BRD4 Regulates Breast Cancer Dissemination through Jagged1/Notch1 Signaling.
BRD4 Regulates Breast Cancer Dissemination through Jagged1/Notch1 Signaling.
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DOI：
10.1158/0008-5472.can-16-0559
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发表时间：
2016-11-15
期刊：
影响因子：
11.2
通讯作者：
Denis GV
中科院分区：
文献类型：
--
作者：
Andrieu G;Tran AH;Strissel KJ;Denis GV
溴结构域和末端外（BET）蛋白是染色质中乙酰化组蛋白的表观遗传“阅读器”，并且已被鉴定为多种癌症中有希望的治疗靶标。然而，目前尚不清楚单个家族成员如何参与癌症进展，小分子抑制剂如JQ 1可以靶向功能独立的BET蛋白。在这里，我们报告了一个信号通路，涉及BRD 4和配体/受体对Jagged 1/Notch 1，维持三阴性乳腺癌的迁移和侵袭。BRD 4而不是BRD 2或BRD 3调节Jagged 1表达和Notch 1信号传导。BRD 4-选择性敲低抑制Notch 1活性并阻止乳腺癌迁移和侵袭。BRD 4是白细胞介素-6刺激、Notch 1诱导的迁移和侵袭所必需的，将微环境炎症与癌症传播偶联。此外，在患者中，BRD 4和Jagged 1表达与远处转移的存在呈正相关。这些结果确定了BRD 4/Jagged 1/Notch 1信号通路，这对三阴性乳腺癌的传播至关重要。
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 how individual 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 interleukin-6-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.