MicroRNA-155-5p, Reduced by Curcumin-Re-Expressed Hypermethylated BRCA1, Is a Molecular Biomarker for Cancer Risk in BRCA1-methylation Carriers

Abstract

Constitutional BRCA1-methylation is a cancer risk factor for breast (BC) and ovarian (OC) cancer. MiR-155, regulated by BRCA1, is a multifunctional microRNA that plays a crucial role in the immune system. The present study assessed the modulation of miR-155-5p expression in peripheral white blood cells (WBCs) of BC and OC patients and cancer-free (CF) BRCA1-methylation female carriers. Additionally, we investigated the potential of curcumin to suppress miR-155-5p in BRCA1-deficient breast cancer cell lines. MiR-155-5p expression was measured using a stem-loop RT-qPCR method. Gene expression levels were determined using qRT-PCR and immunoblotting. MiR-155-5p was more highly expressed in the BRCA1-hypermethylated HCC-38 and UACC-3199 BC cell lines than in the BRCA1-mutated (HCC-1937) and WT BRCA1 (MDA-MB-321) cell lines. Curcumin suppressed miR-155-5p in the HCC-38 cells but not in the HCC-1937 cells via the re-expression of BRCA1. Elevated levels of miR-155-5p were detected in patients with non-aggressive and localized breast tumors and in patients with late-stage aggressive ovarian tumors, as well as in CF BRCA1-methylation carriers. Notably, IL2RG levels were reduced in the OC and CF groups but not in the BC group. Together, our findings suggest opposing effects of WBC miR-155-5p, according to the cell and cancer type. In addition, the results point to miR-155-5p as a candidate biomarker of cancer risk among CF-BRCA1-methylation carriers.

Constitutional BRCA1 and MGMT Methylation Are Significant Risk Factors for Triple-Negative Breast Cancer and High-Grade Serous Ovarian Cancer in Saudi Women

“…Moreover, studying the molecular effects of BRCA1 epimutation in WBCs has shown that there are cancer-related molecular changes that can occur in adult carriers and, more importantly, in newborn carriers. These changes are similar to those seen in females who have been diagnosed with breast cancer and ovarian cancer [ 5 , 9 , 25 ]. Thirdly, in a recent study [ 5 ], we found that the WBCs of CF BRCA1 methylation carriers had less ILR2G (a T cell functional molecule), suggesting that these carriers have reduced antitumor immunity.…”

“…These changes are similar to those seen in females who have been diagnosed with breast cancer and ovarian cancer [ 5 , 9 , 25 ]. Thirdly, in a recent study [ 5 ], we found that the WBCs of CF BRCA1 methylation carriers had less ILR2G (a T cell functional molecule), suggesting that these carriers have reduced antitumor immunity. This discovery aligns with a recent investigation that suggested that modified BRCA1 expression in peripheral T cells could lead to aberrant transcription, which is linked to antitumor immunity, and which could potentially contribute to the elevated cancer risk observed in women carrying BRCA1 mutations [ 34 ].…”

“…Based on our data, almost 19% of CF Saudi women are carriers of constitutional epimutations: 10% carry MGMT epimutations and 8.6% carry BRCA1 epimutations from early on in life. Mounting evidence substantiates the notion that such persons are at a heightened risk of developing breast and/or ovarian cancer [ 4 , 5 , 9 , 25 , 31 , 32 , 33 ]. We previously demonstrated that the levels and arrangements of CpG island methylation at the BRCA1 promoters in WBCs are comparable among cancer patients, newborns, and adult BRCA1 methylation carriers [ 4 ].…”

“…Such constitutional promoter methylation of key tumor suppressors is comparable to the inactivation of the same genes by germline mutations in the genesis of particular cancer types. This is exemplified by constitutional BRCA1 promoter methylation, and numerous studies have demonstrated that this epimutation is substantially associated with early-onset triple-negative breast cancer (TNBC) subtypes and high-grade serous ovarian cancer (HGSOC) [ 3 , 4 , 5 , 6 ]. The error-free homologous recombination pathway [ 7 ], which repairs DNA double-strand breaks, is mediated by the BRCA1 protein.…”

Quantification of MicroRNA in a Single Living Cell via Ionic Current Rectification-Based Nanopore for Triple Negative Breast Cancer Diagnosis

“…Our nanopore sensors were also used to evaluate anticancer drugs including docetaxel (TXT), curcumin, 10-hydroxycamptothecin (HCPT), and Palbociclib, all of which can induce apoptosis in breast cancer cells. − Based on the intracellular miRNA-155 level change, the effectiveness of the nanopore sensors to evaluate drug effects was studied with Hoechst 33342 stained MDA-MB-231 cells. Hoechst 33342 is a specific stain for DNA and can penetrate membranes and fluoresce blue for both live and apoptosis cells but gives stronger fluorescence in apoptotic cells due to the increased membrane permeability of apoptotic cells.…”