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Cell. 2015 Sep 24;163(1):174-86. doi: 10.1016/j.cell.2015.08.063.

CDK7-dependent transcriptional addiction in triple-negative breast cancer.

Author information

1
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
2
Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, MA 02142, USA.
3
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
4
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
5
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115, USA; Department of Surgery, Brigham and Women's Hospital, Boston, MA 02115, USA.
6
Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, MA 02142, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
7
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA. Electronic address: nathanael_gray@dfci.harvard.edu.
8
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA. Electronic address: jean_zhao@dfci.harvard.edu.

Abstract

Triple-negative breast cancer (TNBC) is a highly aggressive form of breast cancer that exhibits extremely high levels of genetic complexity and yet a relatively uniform transcriptional program. We postulate that TNBC might be highly dependent on uninterrupted transcription of a key set of genes within this gene expression program and might therefore be exceptionally sensitive to inhibitors of transcription. Utilizing kinase inhibitors and CRISPR/Cas9-mediated gene editing, we show here that triple-negative but not hormone receptor-positive breast cancer cells are exceptionally dependent on CDK7, a transcriptional cyclin-dependent kinase. TNBC cells are unique in their dependence on this transcriptional CDK and suffer apoptotic cell death upon CDK7 inhibition. An "Achilles cluster" of TNBC-specific genes is especially sensitive to CDK7 inhibition and frequently associated with super-enhancers. We conclude that CDK7 mediates transcriptional addiction to a vital cluster of genes in TNBC and CDK7 inhibition may be a useful therapy for this challenging cancer.

PMID:
26406377
PMCID:
PMC4583659
DOI:
10.1016/j.cell.2015.08.063
[Indexed for MEDLINE]
Free PMC Article

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