Prostate cancer ETS rearrangements switch a cell migration gene expression program from RAS/ERK to PI3K/AKT regulation

dc.contributor.authorSelvaraj, Nagarathinam
dc.contributor.authorBudka, Justin A.
dc.contributor.authorFerris, Mary W.
dc.contributor.authorJerde, Travis J.
dc.contributor.authorHollenhorst, Peter C.
dc.contributor.departmentPharmacology and Toxicology, School of Medicine
dc.date.accessioned2025-04-14T10:46:48Z
dc.date.available2025-04-14T10:46:48Z
dc.date.issued2014-03-19
dc.description.abstractBackground: The RAS/ERK and PI3K/AKT pathways induce oncogenic gene expression programs and are commonly activated together in cancer cells. Often, RAS/ERK signaling is activated by mutation of the RAS or RAF oncogenes, and PI3K/AKT is activated by loss of the tumor suppressor PTEN. In prostate cancer, PTEN deletions are common, but, unlike other carcinomas, RAS and RAF mutations are rare. We have previously shown that over-expression of "oncogenic" ETS transcription factors, which occurs in about one-half of prostate tumors due to chromosome rearrangement, can bypass the need for RAS/ERK signaling in the activation of a cell migration gene expression program. In this study we test the role of RAS/ERK and PI3K/AKT signaling in the function of oncogenic ETS proteins. Results: We find that oncogenic ETS expression negatively correlates with RAS and RAF mutations in prostate tumors. Furthermore, the oncogenic ETS transcription factors only increased cell migration in the absence of RAS/ERK activation. In contrast to RAS/ERK, it has been reported that oncogenic ETS expression positively correlates with PI3K/AKT activation. We identified a mechanistic explanation for this finding by showing that oncogenic ETS proteins required AKT signaling to activate a cell migration gene expression program through ETS/AP-1 binding sequences. Levels of pAKT correlated with the ability of oncogenic ETS proteins to increase cell migration, but this process did not require mTORC1. Conclusions: Our findings indicate that oncogenic ETS rearrangements cause a cell migration gene expression program to switch from RAS/ERK control to PI3K/AKT control and provide a possible explanation for the high frequency of PTEN, but not RAS/RAF mutations in prostate cancer.
dc.eprint.versionFinal published version
dc.identifier.citationSelvaraj N, Budka JA, Ferris MW, Jerde TJ, Hollenhorst PC. Prostate cancer ETS rearrangements switch a cell migration gene expression program from RAS/ERK to PI3K/AKT regulation. Mol Cancer. 2014;13:61. Published 2014 Mar 19. doi:10.1186/1476-4598-13-61
dc.identifier.urihttps://hdl.handle.net/1805/47033
dc.language.isoen_US
dc.publisherSpringer Nature
dc.relation.isversionof10.1186/1476-4598-13-61
dc.relation.journalMolecular Cancer
dc.rightsAttribution 4.0 Internationalen
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.sourcePMC
dc.subjectProstate cancer
dc.subjectETS
dc.subjectRAS/ERK
dc.subjectPI3K/AKT
dc.subjectCell migration
dc.titleProstate cancer ETS rearrangements switch a cell migration gene expression program from RAS/ERK to PI3K/AKT regulation
dc.typeArticle
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