Abstract
Breast cancer-associated fibroblasts (CAFs) have a crucial role in tumor initiation, metastasis and therapeutic resistance by secreting various growth factors, cytokines, protease and extracellular matrix components. Soluble factors secreted by CAFs are involved in many pathways including inflammation, metabolism, proliferation and epigenetic modulation, suggesting that CAF-dependent reprograming of cancer cells affects a large set of genes. This paracrine signaling has an important role in tumor progression, thus deciphering some of these processes could lead to relevant discoveries with subsequent clinical implications. Here, we investigated the mechanisms underlying the changes in gene expression patterns associated with the cross-talk between breast cancer cells and the stroma. From RNAseq data obtained from breast cancer cell lines grown in presence of CAF-secreted factors, we identified 372 upregulated genes, exhibiting an expression level positively correlated with the stromal content of breast cancer specimens. Furthermore, we observed that gene expression changes were not mediated through significant DNA methylation changes. Nevertheless, CAF-secreted factors but also stromal content of the tumors remarkably activated specific genes characterized by a DNA methylation pattern: hypermethylation at transcription start site and shore regions. Experimental approaches (inhibition of DNA methylation, knockdown of methyl-CpG-binding domain protein 2 and chromatin immunoprecipitation assays) indicated that this set of genes was epigenetically controlled. These data elucidate the importance of epigenetics marks in the cancer cell reprogramming induced by stromal cell and indicated that the interpreters of the DNA methylation signal have a major role in the response of the cancer cells to the microenvironment.
Highlights
The tumor microenvironment is composed of a heterogeneous population of non-neoplastic cells including immune cells, vascular endothelial cells and fibroblasts
cancer-associated fibroblasts (CAFs) present some characteristics of myofibroblasts and express specific markers including α-smooth muscle actin, vimentin, neuron glial antigen-2 and fibroblast-specific protein-1.10 CAFs secrete various growth factors, cytokines, proteases and extracellular matrix components involved in tumor initiation, progression and invasion of breast cancer.[11,12,13,14,15,16,17,18]
We identified by RNAseq 292 and 459 genes methylation patterns and gene expression, SKBR3 and AU565 cells upregulated in SKBR3 and AU565 cells, respectively, following siMBD2 were treated with decitabine (DAC), an inhibitor of DNA treatments compared with scrambled control siRNA
Summary
The tumor microenvironment is composed of a heterogeneous population of non-neoplastic cells including immune cells, vascular endothelial cells and fibroblasts. CAF-secreted factors remarkably activate genes characterized by a high level of methylated CpGs on their regulatory region, defining a DNA methylation pattern of genes modulated by stromal cell contents in human breast tumors.
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