Androgen-induced TOP2B-mediated double-strand breaks and prostate cancer gene rearrangements

• DOI: 10.1038/ng.613
• Publication Date: 2010-07-04T18:24:00Z
• 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 Yegnas...
• Keywords: Gene Rearrangement; Male; 0303 health sciences; Serine Endopeptidases; Prostatic Neoplasms; Oncogenes; Article; 3. Good health; DNA-Binding Proteins; 03 medical and health sciences; DNA Topoisomerases, Type II; Receptors, Androgen; Androgens; Humans; Poly-ADP-Ribose Binding Proteins; Signal Transduction

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.