BRCA1 185delAG Mutation Enhances Interleukin-1βExpression in Ovarian Surface Epithelial Cells

Abstract

Familial history remains the strongest risk factor for developing ovarian cancer (OC) and is associated with germline BRCA1 mutations, such as the 185delAG founder mutation. We sought to determine whether normal human ovarian surface epithelial (OSE) cells expressing the BRCA1 185delAG mutant, BRAT, could promote an inflammatory phenotype by investigating its impact on expression of the proinflammatory cytokine, Interleukin-1β (IL-1β). Cultured OSE cells with and without BRAT were analyzed for differential target gene expression by real-time PCR, western blot, ELISA, luciferase reporter, and siRNA assays. We found that BRAT cells expressed increased cellular and secreted levels of active IL-1β. BRAT-expressing OSE cells exhibited 3-fold enhanced IL-1β mRNA expression, transcriptionally regulated, in part, through CREB sites within the (−1800) to (−900) region of its promoter. In addition to transcriptional regulation, BRAT-mediated IL-1β expression appears dualistic through enhanced inflammasome-mediated caspase-1 cleavage and activation of IL-1β. Further investigation is warranted to elucidate the molecular mechanism(s) of BRAT-mediated IL-1β expression since increased IL-1β expression may represent an early step contributing to OC.

Epigenetic reprogramming of fallopian tube fimbriae in BRCA mutation carriers defines early ovarian cancer evolution

“…Experiments with short term cultures of primary fimbrial fallopian tube cells ( Supplementary Fig. 4 ) and with the SKOV3 ovarian cancer cell line demonstrated that NF-κB -activating inflammatory signals (that is, TNF-α and IL1-β), which are known to (i) be released in the pelvis under conditions known as risk factors for HGSEMCs (that is, pelvic inflammatory disease or frequent ovulation associated with the need for repeated repair of ovulatory defects in close proximity to the fimbrial tube) and (ii) be more abundant in women with a family history due to a BRCA1 mutation 27 28 29 , lead to increased expression of AID ( Fig. 4b ).…”

“…Alternatively, cell ‘non-autonomous' factors known to be strongly associated with HGSEMC risk (that is, high number of ovulations and pelvic inflammatory disease 34 ) could lead to aberrantly high AID. Some, although rather preliminary, support for a cell ‘non-autonomous' mechanism comes from the observation that a BRCA1 mutation enhances Interleukin-1β expression in ovarian surface epithelial cells 29 , and that BRCA mutation carriers' associated epigenetic mis-programming of immune cells 18 may lead to subtle immune defects which in turn facilitate microbial ascension from the vagina to the fallopian tube. Additional evidence for a cell ‘non-autonomous' factor comes from our previous observation that BRCA mutation carriers demonstrate higher oestrogen levels in the luteal phase 35 .…”

RING domain–deficient BRCA1 promotes PARP inhibitor and platinum resistance

“…The BRCA1 185delAG mRNA is predicted to produce a short, approximately 5-kDa peptide (E23fsX17). Although this peptide has not been detected endogenously, exogenous overexpression of a BRCA1 peptide consisting of aa 1-23fsX17 was reported to induce phenotypes not associated with full-length BRCA1, including enhanced IL-1β expression, and to promote apoptosis (45,46). However, endogenously generated small peptide products normally located in the structured RING region of the protein may not be folded and are likely to be degraded.…”

Interleukin-1β and Cancer

“…BRCA1 (breast cancer 1) 185delAG mutation in ovarian epithelial cells allows IL-1β expression [ 124 ]. BRCA1 helps the sensing of herpes virus DNA and the activation of caspase-1 and IL-1β production [ 125 ].…”