Oncogenicity and Selective Inhibition of ERG Splicing Variants in Prostate Cancer
Abstract
Genetic rearrangements that result in the formation of oncogenic fusion genes are well-characterized key events in cancer development in several rare haematological malignancies and sarcomas. Recently they have been suggested to play a major role also in common solid tumors, namely in a majority of prostate cancers. ERG, a member of the ETS transcription factor family known to be involved in different oncogenic fusions, is frequently overexpressed in clinical prostate cancer, driven by its fusion to the androgen-responsive TMPRSS2 gene. In particular, The fusion of exon 1 of TMPRSS2 with exon 4 of ERG has been observed in about 50% of human prostate cases, suggesting a causative role in the development of carcinomas. Additional TMPRSS2:ERG fusions (involving different recombination sites) have been described, but their specific functions and oncogenic activities are still unclear. We have started to systematically address the complex gene expression patterns of both the endogenous ERG genes, and found that it alone can generate over 50 variants, some of which appear to correlate with tumor aggressiveness. The systematic characterization of both ERG and TMPRSS2:ERG main variants underscores differences in their biological roles and oncogenic potential, which depends on the presence of the intact Ets domain and on the configuration of the 5' UTR region. In additon, the fusion-derived variants can be preferentially downregulated by antisense-based compounds designed to specifically block their translation initiation site.
Document Details
- Document Type
- Technical Report
- Publication Date
- Sep 01, 2010
- Accession Number
- ADA544999
Entities
People
- Luca Cartegni
Organizations
- Memorial Sloan Kettering Cancer Center