prostate cancers containing high levels of BAG1L are less likely to respond favorably to anti-androgen therapy (due to their decreased sensitivity to anti-androgens), but if these tumors express VDR, then they may be excellent candidates for Vitamin-D-based therapies (due to their increased sensitivity to Vitamin D and synthetic Vitamin D analogs).
Document Details
- Document Type
- Technical Report
- Publication Date
- Sep 01, 2003
- Accession Number
- ADA419661
Entities
People
- John C. Reed
Organizations
- Sanford Burnham Prebys Medical Discovery Institute