Differential Splicing of Oncogenes and Tumor Suppressor Genes in African- and Caucasian-American Populations: Contributing Factor in Prostate Cancer Disparities?

摘要

The overarching goal of this grant award is to characterize differential splicing of oncongenes and tumor suppressor genes in prostate cancer disparities between African American (AA) and Caucasian American (CA) prostate cancer (PCa). In year 1 of this award, we have focused our efforts on two oncogenes, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit delta (PIK3CD) and fibroblast growth factor receptor 3 (FGFR3), undergoing population-dependent differential splicing where the AA-specific variants are engendered with a more aggressive oncogenic phenotype in vitro and in vivo. Full-length cloning of the AA and CA variants of both PIK3CD and FGFR3 have been accomplished. PCa cell lines genetically manipulated to predominantly express the AA-variant of PIK3CD or FGFR3 exhibit greater proliferative and invasive capacity. Detailed analysis of PCa cell lines over-expressing the AA-variant of PIK3CD revealed enhanced activation of the PI3K/AKT pathway compared to the same lines over-expressing the CA-variant. Moreover, proliferative capacity of the CA-variant lines was sensitive to inhibition by CAL-101, a small molecule inhibitor designed specifically against PIK3CD. In contrast, proliferative capacity of the AA-variant lines was resistant to CAL-101 inhibition. And these findings (CA variants sensitive and AA variants insensitive to CAL-101) were recapitulated in a xenograft mouse model of proliferation. We are currently testing a xenograft mouse model of metastasis. Year 2 will focus on in vitro and in vivo characterization of the AA and CA variants of FGFR3.