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Stromal-associated cytokines bias the interplay between gene expression and DNA methylation in human breast cancers.

ABSTRACT: In human tumours, the crosstalk between cancer cells and their microenvironment is involved in tumour progression, metastasis and resistance to anti-cancer therapies. Among the factors involved in this exchange of information pro-inflammatory cytokines seem to play a crucial role. We observed that a group of pro-inflammatory cytokines, interleukin 6 (IL6), interleukin 1-beta (IL1b), and tumour necrosis factor-alpha (TNFa), preferentially activated genes exhibiting a high basal methylation level at their transcription start sites, in the human breast cancer cell line MCF7. In human breast tumours, these responding genes were also hypermethylated, and some of them (N = 104) were differentially methylated across human breast tumour samples (The Cancer Genome Atlas cohort). While their expression was positively correlated with the stromal content of the tumours and the expression of stromal-associated pro-inflammatory cytokines, the expression of this subset of genes was negatively correlated with their methylation level at their 5' end. Nevertheless, while the methylation level of this subset of genes was not correlated with the stromal cell content of the tumours, this negative correlation was partially lost in tumours with high stromal cell content. Consistently, we observed that the methylation level in this subset of genes influenced the correlation between gene expression and stromal cell content. Thus, these data indicated that the stromal component of breast tumours should be taken into account for DNA methylation and gene expression studies and suggest an additional pathway, via DNA methylation, in the cross-talk between cancer cells and their microenvironment in human breast cancers.

SUBMITTER: Hernandez-Vargas H

PROVIDER: S-EPMC7188392 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:IntroductionAberrant DNA methylation has been found frequently in human breast cancers, associated with the loss of expression of a number of regulatory genes for growth and correlated to clinical outcomes. The present study was undertaken to determine whether methylation of a set of growth-suppressor genes would correlate to the expression of estrogen receptors (ERs) and progesterone receptors (PRs).MethodsWe used a pyrosequencing methylation analysis to study the methylation of 12 known growth-suppressor genes in 90 pairs of malignant/normal breast tissues. We also examined the expression of ERs and PRs in those specimens by immunohistochemistry. Mutations of p53 in tumor cells were detected by direct sequencing.ResultsTwelve tumor-suppressor genes: ARHI, RASSF1A, HIN-1, RARbeta2, hMLH1, 14-3-3 sigma, RIZ1, p16, E-cadherin, RIL, CDH13, and NKD2 were selected for this methylation study. Five of them (RIL, HIN-1, RASSF1A, CDH13, and RARbeta2) were frequently methylated in breast cancers (57%, 49%, 58%, 44%, and 17%, respectively) but not the normal breast (0-4%). Two panels of methylation profiles were defined. The methylation of the HIN-1/RASSFIA panel strongly correlated to the expression of ERs, PRs, and hormone receptors (HRs; which were defined as 'positive' if ERs and/or PRs were positive; p < 0.001). Conversely, the methylation of the RIL/CDH13 panel strongly correlated to negative ER, PR, and HR expression (p = 0.001, 0.025, and 0.001, respectively). The subset of triple-negative breast cancers (in other words, those with negative ER, PR, and HER-2/neu status) was positively associated with the methylation of the RIL/CDH13 panel and negatively associated with the HIN-1/RASSF1A panel. Mutations of p53 were found in nine breast tumors (11%), seven of which lacked methylation in both panels.ConclusionWe have defined two panels (HIN-1/RASSFIA, and RIL/CDH13) of methylation profiles, which correlated, either positively or negatively, to HR status.

Project description:BackgroundAbnormal 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 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.MethodsmiRNA expression and DNA methylation data from two breast cancer cohorts, Oslo2 (n = 297) and The Cancer Genome Atlas (n = 439), were integrated through a correlation approach that we term miRNA-methylation Quantitative Trait Loci (mimQTL) analysis. Hierarchical clustering was used to identify clusters of miRNAs and CpGs that were further characterized through analysis of mRNA/protein expression, clinicopathological features, in silico deconvolution, chromatin state and accessibility, transcription factor binding, and long-range interaction data.ResultsClustering of the significant mimQTLs identified distinct groups of miRNAs and CpGs that reflect important biological processes associated with breast cancer pathogenesis. Notably, two major miRNA 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 CpGs associated with the estrogen signaling 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 DNA methyltransferase DNMT3A, a key enzyme regulating DNA methylation. We found deregulation of hsa-miR-29c-5p already present 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.

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Stromal-associated cytokines bias the interplay between gene expression and DNA methylation in human breast cancers.

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