title: Prolonged postovulatory proinflammatory signaling in the fallopian tube epithelium may be mediated through a BRCA1/DAB2 axis.
abstract: OBJECTIVE
  To assess inflammation-related gene expression in nonmalignant fallopian tube epithelium (FTE) from BRCA1/2 mutation carriers and control patients obtained during the luteal and follicular phase, and to determine the impact of BRCA1 and disabled homolog 2 (DAB2) on NF-κB-mediated proinflammatory signaling.
  
  
  METHODS
  A list of inflammation-related and NF-κB-responsive genes was compiled through gene set enrichment and PubMed database search, corresponding probes identified, and unpaired t tests conducted to identify differentially expressed genes in previously profiled FTE samples. ES2 and A549 cells were cotransfected with DAB2- or BRCA1-targeting siRNA and an NF-κB-responsive luciferase reporter, treated with TNF-α and luciferase activity determined. To determine whether DAB2 or BRCA1 alters mRNA expression of NF-κB target genes, cells were transfected with siRNA, treated with TNF-α, and harvested for total RNA extraction and quantitative real-time PCR.
  
  
  RESULTS
  A subset of BRCA1-mutated luteal phase samples previously found to group with adnexal high-grade serous carcinomas (HGSCs) differentially expressed 124 inflammation-associated probesets relative to remaining FTE samples. These samples also differentially expressed 264 probes relative to other luteal phase samples exposed to the same postovulatory environment. Both BRCA1- and DAB2-targeting siRNA increased TNF-α-induced NF-κB activity and mRNA expression of NF-κB-dependent target gene SOD2 relative to nontargeting siRNA, suggesting that both proteins repress proinflammatory signaling.
  
  
  CONCLUSIONS
  These data provide evidence of elevated proinflammatory signaling in a subset of BRCA1-mutated luteal phase FTE, consistent with an altered response to ovulation-associated cytokines. Furthermore, both BRCA1 and DAB2 affect NF-κB activity, indicating a novel link between BRCA mutation status, ovulation, and predisposition to HGSC.
authors: The Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Canada.
authors: Alicia A
authors: AA
authors: Tone
authors: Carl
authors: C
authors: Virtanen
authors: Patricia
authors: P
authors: Shaw
authors: Theodore J
authors: TJ
authors: Brown
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D051017:Apoptosis Regulatory Proteins; D019313:BRCA1 Protein / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D016000:Cluster Analysis; D003907:Dexamethasone / Q000494:pharmacology; D004848:Epithelium / Q000378:metabolism*; D005187:Fallopian Tubes / Q000378:metabolism*; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D011965:Receptors, Glucocorticoid / Q000819:agonists / Q000378:metabolism; D015398:Signal Transduction; D015533:Transcriptional Activation / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D025521:Tumor Suppressor Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; D019313:BRCA1 Protein; C102885:DAB2 protein, human; D016328:NF-kappa B; D011965:Receptors, Glucocorticoid; D014409:Tumor Necrosis Factor-alpha; D025521:Tumor Suppressor Proteins; D003907:Dexamethasone