Abstract
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. 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. 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. 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.
Highlights
High-grade serous carcinoma (HGSC) is the most common and lethal histologic subtype of ovarian and tubal cancer with up to 20% of cases associated with a germline mutation in BRCA1/2 [1]
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
FTEb samples collected during the luteal phase exhibited global molecular profiles more closely resembling that of HGSC than FTE collected during the follicular phase or from control patients [2]
Summary
High-grade serous carcinoma (HGSC) is the most common and lethal histologic subtype of ovarian and tubal cancer with up to 20% of cases associated with a germline mutation in BRCA1/2 [1]. FTEb samples collected during the luteal phase exhibited global molecular profiles more closely resembling that of HGSC than FTE collected during the follicular phase or from control patients [2]. Despite a marked elevation of progesterone during the luteal phase, an overall difference in progesterone receptor signaling in FTE as a function of BRCA mutation status was not observed [3]. This suggests that differential response of BRCA1/2mutated FTE to factors associated with the postovulatory luteal phase other than progesterone underlie its molecular similarity to HGSC
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