title: BRCA1 185delAG Mutation Enhances Interleukin-1β Expression in Ovarian Surface Epithelial Cells.
abstract: Familial history remains the strongest risk factor for developing ovarian cancer (OC) and is associated with germline BRCA1 mutations, such as the 185delAG founder mutation. We sought to determine whether normal human ovarian surface epithelial (OSE) cells expressing the BRCA1 185delAG mutant, BRAT, could promote an inflammatory phenotype by investigating its impact on expression of the proinflammatory cytokine, Interleukin-1β (IL-1β). Cultured OSE cells with and without BRAT were analyzed for differential target gene expression by real-time PCR, western blot, ELISA, luciferase reporter, and siRNA assays. We found that BRAT cells expressed increased cellular and secreted levels of active IL-1β. BRAT-expressing OSE cells exhibited 3-fold enhanced IL-1β mRNA expression, transcriptionally regulated, in part, through CREB sites within the (-1800) to (-900) region of its promoter. In addition to transcriptional regulation, BRAT-mediated IL-1β expression appears dualistic through enhanced inflammasome-mediated caspase-1 cleavage and activation of IL-1β. Further investigation is warranted to elucidate the molecular mechanism(s) of BRAT-mediated IL-1β expression since increased IL-1β expression may represent an early step contributing to OC.
authors.affiliation: Department of Pathology & Cell Biology, University of South Florida, Tampa, FL 33612, USA.
authors.forename: Kamisha T
authors.initials: KT
authors.lastname: Woolery
authors.affiliation: Department of Pathology & Cell Biology, University of South Florida, Tampa, FL 33612, USA.
authors.forename: Mai
authors.initials: M
authors.lastname: Mohamed
authors.affiliation: Department of Pathology & Cell Biology, University of South Florida, Tampa, FL 33612, USA.
authors.forename: Rebecca J
authors.initials: RJ
authors.lastname: Linger
authors.affiliation: Department of Pathology & Cell Biology, University of South Florida, Tampa, FL 33612, USA.
authors.forename: Kimberly P
authors.initials: KP
authors.lastname: Dobrinski
authors.affiliation: Department of Medicine, University of Louisville, Louisville, KY 40202, USA.
authors.forename: Jesse
authors.initials: J
authors.lastname: Roman
authors.affiliation: Department of Pathology & Cell Biology, University of South Florida, Tampa, FL 33612, USA ; Department of Obstetrics & Gynecology, University of South Florida, Tampa, FL 33612, USA ; H. Lee Moffitt Cancer Center, Tampa, FL 33612, USA.
authors.forename: Patricia A
authors.initials: PA
authors.lastname: Kruk
mesh_terms: D019313:BRCA1 Protein / Q000235:genetics*; D002460:Cell Line; D016207:Cytokines / Q000235:genetics; D004847:Epithelial Cells / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation / Q000235:genetics; D006801:Humans; D058847:Inflammasomes / Q000235:genetics; D053583:Interleukin-1beta / Q000235:genetics*; D009154:Mutation / Q000235:genetics*; D010053:Ovary / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics
chemical_list: D019313:BRCA1 Protein; D016207:Cytokines; D058847:Inflammasomes; D053583:Interleukin-1beta; D012333:RNA, Messenger; D034741:RNA, Small Interfering