Genome-wide analysis reveals miR-3184-5p and miR-181c-3p as a critical regulator for adipocytes-associated breast cancer.

Abstract

Obesity is considered as an independent risk factor for breast cancer (BCa) and plays a major role in the breast tumor microenvironment. The etiology and mechanisms by which obesity contributes to BCa development is not yet understood. Herein, we show that in vitro coculture of BCa cells with mature adipocytes (MA-BCa) increased proliferation, migration, and invasive phenotype of BCa cells. MA-BCa coculture led to increased production of proinflammatory cytokines and chemokines. To identify microRNAs (miRNAs) in BCa cells that are modulated by the presence of adipocytes, we used small RNA sequencing analysis. Sequencing data revealed that 98 miRNAs were differentially expressed in MA-BCa. Among them, miR-3184-5p and miR-181c-3p were found to be the most upregulated and downregulated miRNAs, and direct targets are FOXP4 and PPARα, respectively. In vitro functional assays using a combination of miR-3184-5p inhibitor and miR-181c-3p mimic synergistically decreased adipocytes-induced cell proliferation and invasive capacity of BCa cells. Gene Set Enrichment analysis indicated that transcription factors were highly enriched followed by protein kinases, oncogene, and protein regulators in MA-BCa. GeneGo Metacore pathway analysis uncovered "NOTCH-induced EMT pathway" was found to be the most abundant in MA-BCa. Consistently, epithelial-mesenchymal transition-associated markers were also increased in MA-BCa. The disease enrichment analysis of the predict target genes revealed that diabetes mellitus was significantly affected disease in MA-BCa. Taken together, our data suggest that miRNA-based regulatory mechanism associated with deregulation of pathways and biological functions orchestrated by adipocytes-secreted factors might drive the BCa progression and metastasis in obese patients.