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

Abstract

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.

ERG immunohistochemistry is not predictive for PSA recurrence, local recurrence or overall survival after radical prostatectomy for prostate cancer

“…Such a mechanism was proposed because androgen receptor signaling induced TOP2B-mediated double-strands DNA breaks with de novo TMPRSS2-ERG fusion in LAPC4 and LNCaP cells. 33 On the other hand, ERG inhibits androgen receptor signaling by reducing receptor expression and activity, together with the induction of repressive epigenetic programs. 13 In this study, we investigated the relationship between the ERG and androgen receptor pathways as reflected by the respective protein expression in clinical specimens.…”

Exploiting AR-Regulated Drug Transport to Induce Sensitivity to the Survivin Inhibitor YM155

“…AR is also a licensing factor for DNA replication and excessive androgens prevents AR-cycling and re-licensing resulting in cell-cycle block(22,23). Additionally, AR can recruit TOP2B to sites of active transcription resulting in double strand DNA breaks(24). …”

Creative damage unleashes transcription

“…Transcription has been associated with the accumulation of DNA damage and tissues with high transcriptional rates such as growing tumors are at risk for increased levels of mutation. 1 In addition, some proteins involved in repair of DNA damage appear to play key parts in transcription. These include, factors involved in base excision repair, nucleotide excision repair, mismatch repair and recombination repair.…”

“…Inducible gene transcription has been shown to be accompanied by the generation of DNA double strand breaks (DSB) in cells activated by agents as diverse as heat shock, growth serum, androgens, neuronal activation or estrogens. 1,[4][5][6][7] Increased DSB have been detected directly in transcribing cells, as well as indirectly by the Comet assay and by incorporation into chromatin of the histone gH2Ax, a surrogate marker of DNA damage. [5][6][7] Indeed direct generation of DSB in the promoters of the EGR1 and NPAS4 genes, using a CRISPR-CAS approach, was sufficient to drive transcription even in the absence of external stimuli.…”