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Nat Genet. 2017 Sep;49(9):1336-1345. doi: 10.1038/ng.3930. Epub 2017 Aug 7.

TMPRSS2-ERG fusion co-opts master transcription factors and activates NOTCH signaling in primary prostate cancer.

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Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
Ontario Institute for Cancer Research, Toronto, Ontario, Canada.
Department of Pathology and Laboratory Medicine, Toronto General Hospital, University Health Network, Toronto, Ontario, Canada.
Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada.
Department of Radiation Oncology, University of Toronto, Toronto, Ontario, Canada.


TMPRSS2-ERG (T2E) structural rearrangements typify ∼50% of prostate tumors and result in overexpression of the ERG transcription factor. Using chromatin, genomic and expression data, we show distinct cis-regulatory landscapes between T2E-positive and non-T2E primary prostate tumors, which include clusters of regulatory elements (COREs). This difference is mediated by ERG co-option of HOXB13 and FOXA1, implementing a T2E-specific transcriptional profile. We also report a T2E-specific CORE on the structurally rearranged ERG locus arising from spreading of the TMPRSS2 locus pre-existing CORE, assisting in its overexpression. Finally, we show that the T2E-specific cis-regulatory landscape underlies a vulnerability against the NOTCH pathway. Indeed, NOTCH pathway inhibition antagonizes the growth and invasion of T2E-positive prostate cancer cells. Taken together, our work shows that overexpressed ERG co-opts master transcription factors to deploy a unique cis-regulatory landscape, inducing a druggable dependency on NOTCH signaling in T2E-positive prostate tumors.

[Indexed for MEDLINE]

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