Human Cancer Biology 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 BRCA1/2mutation 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-kB–mediated proinflammatory signaling. Experimental Design: A list of inflammation-related and NF-kB–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 cellswere cotransfectedwithDAB2or BRCA1-targeting siRNAand anNF-kB–responsive luciferase reporter, treated with TNF-a and luciferase activity determined. To determine whether DAB2 or BRCA1 alters mRNA expression of NF-kB target genes, cells were transfected with siRNA, treated with TNF-a, 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 BRCA1and DAB2–targeting siRNA increased TNF-a-induced NF-kB activity and mRNA expression of NF-kB–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 BRCA1mutated luteal phase FTE, consistent with an altered response to ovulation-associated cytokines. Furthermore, both BRCA1 and DAB2 affect NF-kB activity, indicating a novel link between BRCAmutation status, ovulation, and predisposition to HGSC. Clin Cancer Res; 1–12. 2012 AACR.