Androgen-induced TOP2B-mediated Double-strand Breaks and Prostate Cancer Gene Rearrangements

Overview

Journal Nat Genet

Specialty Genetics

Date 2010 Jul 6

PMID 20601956

Citations 337

Authors

Michael C Haffner

Martin J Aryee

Antoun Toubaji

David M Esopi

Roula Albadine

Bora Gurel

William B Isaacs

G Steven Bova

Wennuan Liu

Jianfeng Xu

Alan K Meeker

George Netto

Angelo M De Marzo

William G Nelson

Srinivasan Yegnasubramanian

Affiliations

Soon will be listed here.

Abstract

DNA double-strand breaks (DSBs) can lead to the development of genomic rearrangements, which are hallmarks of cancer. Fusions between TMPRSS2, encoding the transmembrane serine protease isoform 2, and ERG, encoding the v-ets erythroblastosis virus E26 oncogene homolog, are among the most common oncogenic rearrangements observed in human cancer. We show that androgen signaling promotes co-recruitment of androgen receptor and topoisomerase II beta (TOP2B) to sites of TMPRSS2-ERG genomic breakpoints, triggering recombinogenic TOP2B-mediated DSBs. Furthermore, androgen stimulation resulted in de novo production of TMPRSS2-ERG fusion transcripts in a process that required TOP2B and components of the DSB repair machinery. Finally, unlike normal prostate epithelium, prostatic intraepithelial neoplasia cells showed strong coexpression of androgen receptor and TOP2B. These findings implicate androgen-induced TOP2B-mediated DSBs in generating TMPRSS2-ERG rearrangements.

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