Genomics,Multiomics

Dataset Information

94

Response and resistance to BET bromodomain inhibitors in triple negative breast cancer [Chem-Seq]


ABSTRACT: 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. Chem-Seq in parental and JQ1 resistant triple negative breast cancer (TNBC)

ORGANISM(S): Homo sapiens  

SUBMITTER: James E Bradner  Kornelia Polyak   Housheng H He   Charles Y Lin   Shaokun Shu    

PROVIDER: E-GEOD-63284 | ArrayExpress| 2016-01-17

SECONDARY ACCESSION(S): GSE63284SRP049808PRJNA267196

REPOSITORIES: GEO, ArrayExpress, ENA

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Publications

Response and resistance to BET bromodomain inhibitors in triple-negative breast cancer.

Shu Shaokun S   Lin Charles Y CY   He Housheng Hansen HH   Witwicki Robert M RM   Tabassum Doris P DP   Roberts Justin M JM   Janiszewska Michalina M   Huh Sung Jin SJ   Liang Yi Y   Ryan Jeremy J   Doherty Ernest E   Mohammed Hisham H   Guo Hao H   Stover Daniel G DG   Ekram Muhammad B MB   Brown Jonathan J   D'Santos Clive C   Krop Ian E IE   Dillon Deborah D   McKeown Michael M   Ott Christopher C   Qi Jun J   Ni Min M   Rao Prakash K PK   Duarte Melissa M   Wu Shwu-Yuan SY   Chiang Cheng-Ming CM   Anders Lars L   Young Richard A RA   Winer Eric E   Letai Antony A   Barry William T WT   Carroll Jason S JS   Long Henry H   Brown Myles M   Liu X Shirley XS   Meyer Clifford A CA   Bradner James E JE   Polyak Kornelia K  

Nature 20160106 7586


Triple-negative breast cancer (TNBC) is a heterogeneous and clinically aggressive disease for which there is no targeted therapy. BET bromodomain inhibitors, which have shown efficacy in several models of cancer, have not been evaluated in TNBC. These inhibitors displace BET bromodomain proteins such as BRD4 from chromatin by competing with their acetyl-lysine recognition modules, leading to inhibition of oncogenic transcriptional programs. Here we report the preferential sensitivity of TNBCs to  ...[more]

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