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ETS factors reprogram the androgen receptor cistrome and prime prostate tumorigenesis in response to PTEN loss

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Abstract

Studies of ETS-mediated prostate oncogenesis have been hampered by a lack of suitable experimental systems. Here we describe a new conditional mouse model that shows robust, homogenous ERG expression throughout the prostate. When combined with homozygous Pten loss, the mice developed accelerated, highly penetrant invasive prostate cancer. In mouse prostate tissue, ERG markedly increased androgen receptor (AR) binding. Robust ERG-mediated transcriptional changes, observed only in the setting of Pten loss, included the restoration of AR transcriptional output and upregulation of genes involved in cell death, migration, inflammation and angiogenesis. Similarly, ETS variant 1 (ETV1) positively regulated the AR cistrome and transcriptional output in ETV1-translocated, PTEN-deficient human prostate cancer cells. In two large clinical cohorts, expression of ERG and ETV1 correlated with higher AR transcriptional output in PTEN-deficient prostate cancer specimens. We propose that ETS factors cause prostate-specific transformation by altering the AR cistrome, priming the prostate epithelium to respond to aberrant upstream signals such as PTEN loss.

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Figure 1: ERG expression induces a minimal histological phenotype in mouse prostates.
Figure 2: ERG robustly cooperates with Pten loss in prostate tumorigenesis.
Figure 3: ERG localizes to predefined H3K4me1-marked regions and reprograms genome-wide localization of AR.
Figure 4: ERG expression primes prostate to respond to Pten loss.
Figure 5: ERG increases AR signaling in prostate cancer with Pten loss.
Figure 6: ETV1 alters the AR cistrome and the AR-dependent transcriptome in LNCaP cells.

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Gene Expression Omnibus

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Acknowledgements

We thank the MSKCC Gene Targeting (C. Yang), Mouse Genetics Core (W. Mark and P. Romanienko), Genomics Core Laboratory (A. Viale), Molecular Cytogenetics (M. Leversha) and Molecular Cytology (K. Manova) core facilities and the Rockefeller University Genomics Core (S. Dewell). This work is supported in part by the Howard Hughes Medical Institute (C.L.S.), the US National Cancer Institute (K08CA140946, Y.C.; 1K08CA151660-01A1, P.C.; U01 CA141502, C.L.S.; and P50CA092629, C.L.S. and B.S.C.), the US Department of Defense (W81XWH-10-1-0197, Y.C.), the Prostate Cancer Foundation (Y.C. and B.S.C.), the Starr Cancer Consortium (Y.C., P.C., C.L.S. and D.Z.) and the US National Institute of Mental Health (R21MH099452, D.Z.). We thank J.P. Martinez-Barbera (University College London) for plasmids, C.D. Allis, F. Giancotti and J. Otero for conceptual input, N. Schultz for bioinformatics assistance and A. Gopalan and S. Couto for pathology input.

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Authors

Contributions

Y.C. and C.L.S. conceived of the project. Y.C. performed the mouse experiments with technical support from J.W., T.S. and D.G. P.C. performed expression profiling and ChIP-seq with technical support from S.S. and I.S. S.R. and D.Z. performed bioinformatics analysis. P.J.I. performed the LNCaP ETV1 knockdown experiments. B.S.C. and H.I.S. provided major intellectual input for the initial project design and further troubleshooting. Y.C., P.C. and C.L.S. wrote the manuscript.

Corresponding authors

Correspondence to Yu Chen or Charles L Sawyers.

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The authors declare no competing financial interests.

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Chen, Y., Chi, P., Rockowitz, S. et al. ETS factors reprogram the androgen receptor cistrome and prime prostate tumorigenesis in response to PTEN loss. Nat Med 19, 1023–1029 (2013). https://doi.org/10.1038/nm.3216

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