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

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

doi:10.1038/ng.613

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

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

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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.

Original language	English (US)
Pages (from-to)	668-675
Number of pages	8
Journal	Nature genetics
Volume	42
Issue number	8
DOIs	https://doi.org/10.1038/ng.613
State	Published - Aug 2010

ASJC Scopus subject areas

Genetics

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Haffner, M. C., Aryee, M. J., Toubaji, A., Esopi, D. M., Albadine, R., Gurel, B., Isaacs, W. B., Bova, G. S., Liu, W., Xu, J., Meeker, A. K., Netto, G., De Marzo, A. M., Nelson, W. G., & Yegnasubramanian, S. (2010). Androgen-induced TOP2B-mediated double-strand breaks and prostate cancer gene rearrangements. Nature genetics, 42(8), 668-675. https://doi.org/10.1038/ng.613

@article{c4affff017244546928222ddabf9fb0f,

title = "Androgen-induced TOP2B-mediated double-strand breaks and prostate cancer gene rearrangements",

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.",

author = "Haffner, {Michael C.} and Aryee, {Martin J.} and Antoun Toubaji and Esopi, {David M.} and Roula Albadine and Bora Gurel and Isaacs, {William B.} and Bova, {G. Steven} and Wennuan Liu and Jianfeng Xu and Meeker, {Alan K.} and George Netto and {De Marzo}, {Angelo M.} and Nelson, {William G.} and Srinivasan Yegnasubramanian",

note = "Funding Information: 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.",

year = "2010",

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doi = "10.1038/ng.613",

language = "English (US)",

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AU - Haffner, Michael C.

AU - Aryee, Martin J.

AU - Toubaji, Antoun

AU - Esopi, David M.

AU - Albadine, Roula

AU - Gurel, Bora

AU - Isaacs, William B.

AU - Bova, G. Steven

AU - Liu, Wennuan

AU - Xu, Jianfeng

AU - Meeker, Alan K.

AU - Netto, George

AU - De Marzo, Angelo M.

AU - Nelson, William G.

AU - Yegnasubramanian, Srinivasan

N1 - Funding Information: 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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N2 - 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.

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

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