Profile of the breast cancer susceptibility marker rs4245739 identifies a role for miRNAs

Abstract

Objective:To determine the influence of the single nucleotide polymorphism (SNP) rs4245739 on the binding and expression of microRNAs and subsequent MDM4 expression and the correlation of these factors with clinical determinants of ER-negative breast cancers. Methods:FindTar and miRanda were used to detect the manner in which potential microRNAs are affected by the SNP rs4245739-flanking sequence. RNA sequencing data for ER-negative breast cancer from The Cancer Genome Atlas (TCGA) were used to compare the expression of miR-184, miR-191, miR-193a, miR-378, and MDM4 in different rs4245739 genotypes. Results:Comparison of ER-negative cancer patients with and without the expression of miR-191 as well as profile microRNAs (miR-184, miR-191, miR-193a and miR-378 altogether) can differentiate the expression of MDM4 among different rs4245739 genotypes. Although simple genotyping alone did not reveal significant clinical relationships, the combination of genotyping and microRNA profiles was able to significantly differentiate individuals with larger tumor size and lower number of involved lymph nodes (P < 0.05) in the risk group (A allele). Conclusions:We present two novel methods to analyze SNPs within 3′UTRs that use: (i) a single miRNA marker expression and (ii) an expression profile of miRNAs predicted to bind to the SNP region. We demonstrate that the application of these two methods, in particular the miRNA profile approach, permits detection of new molecular and clinical features related to the rs4245739 variant in ER-negative breast cancer.

microRNA‐related single‐nucleotide polymorphisms and breast cancer

“…Liu et al (2013) have observed that the C allele in MDM4 rs4245739 decreases breast cancer risk comparing to A allele by affecting MDM4 mRNA stability and levels of protein. Studies in rs4245739 in the 3′ UTR in ovarian cancer patients showed that this SNP forms a prohibited target site for miR-191 and is linked to survival and overall survival in this cancer; the finding of this study then was confirmed by Anwar, Wulaningsih, and Watkins (2017) in breast cancer (Wynendaele et al, 2010). Regarding miR-191 expression level, it has been reported that its expression is downregulated in male breast cancer (MBC) while it is overexpressed in female breast cancer (Nagpal & Kulshreshtha, 2014).…”

Role of Sex in the Therapeutic Targeting of p53 Circuitry

“…Indeed, the frequency of the MDM4-SNP34091 is different between these two populations (90). Finally, other miRNAs may affect SNP function (91).…”

SNPs in miRNAs and Target Sequences: Role in Cancer and Diabetes

“…An SNP rs4245739 (A>C) is located within the 3′UTR region of MDM4. The C allele creates a new binding site for three miRNAs, miRNA-191-5p, miR-887, and miR-3669 ( Wynendaele et al, 2010 ; Stegeman et al, 2015 ; Anwar et al, 2017 ). The variant allele of this polymorphism has been reported as a risk factor for many cancers including ovarian cancer, lung cancer, prostate cancer, BC, non-Hodgkin’s lymphoma, esophageal cancer, and retinoblastoma ( Wynendaele et al, 2010 ; Zhou et al, 2013 ; Gao et al, 2015a ; Stegeman et al, 2015 ; Xu et al, 2016 ; Anwar et al, 2017 ).…”

“…The T allele at 3′UTR allows binding of miR-206 to ESR1 and it is significantly downregulated ( Adams et al, 2007 ). This SNP has been associated with an increased risk of BC ( Anwar et al, 2017 ; Brucker et al, 2017 ).…”