The Androgen receptor (AR) plays a central role in neoplastic growth and progression of prostate cancer (PCa). The PCa incidence and mortality rate is higher in African-American (AA) men than in Caucasians. This disparity may be related in part to the expression or activity of AR in the prostate tissue of AA men or to unique mutations or polymorphisms of the AR. In Caucasians, AR mutations are infrequent (<2%) in localized tumors, but occur at a higher frequency in advanced, metastatic, and hormone-refractory disease. In AAs, the prevalence, clinical, and biological significance of AR mutations in primary PCa are unknown. We discovered genomic amplification and somatic mutations of AR in a PCa cell line (E006AA) we established from an AA patient with an untreated organ-confined PCa. In addition, in a set of 60 organ-confined radical prostatectomy samples (30 AAs and 30 Caucasians), we identified 4 AR mutations in AA patients only. Furthermore, we discovered a novel AR germline missense mutation in several PCa-affected members in an AA family with familial PCa. From these observations, we hypothesize that diversity and a high prevalence of AR mutations contribute significantly to biological and clinical aggressiveness and/or progression of sporadic or familial PCa in AAs.
In Specific Aim 1, we will determine the frequency and type of AR mutations in laser-captured cells from radical prostatectomy specimens in 500 AA men with primary untreated PCa and their association with predictive or prognostic factors (e.g., Gleason's score, PSA) reflecting clinical progression or aggressiveness of PCa.
In Specific Aim 2, we will determine the prevalence of the germline mutation in familial PCa in AAs. We will extend our analysis to all normal and PCa-affected members of 40 high-risk AA and Caucasian families and an additional pool of 400 normal unrelated individuals from both ethnic cohorts.
In Specific Aim 3, we will determine the biological activities of the identified AR mutations in AR-negative PCa cells. Functional characterization will be limited only to those mutations identified in tumors with clinically or histopathologically aggressive features. The result will provide insight enabling the critical assessment of the AR gene in PCa predisposition and progression in AAs.

Public Health Relevance

The incidences, mortality, and aggressiveness of prostate cancer (PCa) in African American (AA) men are higher than in Caucasians. We have discovered a high frequency of androgen receptor mutations and a novel germline mutation in a high risk AA family that may improve prognosis and also lead to new therapies.

Agency
National Institute of Health (NIH)
Institute
National Institute on Minority Health and Health Disparities (NIMHD)
Type
Exploratory Grants (P20)
Project #
5P20MD004817-04
Application #
8434769
Study Section
Special Emphasis Panel (ZMD1-PA)
Project Start
Project End
Budget Start
2013-03-01
Budget End
2014-02-28
Support Year
4
Fiscal Year
2013
Total Cost
$107,554
Indirect Cost
$4,645
Name
Dillard University
Department
Type
DUNS #
062665468
City
New Orleans
State
LA
Country
United States
Zip Code
70122
Koochekpour, Shahriar; Buckles, Erick; Shourideh, Mojgan et al. (2014) Androgen receptor mutations and polymorphisms in African American prostate cancer. Int J Biol Sci 10:643-51
Zabaleta, J; Velasco-Gonzalez, C; Estrada, J et al. (2014) Inverse correlation of serum inflammatory markers with metabolic parameters in healthy, Black and White prepubertal youth. Int J Obes (Lond) 38:563-8
Liu, Zun; Rebowe, Ryan E; Wang, Zemin et al. (2014) KIF3a promotes proliferation and invasion via Wnt signaling in advanced prostate cancer. Mol Cancer Res 12:491-503
Hurst, Charlotte; Dennis, Betty P (2013) Developing a clinical research associate training program at Dillard University: the impact of collaboration. ABNF J 24:104-10
Koochekpour, Shahriar; Hu, Siyi; Vellasco-Gonzalez, Cruz et al. (2012) Serum prosaposin levels are increased in patients with advanced prostate cancer. Prostate 72:253-69
Koochekpour, Shahriar (2010) Androgen receptor signaling and mutations in prostate cancer. Asian J Androl 12:639-57