Crosstalk between microRNA expression and DNA methylation drive the hormone-dependent phenotype of breast cancer

Abstract

Background:Abnormal DNA methylation is observed as an early event in breast carcinogenesis. However, how such alterations arise is still poorly understood. microRNAs (miRNAs) regulate gene expression at the post-transcriptional level and have been shown to play key roles in various biological processes. Here, we integrate miRNA expression and DNA methylation at CpGs to study how miRNAs may affect the breast cancer methylome and how DNA methylation may regulate miRNA expression. ResultsmiRNA expression and DNA methylation data from two breast cancer cohorts were subjected to genome-wide correlation analysis. Clustering of the miRNA expression-DNA methylation association pairs significant in both cohorts identified distinct clusters of miRNAs and CpGs. These clusters recapitulated important biological processes associated with breast cancer pathogenesis. Notably, two major clusters were related to immune or fibroblast infiltration, hence identifying miRNAs associated with cells of the tumor microenvironment, while another large cluster was related to estrogen receptor (ER) signaling. Studying the chromatin landscape surrounding the CpGs associated with the estrogensignaling cluster, we found that miRNAs from this cluster are likely to be regulated through DNA methylation of enhancers bound by FOXA1, GATA2 and ER-alpha. Further, at the hub of the estrogen-cluster, we identified hsa-miR-29c-5p as negatively correlated with the mRNA and protein expression of the DNA methyltransferase DNMT3A, a key enzyme regulating DNA methylation. We found deregulation of hsa-miR-29c-5p already in pre-invasive breast lesions and postulate that hsa-miR-29c-5p may trigger early event abnormal DNA methylation in ER positive breast cancer. ConclusionsWe describe how miRNA expression and DNA methylation interact and associate with distinct breast cancer phenotypes.

Subtype and cell type specific expression of lncRNAs provide insight into breast cancer

“…One such lncRNA was MEG3, which was shown to contribute to the development of cardiac fibrosis 38 . Further, the expression of the mature miRNAs hsa-miR-99a and hsa-miR-100 have previously been associated to fibroblasts in breast cancer 39 . We found that the corresponding miRNA precursor transcripts which themselves are lncRNAs were part of cluster 2 and were indeed expressed in fibroblasts of the tumor breast microenvironment.…”

“…The Oslo2 breast cancer cohort. The Oslo2 breast cancer cohort has been previously described 39,50,51 and is a consecutive study collecting material from breast cancer patients with primary operable disease at several hospitals in south-eastern Norway. Patients were included in the years 2006-2019.…”

Crosstalk between microRNA expression and DNA methylation drives the hormone-dependent phenotype of breast cancer

“…mimQTL analysis R code is avai lab le f rom G it Hu b: h t t p s : / / g i t h u b . c o m / miriamragle/mimQTL.git [31].…”

“…i) ChromHMM [37] enrichment of genomic regions mapped to the CpGs of cluster 1 and 2. j) Pathway enrichment using Enrichr [33] of genes mapped to the CpGs of cluster 2 according to the Illumina HumanMethy-lation450k array. k) Table of 273 Availability of data and materials mimQTL analysis R code is available from GitHub: https://github.com/ miriamragle/mimQTL.git [31]. This study utilizes publicly available data sets: The DNA methylation data of the Oslo2 cohort are available from the Gene Expression Omnibus (GEO) database with accession number GSE84207, https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE84207 [2].…”