AWARD NUMBER: W81XWH-13-1-0449 TITLE: Differential Splicing of Oncogenes and Tumor Suppressor Genes in African- and Caucasian-American Populations: Contributing Factor in Prostate Cancer Disparities? PRINCIPAL INVESTIGATOR:

Purpose: African Americans (AA) exhibit higher rates of prostate cancer incidence and mortality compared with European American (EA) men. In addition to socioeconomic influences, biologic factors are believed to play a critical role in prostate cancer disparities. We investigated whether population-specific and -enriched miRNA–mRNA interactions might contribute to prostate cancer disparities. Experimental Design: Integrative genomics was used, combining miRNA and mRNA profiling, miRNA target prediction, pathway analysis, and functional validation, to map miRNA–mRNA interactions associated with prostate cancer disparities. Results: We identified 22 AA-specific and 18 EA-specific miRNAs in prostate cancer versus patient-matched normal prostate, and 10 "AA-enriched/-depleted" miRNAs in AA prostate cancer versus EAprostate cancer comparisons.Manyof these populationspecific/-enriched miRNAs could be paired with target mRNAs that exhibited an inverse pattern of differential expression. Pathway analysis revealed EGFR (or ERBB) signaling as a critical pathway significantly regulated by AA-specific/-enriched mRNAs andmiRNA–mRNApairings. NovelmiRNA–mRNApairingswere validated by qRT-PCR, Western blot, and/or IHC analyses in prostate cancer specimens. Loss/gain of function assays performed in population-specific prostate cancer cell lines confirmed miR-133a/MCL1, miR-513c/STAT1, miR-96/FOXO3A, miR-145/ ITPR2, and miR-34a/PPP2R2A as critical miRNA–mRNA pairings driving oncogenesis. Manipulating the balance of these pairings resulted in decreased proliferation and invasion, and enhanced sensitization to docetaxel-induced cytotoxicity in AA prostate cancer cells. Conclusion: Our data suggest that AA-specific/-enriched miRNA–mRNA pairings may play a critical role in the activation of oncogenic pathways in AA prostate cancer. Our findings also suggest that miR-133a/MCL1, miR-513c/STAT1, and miR-96/ FOXO3A may have clinical significance in the development of novel strategies for treating aggressive prostate cancer. Clin Cancer Res; 1–15. !2015 AACR.