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Cancer Cell. 2011 May 17;19(5):664-78. doi: 10.1016/j.ccr.2011.04.010.

Mechanistic rationale for inhibition of poly(ADP-ribose) polymerase in ETS gene fusion-positive prostate cancer.

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  • 1Michigan Center for Translational Pathology, University of Michigan, 1400 E. Medical Center Drive, 5316 CCGC, Ann Arbor, MI 48109, USA.

Erratum in

  • Cancer Cell. 2013 Apr 15;23(4):557.

Abstract

Recurrent fusions of ETS genes are considered driving mutations in a diverse array of cancers, including Ewing's sarcoma, acute myeloid leukemia, and prostate cancer. We investigate the mechanisms by which ETS fusions mediate their effects, and find that the product of the predominant ETS gene fusion, TMPRSS2:ERG, interacts in a DNA-independent manner with the enzyme poly (ADP-ribose) polymerase 1 (PARP1) and the catalytic subunit of DNA protein kinase (DNA-PKcs). ETS gene-mediated transcription and cell invasion require PARP1 and DNA-PKcs expression and activity. Importantly, pharmacological inhibition of PARP1 inhibits ETS-positive, but not ETS-negative, prostate cancer xenograft growth. Finally, overexpression of the TMPRSS2:ERG fusion induces DNA damage, which is potentiated by PARP1 inhibition in a manner similar to that of BRCA1/2 deficiency.

Copyright © 2011 Elsevier Inc. All rights reserved.

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PMID:
21575865
[PubMed - indexed for MEDLINE]
PMCID:
PMC3113473
Free PMC Article

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