Prolonged Postovulatory Proinflammatory Signaling in the Fallopian Tube Epithelium May Be Mediated through a BRCA1/DAB2 Axis

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-kappa B-mediated proinflammatory signaling. Experimental Design: A list of inflammation-related and NF-kappa B-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-kappa B-responsive luciferase reporter, treated with TNF-alpha and luciferase activity determined. To determine whether DAB2 or BRCA1 alters mRNA expression of NF-kappa B target genes, cells were transfected with siRNA, treated with TNF-alpha, 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-alpha-induced NF-kappa B activity and mRNA expression of NF-kappa B-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-kappa B activity, indicating a novel link between BRCA mutation status, ovulation, and predisposition to HGSC. Clin Cancer Res; 18(16); 4334-44. (C) 2012 AACR.