title: BRD4 Regulates Breast Cancer Dissemination through Jagged1/Notch1 Signaling.
abstract: 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 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. Cancer Res; 76(22); 6555-67. ©2016 AACR.
authors.affiliation: Cancer Center, Boston University School of Medicine, Boston, Massachusetts.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Andrieu
authors.affiliation: Cancer Center, Boston University School of Medicine, Boston, Massachusetts.
authors.forename: Anna H
authors.initials: AH
authors.lastname: Tran
authors.affiliation: Cancer Center, Boston University School of Medicine, Boston, Massachusetts.
authors.forename: Katherine J
authors.initials: KJ
authors.lastname: Strissel
authors.affiliation: Cancer Center, Boston University School of Medicine, Boston, Massachusetts. gdenis@bu.edu.|Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, Massachusetts.
authors.forename: Gerald V
authors.initials: GV
authors.lastname: Denis
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D018797:Cell Cycle Proteins; D005260:Female; D006801:Humans; D000072100:Jagged-1 Protein / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics*; D051881:Receptor, Notch1 / Q000378:metabolism*; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics*; D014162:Transfection; D000092468:Bromodomain Containing Proteins
chemical_list: D018797:Cell Cycle Proteins; D000072100:Jagged-1 Protein; D009687:Nuclear Proteins; D051881:Receptor, Notch1; D014157:Transcription Factors; C441289:BRD4 protein, human; D000092468:Bromodomain Containing Proteins