CDK7-Dependent Transcriptional Addiction in Triple-Negative Breast Cancer
Author(s)Wang, Yubao; Zhang, Tinghu; Kwiatkowski, Nicholas; Abraham, Brian J.; Lee, Tong Ihn; Xie, Shaozhen; Yuzugullu, Haluk; Von, Thanh; Li, Heyuan; Lin, Ziao; Stover, Daniel G.; Lim, Elgene; Wang, Zhigang C.; Iglehart, J. Dirk; Gray, Nathanael S.; Zhao, Jean J.; Young, Richard A; ... Show more Show less
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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.
DepartmentMassachusetts Institute of Technology. Department of Biology
Wang, Yubao, Tinghu Zhang, Nicholas Kwiatkowski, Brian J. Abraham, Tong Ihn Lee, Shaozhen Xie, Haluk Yuzugullu, et al. “CDK7-Dependent Transcriptional Addiction in Triple-Negative Breast Cancer.” Cell 163, no. 1 (September 2015): 174–186.
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