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|a Wang, Yubao
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|a Massachusetts Institute of Technology. Department of Biology
|e contributor
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|a Young, Richard A
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|a Zhang, Tinghu
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|a Kwiatkowski, Nicholas
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|a Abraham, Brian J.
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|a Lee, Tong Ihn
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|a Xie, Shaozhen
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|a Yuzugullu, Haluk
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|a Von, Thanh
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|a Li, Heyuan
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|a Lin, Ziao
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|a Stover, Daniel G.
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|a Lim, Elgene
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|a Wang, Zhigang C.
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|a Iglehart, J. Dirk
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|a Gray, Nathanael S.
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|a Zhao, Jean J.
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|a Young, Richard A.
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|a CDK7-Dependent Transcriptional Addiction in Triple-Negative Breast Cancer
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|b Elsevier B.V.,
|c 2017-03-27T20:03:34Z.
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|z Get fulltext
|u http://hdl.handle.net/1721.1/107736
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|a 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.
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|a National Institutes of Health (U.S.) (NIH/NCI P50 CA168504)
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|a Dana-Farber Cancer Institute (MIT-DFCI Bridge grant)
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|a National Institutes of Health (U.S.) (NIH R01CA179483-01)
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|a en_US
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|a Article
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|t Cell
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