BRD4 Regulates Breast Cancer Dissemination through Jagged1/Notch1 Signaling

被引：116

作者：

Andrieu, Guillaume ^{[1
]}

Tran, Anna H. ^{[1
]}

Strissel, Katherine J. ^{[1
]}

Denis, Gerald V. ^{[1
,2
]}

机构：

[1] Boston Univ, Sch Med, Ctr Canc, Boston, MA 02118 USA

[2] Boston Univ, Sch Med, Dept Pharmacol & Expt Therapeut, Boston, MA 02118 USA

来源：

CANCER RESEARCH | 2016年 / 76卷 / 22期

关键词：

BET BROMODOMAIN INHIBITION; NOTCH LIGAND; T-CELLS; THERAPEUTIC TARGET; COLORECTAL-CANCER; DENDRITIC CELLS; INFLAMMATION; CHROMATIN; PROTEIN; KINASE;

D O I：

10.1158/0008-5472.CAN-16-0559

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

The bromodomain and extraterminal (BET) proteins are epigenetic "readers" of acetylated histones in chromatin and have been identified as promising therapeutic targets in diverse cancers. However, it remains unclear howindividual family members participate in cancer progression and small molecule inhibitors such as JQ1 can target functionally independent BET proteins. Here, we report a signaling pathway involving BRD4 and the ligand/receptor pair Jagged1/Notch1 that sustains triple-negative breast cancer migration and invasion. BRD4, but not BRD2 or BRD3, regulated Jagged1 expression and Notch1 signaling. BRD4-selective knockdown suppressed Notch1 activity and impeded breast cancer migration and invasion. BRD4 was required for IL6-stimulated, Notch1-induced migration and invasion, coupling microenvironment inflammation with cancer propagation. Moreover, in patients, BRD4 and Jagged1 expression positively correlated with the presence of distant metastases. These results identify a BRD4/Jagged1/Notch1 signaling pathway that is critical for dissemination of triple-negative breast cancer. (C) 2016 AACR.

引用

页码：6555 / 6567

页数：13

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