The EGFR Signaling Modulates in Mesenchymal Stem Cells the Expression of miRNAs Involved in the Interaction with Breast Cancer Cells

SIMPLE SUMMARY: The epidermal growth factor receptor (EGFR) plays a central role in the tumor microenvironment, through the activation of paracrine and autocrine circuits that promote cancer development and progression. Our study for the first time provides evidence that the EGFR system induces in mesenchymal stem cells (MSCs) significant changes in the expression of a wide number of miRNAs, including miR-23c, that might be involved in the cross-talk with breast cancer cells. We also propose a novel mechanism of action of miR-23c in basal/claudin-low breast cancer cell lines. These results might help to increase our knowledge on the mechanisms of breast cancer progression mediated by the EGFR in the tumor microenvironment. ABSTRACT: We previously demonstrated that the epidermal growth factor receptor (EGFR) modulates in mesenchymal stem cells (MSCs) the expression of a number of genes coding for secreted proteins that promote breast cancer progression. However, the role of the EGFR in modulating in MSCs the expression of miRNAs potentially involved in the progression of breast cancer remains largely unexplored. Following small RNA-sequencing, we identified 36 miRNAs differentially expressed between MSCs untreated or treated with the EGFR ligand transforming growth factor α (TGFα), with a fold change (FC) < 0.56 or FC ≥ 1.90 (CI, 95%). KEGG analysis revealed a significant enrichment in signaling pathways involved in cancer development and progression. EGFR activation in MSCs downregulated the expression of different miRNAs, including miR-23c. EGFR signaling also reduced the secretion of miR-23c in conditioned medium from MSCs. Functional assays demonstrated that miR-23c acts as tumor suppressor in basal/claudin-low MDA-MB-231 and MDA-MB-468 cells, through the repression of IL-6R. MiR-23c downregulation promoted cell proliferation, migration and invasion of these breast cancer cell lines. Collectively, our data suggested that the EGFR signaling regulates in MSCs the expression of miRNAs that might be involved in breast cancer progression, providing novel information on the mechanisms that regulate the MSC-tumor cell cross-talk.