The Role of Aberrant Splicing of EVl1 in Ovarian Cancer Pathophysiology

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DESCRIPTION (provided by applicant): Using high resolution comparative genomic hybridization (CGH) array analysis of 235 ovarian cancers, we have narrowed the most frequent region of copy number increase in ovarian cancers to an ~3.2 MB wide region at 3q26.2. Real time PCR of genes within this region indicated that EVI1 (ecotropic viral integration site-1) and an intergenic MDS1/EVI1 fusion transcript were the most highly amplified transcripts within this region. Moreover, EVI1 is aberrantly spliced (Del190-515) in >90% of tumors. MDS1/EVI1 and EVI1 alter proliferation, motility, senescence, and signaling in ovarian epithelial cells. Further, increases in MDS1/EVI1 levels are associated with a good prognosis while EVI1Del190-515 was associated with a poor outcome. Thus, our data suggest that EVI1, MDS1/EVI1, and its splice forms play distinct roles during tumor initiation and progression depending on the cellular context. Patient outcome is likely dependent on the relative levels of the EVI1 splice variants. EVI1 has recently been implicated in cell survival and inhibition of transforming growth factor (TGF beta, TGF?) signaling by increasing PI3K (phosphatidylinositol-3-kinase) activity. Thus, we will test the hypothesis that the relative expression of the EVI1 proto-oncogene and its aberrantly spliced forms contributes to ovarian cancer initiation, progression, and drug responsiveness through differential effects on PI3K and TGF? signaling. We will test this hypothesis through the following three aims: 1) We will determine whether overexpression of aberrantly spliced forms of the proto-oncogene EVI1 contributes to ovarian cancer initiation, progression, and drug responsiveness. 2) We will determine whether EVI1 and its splice variants mediate different cellular effects through regulating the PI3K and TGF? signaling pathways. 3) We will test the hypothesis that splice variants of EVI1 predicts patient outcomes.