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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Gene Expression Omnibus
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.
Extended data figures
This file contains a PDF of extended data figures which show gel source data.