TY - JOUR
T1 - BRD4 amplification facilitates an oncogenic gene expression program in high-grade serous ovarian cancer and confers sensitivity to BET inhibitors
AU - Rhyasen, Garrett W.
AU - Yao, Yi
AU - Zhang, Jingwen
AU - Dulak, Austin
AU - Castriotta, Lillian
AU - Jacques, Kelly
AU - Zhao, Wei
AU - Gharahdaghi, Farzin
AU - Hattersley, Maureen M.
AU - Lyne, Paul D.
AU - Clark, Edwin
AU - Zinda, Michael
AU - Fawell, Stephen E.
AU - Mills, Gordon B.
AU - Chen, Huawei
N1 - Funding Information:
The study is funded mainly by AstraZeneca Pharmaceuticals LP and also partially by grant P50CA083639 from NCI: https://www. cancer.gov/ (GBM). AstraZeneca provided support in the form of salaries for authors G.W.R., Y.Y., A. D., L.C, K.J., J.Z., F.G., M.H., P.L., E.C., M.Z., S.F., and H.C, but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section. We would like to thank Garry Beran for Sanger data processing, Aleksandra Markovets for extracting the copy data from aCGH or SNP array dataset, and Kristen Bell for performing the combination efficacy study of AZD5153 with lapatinib in OV0857F ovarian PDX model. G.B.M. acknowledges the grant support of P50CA083639.
Publisher Copyright:
© 2018 Rhyasen et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Copyright:
Copyright 2019 Elsevier B.V., All rights reserved.
PY - 2018/7
Y1 - 2018/7
N2 - BRD4 is a transcriptional co-activator functioning to recruit regulatory complexes to acetylated chromatin. A subset of High-grade Serous Ovarian Cancer (HGSOC) patients are typified by focal, recurrent BRD4 gene amplifications. Despite previously described cancer dependencies, it is unclear whether BRD4 amplification events are oncogenic in HGSOC. We find that physiologically relevant levels of expression of BRD4 isoforms in non-transformed ovarian cells result in cellular transformation. Transcriptional profiling of BRD4-trans-formed ovarian cells, and BRD4-amplified HGSOC patient samples revealed shared expression patterns, including enriched MYC, and E2F1 gene signatures. Furthermore, we demonstrate that a novel BET inhibitor, AZD5153, is highly active in BRD4-amplified patient derived xenografts and uncover Neuregulin-1 as a novel BRD4 effector. Experiments involving Neuregulin-1 inhibition and exogenous addition, demonstrate Neuregulin-1 as necessary and sufficient for BRD4-mediated transformation. This study demonstrates the oncogenic potential of BRD4 amplification in cancer and establishes BRD4-amplified HGSOC as a potential patient population that could benefit from BET inhibitors.
AB - BRD4 is a transcriptional co-activator functioning to recruit regulatory complexes to acetylated chromatin. A subset of High-grade Serous Ovarian Cancer (HGSOC) patients are typified by focal, recurrent BRD4 gene amplifications. Despite previously described cancer dependencies, it is unclear whether BRD4 amplification events are oncogenic in HGSOC. We find that physiologically relevant levels of expression of BRD4 isoforms in non-transformed ovarian cells result in cellular transformation. Transcriptional profiling of BRD4-trans-formed ovarian cells, and BRD4-amplified HGSOC patient samples revealed shared expression patterns, including enriched MYC, and E2F1 gene signatures. Furthermore, we demonstrate that a novel BET inhibitor, AZD5153, is highly active in BRD4-amplified patient derived xenografts and uncover Neuregulin-1 as a novel BRD4 effector. Experiments involving Neuregulin-1 inhibition and exogenous addition, demonstrate Neuregulin-1 as necessary and sufficient for BRD4-mediated transformation. This study demonstrates the oncogenic potential of BRD4 amplification in cancer and establishes BRD4-amplified HGSOC as a potential patient population that could benefit from BET inhibitors.
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U2 - 10.1371/journal.pone.0200826
DO - 10.1371/journal.pone.0200826
M3 - Article
C2 - 30036377
AN - SCOPUS:85051756798
VL - 13
JO - PLoS One
JF - PLoS One
SN - 1932-6203
IS - 7
M1 - e0200826
ER -