Supporting this hypothesis, sellekchem PTEN deletion is more common in pros tate tumors with TMPRSS2 ERG rearrangements, than in those without, and in mouse models, ERG over expression results in adenocarcinoma only when accompanied by a second mutation that activates the PI3KAKT pathway. Here we test the relationship between oncogenic ETS expression Inhibitors,Modulators,Libraries and both the RASERK and PI3KAKT path ways. We provide the first comprehensive analysis of oncogenic ETS protein expression in prostate cancer cell lines. We then show that the status of both the RAS ERK and PI3KAKT pathways Inhibitors,Modulators,Libraries can change the ability of over expressed ETS proteins to promote prostate cell migration. Significantly, we find that oncogenic ETS ex pression makes cell migration less dependent on RAS ERK signaling, but increases the importance of PI3KAKT signaling.

We provide evidence Inhibitors,Modulators,Libraries that this switch in the sig naling pathway requirement is due to AKT dependent, but mTORC1 independent, regulation of oncogenic ETS function through ETSAP 1 binding sequences. Therefore, switching the ETS protein at ETSAP 1 sequences changes the ability of signaling pathways to regulate a critical oncogenic gene expression program. Results Oncogenic ETS gene rearrangement occurs in tumors lacking RASERK mutations If oncogenic ETS gene Inhibitors,Modulators,Libraries rearrangements replace RAS ERK activation, we predict that RASERK mutations will occur only in ETS rearrangement negative tumors. To test this hypothesis, we examined the results of three re cently published studies that both sequence exons and identify chromosome rearrangements Inhibitors,Modulators,Libraries in pros tate tumors.

Together these studies examine 266 prostate tumors. One half have ERG or ETV1 chromosome rearrangements. We searched for either gene fusions, or point mutations in canonical RASERK pathway genes. Eight tumors had such aberrations, and all eight were negative for oncogenic ETS rearrangements. This indicates that, while genomic CP-690550 alterations in RASERK pathway components are rare in prostate cancer, there is a statistically significant mutual exclusivity of these alterations and ETS rear rangements. It has been previously reported that PI3K AKT activation via PTEN deletion positively correlates with ETS gene rearrangements. A search for PTEN loss in these 266 tumors confirms these findings and indicates that PTEN loss is more than twice as likely in tumors with ETS gene rearrangements than in those without. In con clusion, ERG and ETV1 gene rearrangements positively correlate with PTEN loss and negatively correlate with RASERK mutations in tumors. Prostate cancer cell lines as models of oncogenic ETS function To test the effect of RASERK signaling and PI3KAKT signaling on oncogenic ETS function in prostate cell lines, we must first determine which cell lines have these characteristics.