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

Michael C Haffner1, Martin J Aryee, Antoun Toubaji

  • 1Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, USA.

Nature Genetics
|July 6, 2010
PubMed

Insights

Androgen signaling drives TMPRSS2-ERG gene fusions, common in cancer, by promoting DNA double-strand breaks (DSBs) via topoisomerase II beta (TOP2B). This mechanism is crucial for generating these oncogenic rearrangements.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Genomic rearrangements, particularly gene fusions, are critical drivers of cancer development.
  • The TMPRSS2-ERG fusion is a prevalent oncogenic rearrangement in human cancers, especially prostate cancer.
  • Androgen signaling plays a significant role in prostate cancer pathogenesis.

Purpose of the Study:

  • To elucidate the molecular mechanisms by which androgen signaling contributes to the formation of TMPRSS2-ERG gene fusions.
  • To investigate the role of topoisomerase II beta (TOP2B) in mediating DNA double-strand breaks (DSBs) at TMPRSS2-ERG breakpoints.
  • To examine the expression patterns of androgen receptor and TOP2B in normal and pre-cancerous prostate tissues.

Main Methods:

  • Investigated the co-recruitment of androgen receptor and TOP2B to TMPRSS2-ERG genomic breakpoints under androgen stimulation.
  • Assessed the induction of TMPRSS2-ERG fusion transcripts following androgen stimulation.
  • Utilized techniques to evaluate the requirement of TOP2B and DNA double-strand break repair machinery in fusion transcript production.
  • Compared the coexpression of androgen receptor and TOP2B in normal prostate epithelium versus prostatic intraepithelial neoplasia (PIN) cells.

Main Results:

  • Androgen signaling promotes the co-recruitment of androgen receptor and TOP2B to TMPRSS2-ERG breakpoints.
  • This co-recruitment triggers TOP2B-mediated DNA double-strand breaks (DSBs) at these specific genomic locations.
  • Androgen stimulation leads to the de novo production of TMPRSS2-ERG fusion transcripts, dependent on TOP2B and DSB repair pathways.
  • Prostatic intraepithelial neoplasia (PIN) cells exhibit strong coexpression of androgen receptor and TOP2B, unlike normal prostate epithelium.

Conclusions:

  • Androgen-induced DNA double-strand breaks mediated by TOP2B are implicated in the generation of TMPRSS2-ERG rearrangements.
  • The findings highlight a novel mechanism linking hormonal signaling to oncogenic genomic instability.
  • Targeting the androgen-TOP2B interaction or DSB repair pathways may offer therapeutic strategies for cancers driven by TMPRSS2-ERG fusions.

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