Genome‐wide analysis revealsmiR‐3184‐5p andmiR‐181c‐3p as a critical regulator for adipocytes‐associated breast cancer.

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 enrich�ment 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