Structure and Function of the Splice Variants of TMPRSS2-ERG, a Prevalent Genomic Alteration in Prostate Cancer
Abstract
We hypothesized that specific ERG splice forms in TMPRSS2-ERG fusion transcripts are selectively expressed in CaP cells and are functionally relevant in CaP. The specific aims of this study were to characterize full length sequences of TMPRSS2-ERG transcripts; to quantitatively evaluate selected TMPRSS2-ERG variants in CaP specimens and their prognostic features; and to defined the functional significance of specific splice variants of the rearranged ERG locus in CaP. We have identified two types of TMPRSS2-ERG,Type I, which encodes full-length ERG protein consisting SAM and ETS domains (ERG1, ERG2, ERG3), and Type II, encoding ERG proteins lacking the ETS domain (ERG8 and a new variant, TEPC). Increased ratio of Type I over Type II variants showed a correlation with poorly differentiated pathology /high Gleason score and outcome. We found that ERG3 a product of Type I splice variant, transcriptionally activates gene expression through ETS-regulated enhancers and ERG8 encoded by the Type II splice variant abrogated the transcriptional activator function of ERG3. We have generated an anti-ERG antibodies to detect the protein products of both Type I and Type II splice variants and demonstrated the correlation between detecting ERG genomic rearrangement and ERG oncoprotein human prostate tumors. We showed that Type I/Type II ERG ratios may play a role in defining the levels of C-MYC oncogene in a TMPRSS2-ERG fusion harboring prostate cancer cell culture model and revealed that Type I/Type II ratio correlated with C-MYC levels, higher Gleason sum and poor overall prognosis of prostate cancer patients.
Document Details
- Document Type
- Technical Report
- Publication Date
- Sep 01, 2012
- Accession Number
- ADA566991
Entities
People
- Shiv Srivastava
Organizations
- Henry M. Jackson Foundation for the Advancement of Military Medicine