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

Abstract

BACKGROUND:

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.

• Authors: Nagarathinam Selvaraj, Justin A Budka, Mary W Ferris, Travis J Jerde, Peter C Hollenhorst
• Journal: Molecular cancer (Mol Cancer) Vol. 13 Pg. 61 (Mar 19 2014) ISSN: 1476-4598 [Electronic] England
• PMID: 24642271 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Elafin
• PI3 protein, human
• Proto-Oncogene Proteins c-ets
• Proto-Oncogene Proteins c-akt
• Extracellular Signal-Regulated MAP Kinases
• ras Proteins

Topics

• Blotting, Western
• Cell Line, Tumor
• Cell Movement
• Elafin (genetics, metabolism)
• Extracellular Signal-Regulated MAP Kinases (genetics, metabolism)
• Gene Expression Regulation, Neoplastic (physiology)
• Gene Rearrangement
• Humans
• Male
• Prostatic Neoplasms (genetics, metabolism)
• Proto-Oncogene Proteins c-akt (genetics, metabolism)
• Proto-Oncogene Proteins c-ets (genetics, metabolism)
• Reverse Transcriptase Polymerase Chain Reaction
• Signal Transduction (physiology)
• Transduction, Genetic
• ras Proteins (genetics, metabolism)