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Aberrant ERG expression cooperates with loss of PTEN to promote cancer progression in the prostate

Nature Genetics volume 41, pages 619–624 (2009)Cite this article

An Author Correction to this article was published on 17 August 2020

Abstract

Chromosomal translocations involving the ERG locus are frequent events in human prostate cancer pathogenesis; however, the biological role of aberrant ERG expression is controversial1. Here we show that aberrant expression of ERG is a progression event in prostate tumorigenesis. We find that prostate cancer specimens containing the TMPRSS2-ERG rearrangement are significantly enriched for loss of the tumor suppressor PTEN. In concordance with these findings, transgenic overexpression of ERG in mouse prostate tissue promotes marked acceleration and progression of high-grade prostatic intraepithelial neoplasia (HGPIN) to prostatic adenocarcinoma in a Pten heterozygous background. In vitro overexpression of ERG promotes cell migration, a property necessary for tumorigenesis, without affecting proliferation. ADAMTS1 and CXCR4, two candidate genes strongly associated with cell migration, were upregulated in the presence of ERG overexpression. Thus, ERG has a distinct role in prostate cancer progression and cooperates with PTEN haploinsufficiency to promote progression of HGPIN to invasive adenocarcinoma.

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Figure 1: Genetic and molecular alterations involving ERG and PTEN are frequent and concomitant events in human prostate cancer.
Figure 2: Prostate-specific overexpression of ERG cooperates with Pten haploinsufficiency to promote prostate tumorigenesis.
Figure 3: ERG regulates cell migration.
Figure 4: ERG directly regulates CXCR4 and ADAMTS1.

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Acknowledgements

We are grateful to all members of the Pandolfi laboratory and C. Sawyers and his group for stimulating discussions regarding our study project. We thank P. Romanienko and W. Mark from our genetically engineered mouse core facility for their assistance in generating and genotyping our prostate-specific ERG mouse model. We also thank S. Hayward (Vanderbilt-Ingram Cancer Center) for providing us with the BPH-1 cells used for our experiments, R. Lester at our animal facility for caring for our mice on a daily basis and L. DiSantis for her editorial support. This work was funded through grants from the US National Institutes of Health (R01-CA82328, R01-CA84292, P50-CA92629) and Memorial Sloan Kettering Cancer Center Research in Therapeutics Program in Prostate Cancer award to B.S.C. and P.P.P.

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Authors and Affiliations

  1. Cancer Biology and Genetics Program, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, New York, New York, USA

    Brett S Carver, Jennifer Tran, Zhenbang Chen, Arkaitz Carracedo, Andrea Alimonti, Caterina Nardella, Shohreh Varmeh & Pier Paolo Pandolfi

  2. Department of Surgery, Division of Urology, Memorial Sloan-Kettering Cancer Center, New York, New York, USA

    Brett S Carver, Safa Shaikh & Peter T Scardino

  3. Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York, USA

    Anuradha Gopalan, William Gerald & Pier Paolo Pandolfi

  4. Department of Medicine and Pathology, Cancer Genetics Program, Beth Israel Deaconess Cancer Center, Harvard Medical School, Boston, Massachusetts, USA

    Zhenbang Chen, Arkaitz Carracedo, Andrea Alimonti, Caterina Nardella, Shohreh Varmeh & Pier Paolo Pandolfi

  5. Department of Pathology, Columbia University, New York, New York, USA

    Carlos Cordon-Cardo

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Contributions

B.S.C. designed the study, conducted and supervised all experiments and wrote the manuscript along with P.P.P. J.T. conducted in vivo and in vitro experiments. A.G. designed and performed the human tissue analyses. Z.C. provided the prostate tissue from our Pten/Trp53 prostate conditional null series of mice. S.S. performed the BPH-1 cell experiments. A.C., A.A., C.N., S.V. and P.T.S. provided critical discussion on the generation of our mouse model and experimental design. C.C.-C. reviewed our mouse prostate histology. W.G. supervised A.G. on the human tissue studies and reviewed our mouse prostate histology. P.P.P. supervised and mentored all work. All authors approved of the final manuscript.

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Correspondence to Pier Paolo Pandolfi.

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Carver, B., Tran, J., Gopalan, A. et al. Aberrant ERG expression cooperates with loss of PTEN to promote cancer progression in the prostate. Nat Genet 41, 619–624 (2009). https://doi.org/10.1038/ng.370

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