Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

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

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


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.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Get just this article for as long as you need it


Prices may be subject to local taxes which are calculated during checkout

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.

Accession codes


Gene Expression Omnibus


  1. Tomlins, S.A. et al. Recurrent fusion of TMPRSS2 and ETS transcription factor genes in prostate cancer. Science 310, 644–648 (2005).

    Article  CAS  Google Scholar 

  2. Tu, J.J. et al. Gene fusions between TMPRSS2 and ETS family genes in prostate cancer: frequency and transcript variant analysis by RT-PCR and FISH on paraffin-embedded tissues. Mod. Pathol. 20, 921–928 (2007).

    Article  CAS  Google Scholar 

  3. Perner, S. et al. TMPRSS2-ERG fusion prostate cancer: an early molecular event associated with invasion. Am. J. Surg. Pathol. 31, 882–888 (2007).

    Article  Google Scholar 

  4. Hermans, K.G. et al. Two unique novel prostate-specific and androgen-regulated fusion partners of ETV4 in prostate cancer. Cancer Res. 68, 3094–3098 (2008).

    Article  CAS  Google Scholar 

  5. Helgeson, B.E. et al. Characterization of TMPRSS2:ETV4 and SLC45A3:ETV5 gene fusions in prostate cancer. Cancer Res. 68, 73–80 (2008).

    Article  CAS  Google Scholar 

  6. Tomlins, S.A. et al. Role of the TMPRSS2-ERG gene fusion in prostate cancer. Neoplasia 10, 177–188 (2008).

    Article  CAS  Google Scholar 

  7. Tomlins, S.A. et al. Distinct classes of chromosomal rearrangements create oncogenic ETS gene fusions in prostate cancer. Nature 448, 595–601 (2007).

    Article  CAS  Google Scholar 

  8. Mosquera, J.M. et al. Characterization of TMPRSS2-ERG fusion in high-grade prostatic intraepithelial neoplasia and potential clinical implications. Clin. Cancer Res. 14, 3380–3385 (2008).

    Article  CAS  Google Scholar 

  9. Bettendorf, O. et al. Chromosomal imbalances, loss of heterozygousity, and immunohistochemical expression of TP53, RB1, and PTEN in intraductal cancer, intraepithelial neoplasia, and invasive adenocarcinoma of the prostate. Genes Chromosom. Cancer 47, 565–572 (2008).

    Article  CAS  Google Scholar 

  10. Gray, I.C. et al. Mutation and expression analysis of the putative prostate tumour-suppressor gene PTEN. Br. J. Cancer 78, 1296–1300 (1998).

    Article  CAS  Google Scholar 

  11. Whang, Y.E. et al. Inactivation of the tumor suppressor PTEN/MMAC1 in advanced human prostate cancer through loss of expression. Proc. Natl. Acad. Sci. USA 95, 5246–5250 (1998).

    Article  CAS  Google Scholar 

  12. Di Cristofano, A., Pesce, B., Cordon-Cardo, C. & Pandolfi, P.P. Pten is essential for embryonic development and tumour suppression. Nat. Genet. 19, 348–355 (1998).

    Article  CAS  Google Scholar 

  13. Trotman, L.C. et al. Pten dose dictates cancer progression in the prostate. PLoS Biol. 1, 385–396 (2003).

    Article  CAS  Google Scholar 

  14. Chen, Z. et al. Crucial role of p53-dependent cellular senescence in suppression of Pten-deficient tumorigenesis. Nature 436, 725–730 (2005).

    Article  CAS  Google Scholar 

  15. King, J.C. et al. Cooperativity of TMPRSS2-ERG with PI3-kinase pathway activation in prostate oncogenesis. Nat. Genet. advance online publication, doi:10.1038/ng.371 (26 April 2009).

  16. Yoshimoto, M. et al. Absence of TMPRSS2:ERG fusions and PTEN losses in prostate cancer is associated with a favorable outcome. Mod. Pathol. 21, 1451–1460 (2008).

    Article  CAS  Google Scholar 

  17. Arya, M., Ahmed, H., Silhi, N., Williamson, M. & Patel, H.R. Clinical importance and therapeutic implications of the pivotal CXCL12-CXCR4 (chemokine ligand-receptor) interaction in cancer cell migration. Tumour Biol. 28, 123–131 (2007).

    Article  Google Scholar 

  18. Krampert, M. et al. ADAMTS1 proteinase is up-regulated in wounded skin and regulates migration of fibroblasts and endothelial cells. J. Biol. Chem. 280, 23844–23852 (2005).

    Article  CAS  Google Scholar 

  19. Salvucci, O. et al. The role of CXCR4 receptor expression in breast cancer: a large tissue microarray study. Breast Cancer Res. Treat. 97, 275–283 (2006).

    Article  CAS  Google Scholar 

  20. Ratajczak, M.Z. et al. The pleiotropic effects of the SDF-1-CXCR4 axis in organogenesis, regeneration and tumorigenesis. Leukemia 20, 1915–1924 (2006).

    Article  CAS  Google Scholar 

  21. Arya, M. et al. The importance of the CXCL12-CXCR4 chemokine ligand-receptor interaction in prostate cancer metastasis. J. Exp. Ther. Oncol. 4, 291–303 (2004).

    CAS  PubMed  Google Scholar 

  22. Hart, C.A., Brown, M., Bagley, S., Sharrard, M. & Clarke, N.W. Invasive characteristics of human prostatic epithelial cells: understanding the metastatic process. Br. J. Cancer 92, 503–512 (2005).

    Article  CAS  Google Scholar 

  23. Maroni, P., Bendinelli, P., Matteucci, E. & Desiderio, M.A. HGF induces CXCR4 and CXCL12-mediated tumor invasion through Ets1 and NF-kappaB. Carcinogenesis 28, 267–279 (2007).

    Article  CAS  Google Scholar 

  24. Xing, Y. et al. Tumor cell-specific blockade of CXCR4/SDF-1 interactions in prostate cancer cells by hTERT promoter induced CXCR4 knockdown. Cancer Biol. Ther. 7, 1840–1849 (2008).

    Article  Google Scholar 

  25. Leversha, M.A. Mapping of genomic clones by fluorescence in situ hybridization. Methods Mol. Biol. 175, 109–127 (2001).

    CAS  PubMed  Google Scholar 

  26. Strahl-Bolsinger, S., Hecht, A., Luo, K. & Grunstein, M. SIR2 and SIR4 interactions differ in core and extended telomeric heterochromatin in yeast. Genes Dev. 11, 83–93 (1997).

    Article  CAS  Google Scholar 

Download references


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.

Author information

Authors and Affiliations



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.

Corresponding author

Correspondence to Pier Paolo Pandolfi.

Supplementary information

Supplementary Text and Figures

Supplementary Table 1, Supplementary Figures 1 and 2 (PDF 789 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

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).

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:

This article is cited by


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing