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

Abstract

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-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 cells were cotransfected with DAB2-or BRCA1-targeting siRNA and an NF-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 highgrade 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-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 BRCA1-mutated 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 BRCA mutation status, ovulation, and predisposition to HGSC.

BRCA and Early Events in the Development of Serous Ovarian Cancer

“…Differences in morphologically normal epithelium from BRCA mutation carriers have shed light into the effects of heterozygosity and predisposition to high-grade serous ovarian cancer. In five previous reports, we have used morphologically normal fallopian tubal epithelium from BRCA1 and BRCA 2 (FTE-BRCA) mutation carriers and non-mutation carriers (FTE-normal), to compare gene expression profiles to identify differences conferred by the presence of one mutant allele (67–71). In addition to family history, a major risk factor is number of lifetime ovulations, and oral contraception use and increase in parity lead to a reduction in EOC risk (72).…”

Glucocorticoid-Induced Reversal of Interleukin-1β-Stimulated Inflammatory Gene Expression in Human Oviductal Cells

“…Molecular profiling of microdissected FTE from BRCA mutation carriers and control patients indicated luteal FTE from mutation carriers differed from that of control patients, whereas follicular FTE were highly similar between the two groups [45]. This difference in luteal phase FTE from BRCA mutation carriers predominantly reflected a pro-inflammatory gene signature consistent with increased NFκB signaling and diminished glucocorticoid receptor signaling [21], [46]. The FTE samples were not obtained immediately following ovulation and the response of tubule epithelial cells to inflammatory cytokine or glucocorticoid exposure has not been characterized.…”

“…Glucocorticoids have been shown to exert anti-inflammatory effects in several tissues [20]. We have previously shown that BRCA1 enhances glucocorticoid receptor signaling and found evidence of suppressed glucocorticoid activity in luteal phase FTE from BRCA1 mutation carriers relative to control patients [21]. However, anti-inflammatory activity of glucocorticoids does not occur in all cell types.…”

Dab2 attenuates brain injury in APP/PS1 mice via targeting transforming growth factor-beta/SMAD signaling

“…These results indicate that Dab2 can alleviate the inflammatory reaction in the brain tissue of Alzheimer's disease mice. A previous study has confirmed that Dab2 can inhibit inflammatory reactions by regulating nuclear factor-κB signaling[55]. Therefore, we considered that Dab2 inhibits inflammatory reactions in the brain tissue of Alzheimer's disease mice possibly not only by regulating transforming growth factor-β1/SMAD signaling, but also by other mechanisms, such as inhibition of nuclear factor-κB signaling.…”