Androgen-induced TOP2B-mediated double-strand breaks and prostate cancer gene rearrangements.
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.
Haffner
Michael C
MC
Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, USA.
Aryee
Martin J
MJ
Toubaji
Antoun
A
Esopi
David M
DM
Albadine
Roula
R
Gurel
Bora
B
Isaacs
William B
WB
Bova
G Steven
GS
Liu
Wennuan
W
Xu
Jianfeng
J
Meeker
Alan K
AK
Netto
George
G
De Marzo
Angelo M
AM
Nelson
William G
WG
Yegnasubramanian
Srinivasan
S
D000728:Androgens / Q000235:genetics; D004250:DNA Topoisomerases, Type II / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics*; D015321:Gene Rearrangement; D006801:Humans; D008297:Male; D009857:Oncogenes; D000075223:Poly-ADP-Ribose Binding Proteins; D011471:Prostatic Neoplasms / Q000235:genetics*; D011944:Receptors, Androgen / Q000235:genetics; D012697:Serine Endopeptidases / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics
C410798:AR protein, human; D000728:Androgens; D004268:DNA-Binding Proteins; D000075223:Poly-ADP-Ribose Binding Proteins; D011944:Receptors, Androgen; D012697:Serine Endopeptidases; D004250:DNA Topoisomerases, Type II; C000618814:TOP2B protein, human