Exploring the Mechanisms of Pathogenesis in Prostate Cancer Involving TMPRSS2-ERG (Or ETV1) Gene Rearrangement

摘要

Recently, gene rearrangements involving ETS family transcription factors have been identified in >50% of prostate cancer cases. To address roles of these ETS factors, especially ERG, the most frequently rearranged ETS gene in prostate cancer, as well as in normal prostate development, we planned to, 1. Generate conditional knockin mouse models of prostate cancer based on the newly identified TMPRSS2-ERG (or ETV1) gene arrangements; 2 Explore roles of Erg during development as well as in normal prostate by disrupting its expression in mouse; 3. Identify downstream target genes of ERG or ETV1 in human prostate cancer cell lines carrying these gene arrangements using the ChIP-on-Chip approach. During the first year of this award, we have made significant progress in establishing systems and reagents for all three aims mentioned above. Specifically, we have successfully created conditional knockin mice expressing truncated human ERG and ETV1 (as found in patients) from the endogenous mouse Tmprss2 locus. We have generated an Erg knockdown allele in mice, which would allow us to study its roles during both embryonic development and postnatal prostate development. We have also made biotinylated ERG and ETV1 in prostate cell lines, which would allow us to identify the downstream targets of these factors in prostate epithelial cells. Further studies using these animal and cell culture models would allow us to develop preclinical animal models, and to identify and validate novel therapeutic targets, for treating prostate cancer.