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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We thank D. Coffey for helpful comments and C. Heaphy, H. Zhang and L. Dasko-Vincent from the SKCCC Cell Imaging Core Facility for technical support. We also thank the Brady Urological Research Institute Prostate Specimen Repository for providing TMA sections. This work was supported by funding from the NIH/NCI, Department of Defense PCRP, Prostate Cancer Foundation, Maryland Cigarette Restitution Fund and the Patrick C. Walsh Prostate Cancer Research Fund/Dr. and Mrs. Peter S. Bing Scholarship.
The authors declare no competing financial interests.
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Haffner, M., Aryee, M., Toubaji, A. et al. Androgen-induced TOP2B-mediated double-strand breaks and prostate cancer gene rearrangements. Nat Genet 42, 668–675 (2010). https://doi.org/10.1038/ng.613
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