Prolonged postovulatory proinflammatory signaling in the fallopian tube epithelium may be mediated through a BRCA1/DAB2 axis

Clin Cancer Res. 2012 Aug 15;18(16):4334-44. doi: 10.1158/1078-0432.CCR-12-0199. Epub 2012 Jul 2.


Purpose: 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.

Experimental design: 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism*
  • Apoptosis Regulatory Proteins
  • BRCA1 Protein / genetics
  • BRCA1 Protein / metabolism*
  • Cell Line
  • Cluster Analysis
  • Dexamethasone / pharmacology
  • Epithelium / metabolism*
  • Fallopian Tubes / metabolism*
  • Female
  • Gene Expression Profiling
  • Gene Expression Regulation
  • Humans
  • Inflammation / genetics
  • Inflammation / metabolism
  • NF-kappa B / metabolism
  • Receptors, Glucocorticoid / agonists
  • Receptors, Glucocorticoid / metabolism
  • Signal Transduction*
  • Transcriptional Activation / drug effects
  • Tumor Necrosis Factor-alpha / pharmacology
  • Tumor Suppressor Proteins


  • Adaptor Proteins, Signal Transducing
  • Apoptosis Regulatory Proteins
  • BRCA1 Protein
  • DAB2 protein, human
  • NF-kappa B
  • Receptors, Glucocorticoid
  • Tumor Necrosis Factor-alpha
  • Tumor Suppressor Proteins
  • Dexamethasone