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

By Michael C. Haffner, Martin J. Aryee, A. Toubaji, David Esopi, R. Albadine, B. Gurel, William B. Isaacs, G. Steven Bova, Wennuan Liu, Jianfeng Xu and 6 more. Nature Genetics, 2010

594 citations recorded by the source corpus.

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.

Subfields: Cancer Research, Molecular Biology, Pulmonary and Respiratory Medicine

View Paper: https://www.semanticscholar.org/paper/0dd31304644457c70de606ed2d900a76a4c3c6ca

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Molecular Biology

1. C. Abate-Shen
2. M. Shen

Citations in the corpus

• Activity-Induced DNA Breaks Govern the Expression of Neuronal Early-Response Genes (2015, unknown): “Interestingly, androgen signaling was previously shown to induce Topo IIb-mediated DSBs that results in oncogenic rearrangements observed in human prostate cancer (Haffner et al., 2010).”
• Molecular genetics of prostate cancer: new prospects for old challenges. (2010, background): “In addition, androgen signaling can recruit topoisomerase II to AR-binding sites, leading to induction of double-stranded breaks even in the absence of genotoxic stress (Haffner et al. 2010).”
• Punctuated Evolution of Prostate Cancer Genomes (2013, unknown): “Given that fusion of TMPRSS2 and ERG occurs in the setting of androgen receptor-driven transcription (Haffner et al., 2010), the intricate chains in ETS tumors could reflect DNA injury at transcriptional hubs occupied by loci from multiple chromosomes.”