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Accession Number:
ADA566991
Title:
Structure and Function of the Splice Variants of TMPRSS2-ERG, a Prevalent Genomic Alteration in Prostate Cancer
Descriptive Note:
Final rept. 15 Aug 2008-14 Aug 2012
Corporate Author:
HENRY M JACKSON FOUNDATION FOR THE ADVANCEMENT OF MILITARY MEDICINE BETHESDA MD
Report Date:
2012-09-01
Pagination or Media Count:
85.0
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 IType 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 IType II ratio correlated with C-MYC levels, higher Gleason sum and poor overall prognosis of prostate cancer patients.
Distribution Statement:
APPROVED FOR PUBLIC RELEASE
