title: BET inhibitors block pancreatic stellate cell collagen I production and attenuate fibrosis in vivo.
abstract: The fibrotic reaction, which can account for over 70%-80% of the tumor mass, is a characteristic feature of human pancreatic ductal adenocarcinoma (PDAC) tumors. It is associated with activation and proliferation of pancreatic stellate cells (PSCs), which are key regulators of collagen I production and fibrosis in vivo. In this report, we show that members of the bromodomain and extraterminal (BET) family of proteins are expressed in primary PSCs isolated from human PDAC tumors, with BRD4 positively regulating, and BRD2 and BRD3 negatively regulating, collagen I expression in primary cancer-associated PSCs. We show that the inhibitory effect of pan-BET inhibitors on collagen I expression in primary cancer-associated PSCs is through blocking of BRD4 function. Importantly, we show that FOSL1 is repressed by BRD4 in primary cancer-associated PSCs and negatively regulates collagen I expression. While BET inhibitors do not affect viability or induce PSC apoptosis or senescence, BET inhibitors induce primary cancer-associated PSCs to become quiescent. Finally, we show that BET inhibitors attenuate stellate cell activation, fibrosis, and collagen I production in the EL-KrasG12Dtransgenic mouse model of pancreatic tumorigenesis. Our results demonstrate that BET inhibitors regulate fibrosis by modulating the activation and function of cancer-associated PSCs.
authors.affiliation: Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.
authors.forename: Krishan
authors.initials: K
authors.lastname: Kumar
authors.affiliation: Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.
authors.forename: Brian T
authors.initials: BT
authors.lastname: DeCant
authors.affiliation: Department of Medicine, University of Illinois, Chicago, Illinois, USA.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Grippo
authors.affiliation: Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Rosa F
authors.initials: RF
authors.lastname: Hwang
authors.affiliation: Department of Surgery, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.|Jesse Brown VA Medical Center, Chicago, Illinois, USA.|Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, Illinois, USA.
authors.forename: David J
authors.initials: DJ
authors.lastname: Bentrem
authors.affiliation: Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.
authors.forename: Kazumi
authors.initials: K
authors.lastname: Ebine
authors.affiliation: Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.|Department of Surgery, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.|Jesse Brown VA Medical Center, Chicago, Illinois, USA.|Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, Illinois, USA.
authors.forename: Hidayatullah G
authors.initials: HG
authors.lastname: Munshi
mesh_terms: D000818:Animals; D001381:Azepines / Q000008:administration & dosage* / Q000494:pharmacology; D021441:Carcinoma, Pancreatic Ductal / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D024042:Collagen Type I / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006576:Heterocyclic Compounds, 4 or More Rings / Q000008:administration & dosage* / Q000494:pharmacology; D006801:Humans; D051379:Mice; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D058954:Pancreatic Stellate Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics; D016601:RNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014230:Triazoles / Q000008:administration & dosage* / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays; D000099169:Fos-Related Antigen 1; D000092468:Bromodomain Containing Proteins
chemical_list: D001381:Azepines; D018797:Cell Cycle Proteins; D024042:Collagen Type I; D006576:Heterocyclic Compounds, 4 or More Rings; D009687:Nuclear Proteins; D017346:Protein Serine-Threonine Kinases; D016760:Proto-Oncogene Proteins c-fos; D016283:Proto-Oncogene Proteins p21(ras); D016601:RNA-Binding Proteins; D014157:Transcription Factors; D014230:Triazoles; D000099169:Fos-Related Antigen 1; C561695:(+)-JQ1 compound; C098415:BRD2 protein, human; D000092468:Bromodomain Containing Proteins; C109106:BRD3 protein, human; C441289:BRD4 protein, human; C568713:GSK1210151A; C495971:Hras protein, mouse