Breast cancer metastasis in obesity: extracellular vesicles as drivers.

[ABSTRACT] Obesity, a significant risk factor for breast cancer, contributes to tumor progression by releasing proinflammatory adipokines through extracellular vesicles (EVs) secreted by adipose tissue (AT). These EVs, which are small membrane vesicles, have the potential to modulate tumor cell behavior, yet the mechanisms underlying this communication remain largely unclear. This study investigates how EVs derived from obese AT influence malignancy-related processes in MCF-7 breast cancer cells. To assess the effects of obese AT-EVs on MCF-7 cells, EVs were isolated from the AT secretome obtained from obese and lean individuals (control group). MCF-7 cells were stimulated with these EVs, and subsequent analyses were performed to assess changes in cellular functions, epithelial marker expression, and signaling pathways. Obese AT-derived EVs exhibited significantly elevated levels of TGF-β, leading to activation of the TGF-β/SMAD signaling pathway. This activation resulted in reduced E-cadherin expression and enhanced migration and invasiveness of MCF-7 cells. Additionally, these EVs were enriched in fatty acids, which fueled the tumor cells via fatty acid oxidation (FAO), further contributing to their migratory capacity. This study identifies TGF-β signaling and FAO as central mechanisms by which obese adipose tissue-derived EVs promote a metastatic phenotype in breast cancer cells. These findings provide insight into the molecular crosstalk between obesity and breast cancer and highlight potential targets for therapeutic intervention.