BRCA1 185delAG Mutation Enhances Interleukin-1β Expression in Ovarian Surface Epithelial Cells.

Kamisha T Woolery,Kimberly P Dobrinski,Mai Mohamed,Rebecca J Linger,Patricia A Kruk,Jesse Roman

doi:10.1155/2015/652017

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.

Highlights

Ovarian cancer (OC), an inflammation associated cancer, is the deadliest gynecologic malignancy and is the 9th most common cancer among women [1]
Most OCs are epithelial ovarian carcinomas traditionally thought to arise from the ovarian surface epithelium (OSE) [2]; though more recently, studies have suggested that OC may arise from the fallopian tube epithelium [3, 4]
The following SV 40-Large T-Antigen transfected human OSE (IOSE) cell lines were used: IOSE118 derived from a normal patient with a family history (FH) of breast and/or OC with wtBRCA1 status confirmed [13]; IOSE 121 derived from a normal patient with no family history (NFH) of breast and/or OC though breast cancer susceptibility gene 1 (BRCA1) mutation status was not determined; and IOSE 3261-77 and IOSE 1816-686 derived from normal patients with a FH of breast and/or OC as well as confirmed carriers of the BRCA1 185delAG mutation

Summary

Introduction

Ovarian cancer (OC), an inflammation associated cancer, is the deadliest gynecologic malignancy and is the 9th most common cancer among women [1]. Carriers of the BRCA1 mutation have a 30% risk of developing OC during their lifetime [7]. BRCA1 plays a role in DNA damage response, cell cycle signaling, recruitment of chromatin modifying proteins, interaction with transcription factors, and ubiquitin ligase activity [8]. Loss of these functions may contribute to the development of cancer by promoting genomic instability and accumulation of cancer-causing mutations. Among possible gain-of-function BRCA1 mutations, the 185delAG mutation is one of the most common founder mutations and is associated with a 66% lifetime risk of developing OC [10]

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