Extracellular vesicles obesity-related proteins: putative contribution to breast cancer malignancy and prognosis

The association of obesity (OB) with poorer outcomes of breast cancer (BC) patients is far recognized, underscoring the influence of soluble factors secreted by the dysfunctional obese adipose tissue (AT) upon increased tumor aggressiveness. However, the molecular mechanisms underlying this association remain incompletely understood. The relevance of extracellular vesicles (EVs) in human diseases reinforces their value as a minimally invasive, tissue-specific biological source. In this context, based on large-scale protein profiling of OB-EVs followed by a bioinformatic approach, we sought to translationally investigate proteins of interest in OB-EVs and map relevant biological processes to BC, deepening our analysis of putative and specific prognostic candidate proteins in BC under obese conditions. For this purpose, untargeted proteomics (nano-HPLC–MS/MS) of EVs isolated from AT from lean and obese subjects (CAAE: 03769618.3.00005646, CAAE: 56,302,121.2.0000.5259) was performed. Bioinformatic treatment, integration with open-access databases, and literature-based evidence supported EV-protein annotation (ExoCarta), functional and pathway analysis (Reactome, Panther DB, Pathway Commons), BC-associated gene expression (GSCA), and prognostic association (KM Plotter Platform). OB-EVs proteins were mainly located within the cytoplasm, plasma membrane, and intracellular structures. Neutrophil degranulation, extracellular matrix organization, endoplasmic reticulum stress, unfolded protein response, and chemoresistance in HER2 + BC were mapped for up-abundant proteins within the OB-EVs group. 37.2% of these proteins correlated with increased mRNA expression in BC tumor tissues, highlighting standard biological processes that were significantly enriched in OB-EVs. Tumor invasion and metastasis emerged as significant hallmarks associated with up-abundant proteins in both OB-EVs and BC, including CALML5, DSP, YWHAH, CALR, PPIB, COL6A3, and LCP1. Specific protein candidates with potential relevance to prognosis were mapped for different molecular subtypes of BC: triple-negative (CALML5, COL6A3, TMED2); HER2 + (ANP32E, DDB1, VDAC1, SYNGR2); ER + /PR + (ARHGDIB); ER + (HSPA5, TAGLN2, TPM4). Moving beyond the traditional descriptive proteomic approach, our distinctive translational perspective provided context-specific insights into molecular signatures shared by BC and obesity, as well as putative prognostic candidates specific to each BC molecular subtype. Our contribution may provide a roadmap for further functional validation to support personalized interventions in coexisting BC and obesity.