BRD4 amplification facilitates an oncogenic gene expression program in high-grade serous ovarian cancer and confers sensitivity to BET inhibitors.
BRD4 amplification facilitates an oncogenic gene expression program in high-grade serous ovarian cancer and confers sensitivity to BET inhibitors.
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DOI：
10.1371/journal.pone.0200826
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发表时间：
2018
期刊：
影响因子：
3.7
通讯作者：
Chen H
中科院分区：
文献类型：
--
作者：
Rhyasen GW;Yao Y;Zhang J;Dulak A;Castriotta L;Jacques K;Zhao W;Gharahdaghi F;Hattersley MM;Lyne PD;Clark E;Zinda M;Fawell SE;Mills GB;Chen H
BRD 4是一种转录共激活因子，其功能是将调节复合物募集到乙酰化染色质。高级别浆液性卵巢癌（HGSOC）患者的一个子集以局灶性复发性BRD 4基因扩增为代表。尽管先前描述了癌症依赖性，但尚不清楚BRD 4扩增事件在HGSOC中是否是致癌的。我们发现，生理相关水平的表达BRD 4亚型在非转化卵巢细胞的细胞转化的结果。BRD 4转化的卵巢细胞和BRD 4扩增的HGSOC患者样本的转录谱显示了共同的表达模式，包括富集的MYC和E2 F1基因特征。此外，我们证明了一种新的BET抑制剂AZD 5153在BRD 4扩增的患者来源的异种移植物中具有高度活性，并揭示了Neuregulin-1作为一种新的BRD 4效应物。涉及Neuregulin-1抑制和外源添加的实验证明Neuregulin-1对于BRD 4介导的转化是必要和充分的。这项研究证明了BRD 4扩增在癌症中的致癌潜力，并将BRD 4扩增的HGSOC确定为可能受益于BET抑制剂的潜在患者人群。
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-transformed 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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影响因子：
10.5
作者：
Shi J;Whyte WA;Zepeda-Mendoza CJ;Milazzo JP;Shen C;Roe JS;Minder JL;Mercan F;Wang E;Eckersley-Maslin MA;Campbell AE;Kawaoka S;Shareef S;Zhu Z;Kendall J;Muhar M;Haslinger C;Yu M;Roeder RG;Wigler MH;Blobel GA;Zuber J;Spector DL;Young RA;Vakoc CR
通讯作者：
Vakoc CR
选择性抑制BET溴结构域。
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
6.4
作者：
Goundiam, Oumou;Gestraud, Pierre;Sastre-Garau, Xavier
通讯作者：
Sastre-Garau, Xavier
影响因子：
64.8
作者：
Garnett, Mathew J.;Edelman, Elena J.;Heidorn, Sonja J.;Greenman, Chris D.;Dastur, Anahita;Lau, King Wai;Greninger, Patricia;Thompson, I. Richard;Luo, Xi;Soares, Jorge;Liu, Qingsong;Iorio, Francesco;Surdez, Didier;Chen, Li;Milano, Randy J.;Bignell, Graham R.;Tam, Ah T.;Davies, Helen;Stevenson, Jesse A.;Barthorpe, Syd;Lutz, Stephen R.;Kogera, Fiona;Lawrence, Karl;McLaren-Douglas, Anne;Mitropoulos, Xeni;Mironenko, Tatiana;Thi, Helen;Richardson, Laura;Zhou, Wenjun;Jewitt, Frances;Zhang, Tinghu;O'Brien, Patrick;Boisvert, Jessica L.;Price, Stacey;Hur, Wooyoung;Yang, Wanjuan;Deng, Xianming;Butler, Adam;Choi, Hwan Geun;Chang, JaeWon;Baselga, Jose;Stamenkovic, Ivan;Engelman, Jeffrey A.;Sharma, Sreenath V.;Delattre, Olivier;Saez-Rodriguez, Julio;Gray, Nathanael S.;Settleman, Jeffrey;Futreal, P. Andrew;Haber, Daniel A.;Stratton, Michael R.;Ramaswamy, Sridhar;McDermott, Ultan;Benes, Cyril H.
通讯作者：
Benes, Cyril H.
影响因子：
50.3
作者：
Pradeep S;Kim SW;Wu SY;Nishimura M;Chaluvally-Raghavan P;Miyake T;Pecot CV;Kim SJ;Choi HJ;Bischoff FZ;Mayer JA;Huang L;Nick AM;Hall CS;Rodriguez-Aguayo C;Zand B;Dalton HJ;Arumugam T;Lee HJ;Han HD;Cho MS;Rupaimoole R;Mangala LS;Sehgal V;Oh SC;Liu J;Lee JS;Coleman RL;Ram P;Lopez-Berestein G;Fidler IJ;Sood AK
通讯作者：
Sood AK