Elsevier

Neoplasia

Volume 12, Issue 12, December 2010, Pages 1031-1040, IN18-IN22
Neoplasia

ERG Cooperates with Androgen Receptor in Regulating Trefoil Factor 3 in Prostate Cancer Disease Progression1,2,3

https://doi.org/10.1593/neo.10866Get rights and content
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open access

Abstract

To elucidate the role of ETS gene fusions in castration-resistant prostate cancer (CRPC), we characterized the transcriptome of 54 CRPC tumor samples from men with locally advanced or metastatic disease. Trefoil factor 3 (TFF3) emerged as the most highly differentially regulated gene with respect to ERG rearrangement status and resistance to hormone ablation therapy. Conventional chromatin immunoprecipitation (ChIP)-polymerase chain reaction and ChIP followed by DNA sequencing (ChIP-seq) revealed direct binding of ERG to ETS binding sites in the TFF3 promoter in ERG-rearranged prostate cancer cell lines. These results were confirmed in ERG-rearranged hormone-naive prostate cancer (HNPC) and CRPC tissue samples. Functional studies demonstrated that ERG has an inhibitory effect on TFF3 expression in hormone-naive cancer but not in the castration-resistant state. In addition, we provide evidence suggesting an effect of androgen receptor signaling on ERG-regulated TFF3 expression. Furthermore, TFF3 overexpression enhances ERG-mediated cell invasion in CRPC prostate cancer cells. Taken together, our findings reveal a novel mechanism for enhanced tumor cell aggressiveness resulting from ERG rearrangement in the castration-resistant setting through TFF3 gene expression.

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1

This study was funded by the Department of Defense New Investigator Award PC081337 (D.S.R.), the National Cancer Institute R01 CA125612-01 (F.D. and M.A.R.), the Prostate Cancer Canada, and The Young Investigator Award of the Prostate Cancer Foundation, USA (T.A.B.).

2

S. Perner, A. M. Chinnaiyan, M. A. Rubin, and F. Demichelis are coinventors on a patent filed by The University of Michigan and The Brigham and Women's Hospital covering the diagnostic and therapeutic fields for ETS fusions in prostate cancer. The diagnostic field has been licensed to Gen-Probe, Inc.

3

This article refers to supplementary materials, which are designated by Tables W1 and W2 and Figures W1 to W3 and are available online at www.neoplasia.com.

4

These authors equally contributed to this study.

5

These authors share the senior authorship.