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

Yu Chen, Ping Chi, Shira Rockowitz, Phillip J. Iaquinta, Tambudzai Shamu, Shipra Shukla, Dong Gao, Inna Sirota, Brett S. Carver, John Wongvipat, Howard I. Scher, Deyou Zheng, Charles L. Sawyers

Research output: Contribution to journalArticle

166 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1023-1029
Number of pages7
JournalNature Medicine
Volume19
Issue number8
DOIs
StatePublished - Aug 2013

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Chen, Y., Chi, P., Rockowitz, S., Iaquinta, P. J., Shamu, T., Shukla, S., Gao, D., Sirota, I., Carver, B. S., Wongvipat, J., Scher, H. I., Zheng, D., & Sawyers, C. L. (2013). ETS factors reprogram the androgen receptor cistrome and prime prostate tumorigenesis in response to PTEN loss. Nature Medicine, 19(8), 1023-1029. https://doi.org/10.1038/nm.3216