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

Nagarathinam Selvaraj,Travis J Jerde,Peter C Hollenhorst,Mary W Ferris,Justin A Budka

doi:10.1186/1476-4598-13-61

Nagarathinam Selvaraj, Travis J Jerde + Show 3 more

Open Access

https://doi.org/10.1186/1476-4598-13-61

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Abstract

BackgroundThe 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.ResultsWe 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.ConclusionsOur 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.

Highlights

The RAS/RAF/MEK/ERK pathway (RAS/ERK) and PI3K/AKT pathways induce oncogenic gene expression programs and are commonly activated together in cancer cells
Whereas a RAS mutation in other carcinomas might activate both ERK and PI3K signaling, we propose that prostate tumors have an alternative way to activate these pathways: PTEN deletion (PI3K/AKT activation) coupled with oncogenic ETS-overexpression
Oncogenic ETS gene rearrangement occurs in tumors lacking RAS/ERK mutations If oncogenic ETS gene rearrangements replace RAS/ ERK activation, we predict that RAS/ERK mutations will occur only in ETS rearrangement negative tumors

Summary

Introduction

The RAS/ERK and PI3K/AKT pathways induce oncogenic gene expression programs and are commonly activated together in cancer cells. 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. PTEN deletions are common, but, unlike other carcinomas, RAS and RAF mutations are rare. The RAS/RAF/MEK/ERK (RAS/ERK) and PI3K/AKT signaling pathways regulate gene expression programs that promote cell growth, proliferation, motility, and survival [1,2]. Mutations that cause constitutive RAS/ERK or PI3K/AKT signaling are among the most common alterations in human cancer and both pathways are often activated in the same tumor [3,4]. PI3K/AKT activation is common in prostate cancer, often due to loss of a suppressor of the pathway, PTEN [5]. RAS can activate PI3K, and AKT can phosphorylate and inhibit RAF [9,10]

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