Splicing Variants of Androgen Receptor and Target Genes in Prostate Cancer Racial Disparity
Abstract
The long-term objectives of this application are to understand the biological mechanisms underlying the well-recognized disparity in incidence and mortality rates of prostate cancer (PCa) between African American (AA) and Caucasian (CA) men and to develop effective strategies to reduce this disparity. AA men have the highest incidence of PCa in the world, and the age-adjusted mortality rate from PCa is twice as high in AA men as in CA men, with the age-specific mortality rate from PCa three times greater among AA men than CA men. Androgen receptor (AR) and its signaling pathway, which are critical for PCa tumorigenesis and progression, are associated with PCa racial disparity. The recent discovery of a new class of AR, the AR splice variants (AR-Vs), has shed new insights into AR signaling. Unlike the canonical AR, AR-Vs do not depend on the presence of androgen to become activated, thereby promoting tumor recurrence and progression in a low androgen environment. There is accumulating evidence to suggest these AR-Vs are involved in the development of primary tumor, in recurrence after radical prostatectomy, and in the resistance to hormonal therapies. Additionally, emerging evidence links certain AR-Vs to PCa aggressiveness. Despite the great discovery of AR-Vs and their clinical relevance, there is a glaring gap in knowledge with regard to the role of AR-Vs in PCa racial disparity. Our preliminary studies reveal a discrete expression pattern of AR-Vs between AA and CA PCa, providing support to our novel hypothesis that AR-Vs and their target genes are associated with and responsible for the disparity in PCa aggressiveness between AA and CA populations. In this application, we have designed a series of experiments utilizing clinical samples, animal models, and cell lines from AA and CA PCa to test this hypothesis and to understand the underlying mechanisms. We hope to establish the prognostic value of AR-Vs in AA PCa and identify AR-V target genes associated with aggressive PCa behavior in AA patients. Furthermore, these ARVs and target genes may serve as novel pathway-based targets for treating the most recalcitrant PCa in AA patients. Overall, the outcome of this study is expected to address a gap in PCa racial disparity, with a direct impact on biomarker development and rational drug design to reduce suffering and improve quality of life in AA patients.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810272
Entities
People
- Peng Lee
Organizations
- Grossman School of Medicine
- United States Army