Dataset Information


Global transcriptome profiling of triple-negative breast cancer cell lines treated with small-molecules targeting Bromodomain and Extra Terminal (BET) proteins

ABSTRACT: Triple negative breast cancer (TNBC) represents the most clinically challenging subtypes of breast cancer for which targeted therapeutics are still lacking. Bromodomain and Extra Terminal (BET) proteins, including ubiquitously expressed BRD2, BRD3, BRD4 and testis-specific BRDT, are epigenetic “readers” and play a major role in epigenetic regulation of gene transcription. BET proteins have emerged as new therapeutic targets for human cancer and other diseases. Based upon a new class of BET bromodomain (BRD) inhibitor, BETi-211, we have developed a highly selective and potent BET protein degrader, BETd-246. In comparison, BETd-246 is much more potent and effective than the corresponding BET inhibitor BETi-211 in growth inhibition and apoptosis induction in TNBC cell lines, indicating critical differences between these two different BET targeting approaches in their regulation of gene transcription. To understand the mechanisms of actions of BETi-211 and BETd-246 in TNBC, we performed RNA-seq analysis on MDA-MB-157, MDA-MB-231 and MDA-MB-468. These cell lines were treated for 3 h to capture the early transcriptional responses to BETi-211 or BETd-246. RNA-seq analysis reveals that BETd-246 predominantly down-regulates the expression of a large number of genes whereas BETi-211 up- and down-regulates an approximately equal number of genes in TNBC cells. Critically, transcriptomic analysis uncovers that a set of proliferation and survival-related genes, including MCL1 and BRD2, were oppositely regulated by BETd-246 and BETi-211 in these TNBC cell lines. Overall design: Global gene transcription profiling was performed in MDA-MB-157, MDA-MB-231 and MDA-MB-468 cell lines treated with DMSO, Thalidomide (1000 nmol/L), BETi-211 (1000 nmol/L) or BETd-246 (100 nmol/L) for 3 hours. Independent biological replicates (such as DMSO1 and DMSO2) were analyzed for each cell line under each condition. Both DMSO- and Thalidomide-treated samples were used as controls.

INSTRUMENT(S): Illumina HiSeq 2500 (Homo sapiens)

SUBMITTER: Shaomeng Wang  

PROVIDER: GSE95375 | GEO | 2017-02-28



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Triple-negative breast cancers (TNBC) remain clinically challenging with a lack of options for targeted therapy. In this study, we report the development of a second-generation BET protein degrader, BETd-246, which exhibits superior selectivity, potency, and antitumor activity. In human TNBC cells, BETd-246 induced degradation of BET proteins at low nanomolar concentrations within 1 hour of exposure, resulting in robust growth inhibition and apoptosis. BETd-246 was more potent and effective in T  ...[more]

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