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.
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.
|Serrano-Gómez, Silvia J; Fejerman, Laura; Zabaleta, Jovanny (2018) Breast Cancer in Latinas: A Focus on Intrinsic Subtypes Distribution. Cancer Epidemiol Biomarkers Prev 27:3-10|
|Kuhns, Katherine J; Zhang, Guanyi; Wang, Zehua et al. (2018) ARD1/NAA10 acetylation in prostate cancer. Exp Mol Med 50:89|
|Sanabria-Salas, María Carolina; Hernández-Suárez, Gustavo; Umaña-Pérez, Adriana et al. (2017) IL1B-CGTC haplotype is associated with colorectal cancer in admixed individuals with increased African ancestry. Sci Rep 7:41920|
|Loupe, Jacob M; Miller, Patrick J; Crabtree, Judy S et al. (2017) Acquisition of an oncogenic fusion protein is sufficient to globally alter the landscape of miRNA expression to inhibit myogenic differentiation. Oncotarget 8:87054-87072|
|Rawlik, Konrad; Rowlatt, Amy; Sanabria-Salas, María Carolina et al. (2017) Evidence of epigenetic admixture in the Colombian population. Hum Mol Genet 26:501-508|
|Garay, Jone; Piazuelo, M Blanca; Lopez-Carrillo, Lizbeth et al. (2017) Increased expression of deleted in malignant brain tumors (DMBT1) gene in precancerous gastric lesions: Findings from human and animal studies. Oncotarget 8:47076-47089|
|Serrano-Gomez, Silvia Juliana; Sanabria-Salas, Maria Carolina; Hernández-Suarez, Gustavo et al. (2016) High prevalence of luminal B breast cancer intrinsic subtype in Colombian women. Carcinogenesis 37:669-676|
|Joseph, Ann Mary; Srivastava, Ratika; Zabaleta, Jovanny et al. (2016) Cross-talk between 4-1BB and TLR1-TLR2 Signaling in CD8+ T Cells Regulates TLR2's Costimulatory Effects. Cancer Immunol Res 4:708-16|
|Dai, Lu; Bai, Lihua; Lin, Zhen et al. (2016) Transcriptomic analysis of KSHV-infected primary oral fibroblasts: The role of interferon-induced genes in the latency of oncogenic virus. Oncotarget 7:47052-47060|
|Maxi, John K; Dean, Matt; Zabaleta, Jovanny et al. (2016) Chronic Binge Alcohol Administration Dysregulates Hippocampal Genes Involved in Immunity and Neurogenesis in Simian Immunodeficiency Virus-Infected Macaques. Biomolecules 6:|
Showing the most recent 10 out of 26 publications