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

被引：470

作者：

Haffner, Michael C. ^{[1
]}

Aryee, Martin J. ^{[1
,2
]}

Toubaji, Antoun ^{[3
]}

Esopi, David M. ^{[1
]}

Albadine, Roula ^{[3
]}

Gurel, Bora ^{[3
]}

Isaacs, William B. ^{[4
]}

Bova, G. Steven ^{[3
]}

Liu, Wennuan ^{[5
]}

Xu, Jianfeng ^{[5
]}

Meeker, Alan K. ^{[1
,3
,4
]}

Netto, George ^{[1
,3
,4
]}

De Marzo, Angelo M. ^{[1
,3
,4
]}

Nelson, William G. ^{[1
,3
,4
]}

Yegnasubramanian, Srinivasan ^{[1
]}

机构：

[1] Johns Hopkins Univ, Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD 21218 USA

[2] Johns Hopkins Univ, Dept Biostat, Bloomberg Sch Publ Hlth, Baltimore, MD 21205 USA

[3] Johns Hopkins Univ, Dept Pathol, Baltimore, MD 21205 USA

[4] Johns Hopkins Univ, Sch Med, James Buchanan Brady Urol Inst, Baltimore, MD 21205 USA

[5] Wake Forest Univ Hlth Sci, Ctr Canc Genom, Winston Salem, NC USA

来源：

NATURE GENETICS | 2010年 / 42卷 / 08期

关键词：

DNA-TOPOISOMERASE-II; CHROMOSOMAL TRANSLOCATIONS; RECEPTOR; FUSION; PROGRESSION; ERG; CHEMOTHERAPY; TMPRSS2-ERG; ABERRATIONS; ACTIVATION;

D O I：

10.1038/ng.613

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

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.

引用

页码：668 / U45

页数：10

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