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

Nature Genetics volume 42, pages 668–675 (2010)Cite this article

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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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Figure 1: TOP2B is required for efficient induction of androgen receptor target gene expression after androgen stimulation.
Figure 2: Androgen stimulation induced recruitment of androgen receptor–TOP2B and TOP2B catalytic cleavage at known regulatory regions of androgen receptor target genes.
Figure 3: Androgen stimulation induces androgen receptor–TOP2B recruitment and TOP2B catalytic cleavage at genomic breakpoints of TMPRSS2 and ERG observed in human prostate cancer.
Figure 4: Androgen stimulation results in TOP2B-dependent DSB formation.
Figure 5: Androgen-induced TOP2B-mediated DSBs are recombinogenic and promote de novo production of TMPRSS2-ERG fusion genes.
Figure 6: TMPRSS2-ERG rearrangements are observed in PIN prostate cancer precursor lesions and are associated with changes in TOP2B expression.
Figure 7: Proposed model for androgen-induced TOP2B-mediated double strand breaks and TOP2B instability (TIN) for the formation of TMPRSS2-ERG gene fusions.

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  • 18 July 2010

    In the version of this article initially published online, there were four sentences (in the Results on pages 2 and 3, in the legend to Figure 3 and in the Online Methods) containing minor errors. These errors have been corrected for the print, PDF and HTML versions of this article.

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Acknowledgements

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.

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Author notes

  1. Martin J Aryee and Antoun Toubaji: These authors contributed equally to this work.

Authors and Affiliations

  1. Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, USA

    Michael C Haffner, Martin J Aryee, David M Esopi, William B Isaacs, Alan K Meeker, George Netto, Angelo M De Marzo, William G Nelson & Srinivasan Yegnasubramanian

  2. Department of Biostatistics, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland, USA

    Martin J Aryee

  3. Department of Pathology, Johns Hopkins University, Baltimore, Maryland, USA

    Antoun Toubaji, Roula Albadine, Bora Gurel, G Steven Bova, Alan K Meeker, George Netto, Angelo M De Marzo & William G Nelson

  4. Brady Urological Institute, School of Medicine, Johns Hopkins University, Baltimore, Maryland, USA

    William B Isaacs, Alan K Meeker, George Netto, Angelo M De Marzo & William G Nelson

  5. Center for Cancer Genomics, Wake Forest University Health Sciences, Winston-Salem, North Carolina, USA

    Wennuan Liu & Jianfeng Xu

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Contributions

M.C.H. executed and analyzed all experiments and assisted in writing the manuscript. M.J.A. analyzed microarray data and assisted with statistical analysis of data. A.T., R.A., B.G., A.K.M., G.N. and A.M.D.M. assisted with execution and analysis of FISH, immunostaining and pathology experiments. D.M.E. assisted with execution of experiments. W.B.I., G.S.B., W.L. and J.X. contributed to analysis of microarray data in determination of prostate cancer TMPRSS2-ERG genomic breakpoints. W.G.N. assisted in experimental design and analysis and contributed to writing the manuscript. S.Y. conceived the study together with W.G.N., assisted in experimental design, execution and analysis and wrote the manuscript. All authors assisted in editing the manuscript.

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Correspondence to William G Nelson or Srinivasan Yegnasubramanian.

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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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