Abstract

Half of all prostate cancers are caused by the TMPRSS2–ERG gene-fusion, which enables androgens to drive expression of the normally silent E26 transformation-specific (ETS) transcription factor ERG in prostate cells1,2. Recent genomic landscape studies of such cancers3,4,5,6,7,8 have reported recurrent point mutations and focal deletions of another ETS member, the ETS2 repressor factor ERF9. Here we show these ERF mutations cause decreased protein stability and mostly occur in tumours without ERG upregulation. ERF loss recapitulates the morphological and phenotypic features of ERG gain in normal mouse prostate cells, including expansion of the androgen receptor transcriptional repertoire, and ERF has tumour suppressor activity in the same genetic background of Pten loss that yields oncogenic activity by ERG. In the more common scenario of ERG upregulation, chromatin immunoprecipitation followed by sequencing indicates that ERG inhibits the ability of ERF to bind DNA at consensus ETS sites both in normal and in cancerous prostate cells. Consistent with a competition model, ERF overexpression blocks ERG-dependent tumour growth, and ERF loss rescues TMPRSS2–ERG-positive prostate cancer cells from ERG dependency. Collectively, these data provide evidence that the oncogenicity of ERG is mediated, in part, by competition with ERF and they raise the larger question of whether other gain-of-function oncogenic transcription factors might also inactivate endogenous tumour suppressors.

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Acknowledgements

We thank A. Heguy, H. Hieronymous, J. Li, Y. Liang, E. Peguero, M. Pirun, N. Socci, P. Watson, A. Viale, Y. Zhang, Memorial Sloan Kettering Cancer Center core facilities, and the members of the Sawyers laboratory for comments. R.B. was supported by an American Society of Clinical Oncology (ASCO) Young Investigator Award, a Department of Defense Physician Training Award, and a Prostate Cancer Foundation Young Investigator Award. W.A. was supported by an ASCO Young Investigator Award and Prostate Cancer Foundation Young Investigator Award. M.G.D. was supported by a Howard Hughes Medical Institute (HHMI) Summer Medical Fellowship. N.Sch. is supported by the Prostate Cancer Foundation. C.L.S. is an investigator of the HHMI and this project was supported by National Institutes of Health grants CA155169, CA19387, CA092629, and CA008748.

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Affiliations

  1. Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, New York 10065, USA

    • Rohit Bose
    • , Wouter R. Karthaus
    • , Joshua Armenia
    • , Phillip J. Iaquinta
    • , Zeda Zhang
    • , John Wongvipat
    • , Elizabeth V. Wasmuth
    • , Neel Shah
    • , Patrick S. Sullivan
    • , Michael G. Doran
    • , Nikolaus Schultz
    •  & Charles L. Sawyers
  2. Department of Medicine, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, New York 10065, USA

    • Rohit Bose
    • , Wassim Abida
    •  & Anna Patruno
  3. Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, New York 10065, USA

    • Joshua Armenia
    • , Philip Kantoff
    •  & Nikolaus Schultz
  4. Louis V. Gerstner, Jr. Graduate School of Biomedical Sciences, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA

    • Zeda Zhang
    •  & Neel Shah
  5. Department of Genetics, Albert Einstein College of Medicine, Bronx, New York 10461, USA

    • Ping Wang
    • , Yilin Zhao
    •  & Deyou Zheng
  6. Department of Neurology, Albert Einstein College of Medicine, Bronx, New York 10461, USA

    • Deyou Zheng
  7. Department of Neuroscience, Albert Einstein College of Medicine, Bronx, New York 10461, USA

    • Deyou Zheng
  8. Howard Hughes Medical Institute, Chevy Chase, Maryland 20185, USA

    • Charles L. Sawyers
  9. Michigan Center for Translational Pathology, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA

    • Dan Robinson
    • , Yi-Mi Wu
    • , Robert J. Lonigro
    • , Xuhong Cao
    • , Pankaj Vats
    • , Lakshmi P. Kunju
    • , Scott A. Tomlins
    • , Christine Brennan
    • , Javed Siddiqui
    • , Rohit Mehra
    • , Yu Chen
    •  & Arul M. Chinnaiyan
  10. Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA

    • Dan Robinson
    • , Yi-Mi Wu
    • , Lakshmi P. Kunju
    • , Scott A. Tomlins
    • , Rohit Mehra
    •  & Arul M. Chinnaiyan
  11. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA

    • Eliezer M. Van Allen
    • , Mary-Ellen Taplin
    • , Massimo Loda
    • , Rosina T. Lis
    • , Michaela Bowden
    •  & Levi A. Garraway
  12. Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, Massachusetts 02142, USA

    • Eliezer M. Van Allen
    • , Massimo Loda
    • , Carrie Sougnez
    • , Manaswi Gupta
    •  & Levi A. Garraway
  13. Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA

    • Nikolaus Schultz
  14. Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA

    • Nikolaus Schultz
    •  & Jianjiong Gao
  15. Department of Pathology and Laboratory Medicine, Weill Medical College of Cornell University, New York, New York 10021, USA

    • Juan-Miguel Mosquera
    • , Brian D. Robinson
    • , Marc Schiffman
    • , Andrea Sboner
    •  & Mark A. Rubin
  16. Institute for Precision Medicine, Weill Medical College of Cornell University, New York, New York 10021, USA

    • Juan-Miguel Mosquera
    • , Himisha Beltran
    • , Francesca Demichelis
    • , Brian D. Robinson
    • , David M. Nanus
    • , Scott T. Tagawa
    • , Alexandros Sigaras
    • , Kenneth W. Eng
    • , Andrea Sboner
    •  & Mark A. Rubin
  17. New York Presbyterian Hospital, New York, New York 10021, USA

    • Juan-Miguel Mosquera
    • , Himisha Beltran
    • , Brian D. Robinson
    • , David M. Nanus
    • , Scott T. Tagawa
    •  & Mark A. Rubin
  18. Meyer Cancer, Weill Medical College of Cornell University, New York, New York 10021, USA

    • Juan-Miguel Mosquera
    • , Himisha Beltran
    • , Brian D. Robinson
    • , Marc Schiffman
    • , David M. Nanus
    • , Scott T. Tagawa
    • , Andrea Sboner
    • , Mark A. Rubin
    •  & Peter S. Nelson
  19. Computational Biology Program, Public Health Sciences Division and Basic Science Division, Fred Hutchinson Cancer Center, University of Washington, Seattle, Washington 98109, USA

    • Bruce Montgomery
    • , Robert K. Bradley
    • , Elahe A. Mostaghel
    • , Heather H. Cheng
    •  & Heidi Dvinge
  20. Department of Medicine, University of Washington, Seattle, Washington 98109, USA

    • Bruce Montgomery
    • , Evan Y. Yu
    • , Elahe A. Mostaghel
    • , Heather H. Cheng
    • , Stephen R. Plymate
    •  & Peter S. Nelson
  21. Veterans Affairs Puget Sound Health Care System, University of Washington, Seattle, Washington 98109, USA

    • Bruce Montgomery
    • , Evan Y. Yu
    • , Elahe A. Mostaghel
    • , Heather H. Cheng
    • , Stephen R. Plymate
    •  & Peter S. Nelson
  22. Department of Laboratory Medicine, University of Washington, Seattle, Washington 98195, USA

    • Colin C. Pritchard
  23. The Royal Marsden, Downs Road, Sutton SM2 5PT, UK

    • Gerhardt Attard
    • , Roberta Ferraldeschi
    • , Penny Flohr
    • , Susana Miranda
    • , Zafeiris Zafeiriou
    • , Nina Tunariu
    • , Joaquin Mateo
    • , Raquel Perez-Lopez
    •  & Johann S. de Bono
  24. The Institute of Cancer Research, Downs Road, Sutton SM2 5PT, UK

    • Gerhardt Attard
    • , Roberta Ferraldeschi
    • , Penny Flohr
    • , Susana Miranda
    • , Zafeiris Zafeiriou
    • , Nina Tunariu
    • , Joaquin Mateo
    • , Raquel Perez-Lopez
    •  & Johann S. de Bono
  25. Department of Medicine, Weill Medical College of Cornell University, New York, New York 10021, USA

    • Himisha Beltran
    • , Yu Chen
    • , Dana E. Rathkopf
    • , Michael J. Morris
    • , David M. Nanus
    • , Scott T. Tagawa
    •  & Howard I. Scher
  26. Genitourinary Oncology Service, Department of Medicine, Sidney Kimmel Center for Prostate and Urologic Cancers, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA

    • Wassim Abida
    • , Yu Chen
    • , Dana E. Rathkopf
    • , Michael J. Morris
    •  & Howard I. Scher
  27. Prostate Cancer Clinical Trials Consortium, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA

    • Jake Vinson
  28. Howard Hughes Medical Institute, University of Michigan, Ann Arbor, Michigan 48109, USA

    • Xuhong Cao
    •  & Arul M. Chinnaiyan
  29. Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA

    • Lakshmi P. Kunju
    • , Maha Hussain
    • , Scott A. Tomlins
    • , Kathleen A. Cooney
    • , David C. Smith
    •  & Arul M. Chinnaiyan
  30. Department of Internal Medicine, Division of Hematology Oncology, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA

    • Maha Hussain
    • , Kathleen A. Cooney
    •  & David C. Smith
  31. Department of Urology, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA

    • Maha Hussain
    • , Scott A. Tomlins
    • , Kathleen A. Cooney
    • , David C. Smith
    •  & Arul M. Chinnaiyan
  32. Interventional Radiology, Department of Radiology Service, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA

    • Stephen B. Solomon
    •  & Jeremy C. Durack
  33. Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA

    • Victor E. Reuter
    •  & Anuradha Gopalan
  34. Center for Molecular Oncologic Pathology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA

    • Massimo Loda
    • , Rosina T. Lis
    •  & Michaela Bowden
  35. Department of Pathology, Brigham & Women’s Hospital, Boston, Massachusetts 02115, USA

    • Massimo Loda
    •  & Michaela Bowden
  36. Division of Hematology-Oncology, Department of Medicine, Beth Israel Deaconess Cancer Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA

    • Stephen P. Balk
  37. Department of Musculoskeletal Radiology, Brigham and Women’s Hospital, Boston, Massachusetts 02115, USA

    • Glenn Gaviola
  38. Department of Radiology, University of Washington, Seattle, Washington 98109, USA

    • Hyojeong Mulcahy
  39. Department of Pathology, University of Washington Medical Center, Seattle, Washington 98109, USA

    • Lawrence D. True
  40. Laboratory of Computational Oncology, CIBIO, Centre for Integrative Biology, University of Trento, 38123 Mattarello TN, Italy

    • Francesca Demichelis
  41. Division of Interventional Radiology, Department of Radiology, New York-Presbyterian Hospital/Weill Cornell Medical Center, New York, New York 10021, USA

    • Marc Schiffman
  42. Institute for Computational Biomedicine, Department of Physiology and Biophysics, Weill Medical College of Cornell University, New York, New York 10021, USA

    • Alexandros Sigaras
    • , Kenneth W. Eng
    • , Olivier Elemento
    •  & Andrea Sboner
  43. Department of Physiology & Biophysics, Weill Medical College of Cornell University, New York, New York 10021, USA

    • Alexandros Sigaras
    •  & Kenneth W. Eng
  44. Department of Oncology, Wayne State University School of Medicine, Detroit, Michigan 48201, USA

    • Elisabeth I. Heath
  45. Molecular Therapeutics Program, Barbara Ann Karmanos Cancer Institute, Detroit, Michigan 48201, USA

    • Elisabeth I. Heath
  46. The James Buchanan Brady Urological Institute and Department of Urology, Johns Hopkins School of Medicine, Baltimore, Maryland 21205, USA

    • Kenneth J. Pienta
  47. Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA

    • Peter S. Nelson
  48. Division of Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA

    • Peter S. Nelson
  49. Howard Hughes Medical Institute, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA

    • Charles L. Sawyers

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Contributions

R.B. and C.L.S. conceived and oversaw the project, performed data interpretation, and co-wrote the manuscript. R.B., E.V.W., W.A., Z.Z., and P.S.S. performed immunoblots, R.B. and P.S.S. performed RNA analysis, W.R.K., P.J.I. and R.B. performed immunohistochemistry, J.W. performed the mouse grafting, R.B. and A.P. prepared experiments for ChIP–seq, and R.B. performed in vitro cell growth assays. W.R.K. made three-dimensional organoid cultures, E.V.W. made bacterially expressed proteins, and R.B., W.R.K., W.A., E.V.W., P.J.I., and M.G.D. cloned plasmid reagents. E.V.W. performed ETS stability analysis, J.A., N.Sch., and R.B. performed analysis of human prostate cancer cohorts, N.Sh. performed gene set enrichment analysis (GSEA), and P.W., Y.Z., and D.Z. performed ChIP–seq analysis. All individual authors made intellectual contributions and reviewed the manuscript. The International SU2C/PCF Cancer Dream provided four unpublished ERF point mutations. The International SU2C-PCF Dream Team is led by A.M.C. and C.L.S.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Charles L. Sawyers.

Reviewer Information Nature thanks J. Carroll, T. Sato, L. Trotman and the other anonymous reviewer(s) for their contribution to the peer review of this work.

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