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Breast cancer remains a leading cause of cancer-related mortality worldwide, with obesity markedly increasing the risk in affected individuals. Liquid biopsy-based extracellular vesicles (EVs) offer a minimally invasive platform for molecular profiling of tumor-derived markers. Plasma small-EVs from obese, chemotherapy-naïve breast cancer patients (n = 76; stages I-III) and age-matched obese controls (n = 36) were enriched and characterized by high-resolution transmission electron microscopy, dynamic light scattering (DLS) and specific EV markers. Proteomic profile of the enriched small-EVs using nanoLC-MS/MS identified Fibronectin 1 (FN1) and von Willebrand Factor (VWF) as candidate markers. Bioinformatics and STRING networks revealed interactions with Syndecan-2 (SDC2) and Galectin-3 (Gal-3). As an independent validation, western blot confirmed that FN1, VWF, and SDC2 were higher enriched in the small-EVs of breast cancer with different stages than in those of normal and that high content of small-EVs FN1 and SDC2 was primarily associated with the aggressive triple-negative breast cancer (TNBC) subtype. Interestingly, Gal-3 was reduced in small-EVs but elevated in breast carcinoma tissues and microvesicle (MV)-enriched EVs. Functionally, treatment with TNBC-derived plasma small-EVs not only downregulated expression of epithelial marker CDH1, and upregulated expression of the mesenchymal markers ZEB2 and FN1 in low-invasive MCF-7 breast cancer cells, but also elevated expression of inflammatory and matrix-remodeling mediators (Il-6, Tnf-α, and Mmp-9) in BNL CL.2 normal liver cells. ROC-Plotter and drug-gene interaction analyses indicated associations with therapy response, with approved compounds targeting FN1 and VWF. Overall, these findings reveal proteomic signatures of minimally invasive plasma small-EVs as promising markers associated with diagnosis, molecular subtyping, disease progression, and guiding therapeutic strategies in obese breast cancer patients.