BRD4 regulates breast cancer dissemination through Jagged1/Notch1 signaling
Menée in vitro et à l'aide de données portant sur 664 patientes atteintes d'un cancer du sein, cette étude met en évidence des mécanismes par lesquels, via la signalisation Jagged1/Notch1, la protéine BRD4 favorise le processus métastatique d'un cancer du sein triplement négatif
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.
Cancer Research 2016