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Series GSE63284 Query DataSets for GSE63284
Status Public on Jan 07, 2016
Title Response and resistance to BET bromodomain inhibitors in triple negative breast cancer [Chem-Seq]
Organism Homo sapiens
Experiment type Genome binding/occupancy profiling by high throughput sequencing
Summary Triple negative breast cancer (TNBC) is a heterogeneous and clinically aggressive disease for which there is no targeted therapy. Here we report the preferential and high sensitivity of TNBCs to BET bromodomain inhibitors such as JQ1 manifested by cell cycle arrest in early G1, apoptosis, and induction of markers of luminal epithelial differentiation in vitro and in vivo. The sensitivity of TNBC and other tumor types to BET inhibition establishes a rationale for clinical investigation, and a motivation to understand mechanisms of resistance. After engendering acquired resistance to BET inhibition in previously sensitive TNBCs, we utilized integrative approaches to identify a unique mechanism of epigenomic resistance to this epigenetic therapy. Resistant cells remain dependent on BRD4, confirmed by RNA interference. However, TNBC cells adapt to BET bromodomain inhibition by re-recruitment of unmutated BRD4 to super-enhancers, now in a bromodomain-independent manner. Proteomic studies of resistant TNBC identify hyper-phosphorylation of BRD4 and strong association with MED1. Together, these studies provide a rationale for BET inhibition in TNBC and argue for combination strategies to anticipate clinical drug resistance.
Overall design Chem-Seq in parental and JQ1 resistant triple negative breast cancer (TNBC)
Contributor(s) Shu S, Lin CY, He HH, Bradner JE, Polyak K
Citation(s) 26735014
Submission date Nov 14, 2014
Last update date May 15, 2019
Contact name Kornelia Polyak
Phone 617-632-2106
Organization name Dana-Farber Cancer Institute
Department Medical Oncology
Lab Polyak
Street address 450 Brookline Ave
City Boston
State/province MA
ZIP/Postal code 02215
Country USA
Platforms (1)
GPL18573 Illumina NextSeq 500 (Homo sapiens)
Samples (2)
GSM1545037 SUM159R_JQ1_CHEM_SEQ_R1
GSM1545038 SUM159_JQ1_CHEM_SEQ_R1
This SubSeries is part of SuperSeries:
GSE63584 Response and resistance to BET bromodomain inhibitors in triple negative breast cancer
BioProject PRJNA267196
SRA SRP049808

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Supplementary file Size Download File type/resource
GSE63284_RAW.tar 230.5 Mb (http)(custom) TAR (of WIG)
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Raw data are available in SRA
Processed data provided as supplementary file

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