Project Details
Description
PUBLIC ABSTRACT
Genetic rearrangements are known to play a key role in the development of many tumors, typically haematological and mesenchymal, but have been rarely identified as the molecular aetiology of common epithelial cancers. However, it has recently been reported that a majority of prostate carcinomas carry specific oncogenic translocations, in which the transcription factor ERG (or other members of the ETS family such as ETV1 or ETV4) is expressed under the control of the TMPRSS2 promoter, a prostate-specific, androgen-dependent protease, suggesting that the androgen-dependent over-expression of ERG following the TMPRSS2 fusion could be a driving mechanism of prostate carcinogenesis.
ETS family members are transcription factors that act as nuclear targets of the Ras-MAP kinase signaling pathway, and can affect proliferation by regulating immediate early response, growth-related and antiapoptotic genes. ETS family members also participate in malignant development of tumor cells, including invasion and metastasis, by activating the transcription of proteases and angiogenesis-related genes, and are known to be involved in oncogenic translocations in various cancers, such as Ewing's sarcoma.
Prostate cancer is the most common male malignancy and a leading cause of cancer mortality in men in the western world. If a functional, causal role for the TMPRSS2/ETS fusions is established, the uncovering of a major genetic cause of primary prostate tumors will have a profound impact on our understanding of the molecular mechanism(s) that drive prostate carcinogenesis, and very likely on future therapeutic approaches. The frequent occurrence of the translocation has been independently validated at the DNA and RNA level, but very little is still known about the mechanistic aspects of theTMPRSS2/ERG fusions or their putative products. The correct identification and functional characterization of the fusion product(s) is further complicated by the presence of multiple ERG variants both in normal and fusion-carrying contexts that derive from alternative splicing, multiple promoters, and polyadenylation signals and from variation in the translation initiation sites.
Interestingly, the presence of specific fusion isoforms seems to correlate with tumor aggressiveness. It is therefore important to properly identify and characterize these multiple natural and tumor-specific variants in order to understand their function and oncogenic potential and, possibly, to specifically target the tumorigenic fusion product(s) without affecting the expression of normal ERG in other tissues. For example, the common TMPRSS2:ERG 1:4 fusion mRNA lacks the natural initiation codons of both TMPRSS2 (normally in exon 2) and ERG (in exon 3), suggesting that an alternative downstream ATG, in frame with the rest of the ERG protein and specific for the fusion protein, must be used.
The initial aims of this project are to identify and characterize the multiple ERG variants in prostate tumors, to understand their respective biological role and mechanism of action, and to determine their oncogenic potential in vitro and in vivo.
This knowledge will serve as a basis to develop antisense-based compounds to selectively inhibit the oncogenic variants of TMPRSS2/ERG by interfering with specific alternative splicing events and/or with ATG usage. In addition, some of the identified splicing variants encode for putative dominant-negative isoforms and appear underrepresented in tumors. The pharmacological manipulation of the Tmprss2/ERG splicing pattern, would therefore allow for the elimination the more aggressive oncogenic isoforms while simultaneously introducing beneficial ones with dominant-negative properties.
The aims proposed will address a key molecular aberration in prostate cancer that would provide tumor-specific diagnostic and therapeutic stratification for nearly half of all prostate cancer patients, would increase our understanding of the mechanism of prostate cancer progression, and could finally lead to innovative therapeutic approaches of broad impact.
Status | Finished |
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Effective start/end date | 1/1/08 → 12/31/08 |
Funding
- U.S. Department of Defense: $707,118.00