Cooperativity Of TMPRSS2-ERGwith PI3-Kinase Pathway Activation In Prostate Oncogenesis

Main Category: Prostate / Prostate Cancer
Also Included In: Urology / Nephrology;  Cancer / Oncology
Article Date: 12 Jun 2009 - 5:00 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 and the PI3-kinase pathway in the early stages of prostate cancer (CaP) progression. Both are reviewed by Urotoday.

In this paper from the group of Dr. Charles Sawyers at Memorial Sloan Kettering Cancer Center, transgenic mouse models are used to study The TMPRSS2-ERG fusion gene, the most common chromosomal rearrangement found in localized prostate cancer (CaP) tumors. The authors point out the TMPRSS2-ERG fusion gene is not common in PIN, even when adjacent to fusion positive prostate cells.

The investigators designed TMPRSS2-ERG fusion gene constructs, and identified methionine 40 in the TMPRSS2-ERG fusion as the principle start site for ERG expression. This construct was controlled by the probasin promoter and 17 transgene-positive founder mice were generated, with 4 showing stable germline transmission of the transgene. Two lines were expanded and the prostates from the TMPRSS2-ERG fusion gene mice were harvested at 2, 6, 12 and 14 months and compared with littermate controls. In the TMPRSS2-ERG mice, no PIN or CaP was found, suggesting that TMPRSS2-ERG is by itself insufficient to initiate CaP and those interactions with other oncogenes are needed.

They evaluated 121 human tumors for alterations in PTEN and MYC by array-based comparative genomic hybridization. Tumors with PTEN loss were highly enriched for ERG rearrangement. MYC amplification was not associated with ERG rearrangement. TMPRSS2-ERG mice crossed with PTEN mice all demonstrated PIN at 6 months of age. TMPRSS2-ERG mice were crossed with prostate specific AKT transgenic mice, which develop low grade PIN but not invasive cancer. All bigenic mice developed cancer.

These observations along with those of the Carver paper suggest that cooperativity between PI3K-pathway activation and ERG aberration result in PIN but additional events are required for the development of invasive cancer.

King JC, Xu J, Wongvipat J, Hieronymus H, Carver BS, Leung DH, Taylor BS, Sander C, Cardiff RD, Couto SS, Gerald WL, Sawyers CL
Nat Genet. 2009 May; 41(5):524-6
doi: 10.1038/ng.371

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

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