Aberrant ERG Expression Cooperates With Loss Of PTEN To Promote Cancer Progression In The Prostate

Main Category: Prostate / Prostate Cancer
Also Included In: Urology / Nephrology;  Cancer / Oncology
Article Date: 15 Jun 2009 - 0:00 PDT

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UroToday.com - Two papers in the May 5, 2009 edition of Nature Genetics link ERG chromosomal gene translocations with loss of PTEN in the early stages of prostate cancer (CaP) progression. Both are reviewed in Urotoday.

In this report, Dr. Brett Carver and colleagues studied TMPRSS2-ERG genetic rearrangement, which are reported in up to 50% of primary prostate cancer tumors. The ETS overexpression is also linked to the invasive and metastatic phenotype. ERG rearrangements are not commonly found in high-grade PIN (HGPIN), even though it is present in surrounding CaP areas from the same primary tumor. They validated this by microarray of 40 CaP tumors. PTEN loss or alteration occurs in 30-70% of CaP tumors, and the investigators evaluated whether loss of PTEN and ERG genetic rearrangements is a concomitant event in CaP. Among 40 CaP specimens, PTEN protein expression was decreased or absent in 68% of samples and ERG rearrangements by FISH analysis were present in 38%. Fourteen of 15 ERG-positive samples had altered PTEN expression.

They also tested their hypothesis in mice. In Pten knockout mice with concomitant p53 loss, mRNA levels in tumors showed markedly increased levels of ERG. To further understand whether aberrant prostatic expression of ERG would interact with PTEN loss to promote CaP development and progression in mice, they generated mice expressing ERG under the control of the probasin promoter (PB-ERG). The phenotype was a highly invasive CaP with reduced cancer latency. The overexpression of ERG did not seem to directly affect PTEN levels, but it somehow interacted through a complementary pathway. In vitro delineation of this found that while proliferation was not altered, tumor cell migration was increased. Microarray identified the chemokine receptor CXCR4 as transcriptionally upregulated. CXCR4 was found to have 2 ETS promoter binding regions and knockdown of CXCR4 inhibited cell migration. These data link two frequent and critical events in CaP to promote tumor development and progression.

Carver BS, Tran J, Gopalan A, Chen Z, Shaikh S, Carracedo A, Alimonti A, Nardella C, Varmeh S, Scardino PT, Cordon-Cardo C, Gerald W, Pandolfi PP
Nat Genet. 2009 May;41(5):619-24.
doi: 10.1038/ng.370

Written by UroToday.com Contributing Editor Christopher P. Evans, MD, FACS

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