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

DNA double strand breaks (DSB) can lead to development of genomic rearrangements, which are hallmarks of cancer. TMPRSS2-ERG gene fusions in prostate cancer (PCa) are among the most common genomic rearrangements observed in human cancer. We show that androgen signaling promotes co-recruitment of and...

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Detalles Bibliográficos
Autores principales: Haffner, Michael C., Aryee, Martin J., Toubaji, Antoun, Esopi, David M., Albadine, Roula, Gurel, Bora, Isaacs, William B., Bova, G. Steven, Liu, Wennuan, Xu, Jianfeng, Meeker, Alan K., Netto, George, De Marzo, Angelo M., Nelson, William G., Yegnasubramanian, Srinivasan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2010
Materias:
Article
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3157086/
https://www.ncbi.nlm.nih.gov/pubmed/20601956
http://dx.doi.org/10.1038/ng.613
Descripción
Sumario:DNA double strand breaks (DSB) can lead to development of genomic rearrangements, which are hallmarks of cancer. TMPRSS2-ERG gene fusions in prostate cancer (PCa) are among the most common genomic rearrangements observed in human cancer. We show that androgen signaling promotes co-recruitment of androgen receptor (AR) and topoisomerase II beta (TOP2B) to sites of TMPRSS2-ERG genomic breakpoints, triggering recombinogenic TOP2B-mediated DSB. Furthermore, androgen stimulation resulted in de novo production of TMPRSS2-ERG fusion transcripts in a process requiring TOP2B and components of DSB repair machinery. Finally, unlike normal prostate epithelium, prostatic intraepithelial neoplasia (PIN) cells showed strong co-expression of AR and TOP2B. These findings implicate androgen-induced TOP2B-mediated DSB in generating TMPRSS2-ERG rearrangements.

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