肥胖症是多种代谢和慢性疾病的已知危险因素，包括多种恶性肿瘤，在全球范围内急剧上升。许多临床研究表明，过高的身体质量指数（BMI）可能会加重乳腺癌的发生率、预后和死亡率。因此，理解肥胖和乳腺癌起始和进展之间的联系至关重要，因为它可能会影响患者的生存和生活质量。最近，来源于细胞外囊泡（EV）的miRNA因其在肿瘤学研究中的诊断、预后和治疗潜力而受到广泛关注。虽然EV来源的miRNA在乳腺癌早期检测方面的潜在作用已经反复提到，但在肥胖病人中包含在血清EV中的miRNA的筛查尚未报道。本研究从正常体重（NW）和超重/肥胖（OW/Ob）乳腺癌患者的循环EV中分离出miRNA，并使用转录组学、生物信息学和临床分析等方法，对与BMI相关的miRNA进行了分析，发现EV来源的let-7a miRNA表达下调与乳腺癌患者BMI值、肿瘤分级和预后密切相关。这些结果表明，血清EV来源的miRNA可能与患者的BMI有关，一旦在大量病人中得到验证，就可以为发现新的特异性生物标志物和创新靶标提供新思路，以防止肥胖介导的乳腺癌进展。

The incidence of obesity, a known risk factor for several metabolic and chronic diseases, including numerous malignancies, has risen sharply in the world. Various clinical studies demonstrate that excessive Body Mass Index (BMI) may worsen the incidence, prognosis, and mortality rates of breast cancer. Thus, understanding the link tying up obesity and breast cancer onset and progression is critically important, as it can impact patients' survival and quality of life. Recently, circulating extracellular vesicle (EV) derived miRNAs have attracted much attention for their diagnostic, prognostic and therapeutic potential in oncology research. Although the potential role of EV-derived miRNAs in the early detection of breast cancer has been repeatedly mentioned, screening of miRNAs packaged within serum EVs has not yet been reported in patients with obesity.Circulating EVs were isolated from normal weight (NW), and overweight/obese (OW/Ob) breast cancer patients and characterized by Transmission Electron Microscopy (TEM), Nanoparticle Tracking Analysis (NTA), and protein marker expression. Evaluation of EV-associated miRNAs was conducted in a screening (RNA-seq) and a validation (qRT-PCR) cohort. Bioinformatic analysis was performed to uncover significantly enriched biological processes, molecular functions and pathways. ROC and Kaplain-Meier survival analyses were used for clinical significance.Comparison of serum EV-derived miRNAs from NW and OW/Ob patients detected seven differentially expressed miRNAs (let-7a-5p, miR-122-5p, miR-30d-5p, miR-126-3p, miR-27b-3p, miR-4772-3p, and miR-10a-5p) in the screening cohort. GO analysis revealed the enrichment of protein phosphorylation, intracellular signal transduction, signal transduction, and vesicle-mediated transport among the top biological processes. In addition, the target genes were significantly enriched in pathways related to PI3K/Akt, growth hormones, and insulin signalings, which are all involved in obesity-related diseases and/or breast cancer progression. In the validation cohort, qRT-PCR confirmed a significant down-regulation of EV-derived let-7a in the serum of OW/Ob breast cancer patients compared to NW patients. Let-7a levels also exhibited a negative correlation with BMI values. Importantly, decreased let-7a miRNA expression was associated with higher tumor grade and poor survival in patients with breast cancer.These results suggest that serum-EV derived miRNAs may reflect a differential profile in relation to a patient's BMI, which, once validated in larger cohorts of patients, could provide insights into novel specific biomarkers and innovative targets to prevent the progression of obesity-mediated breast cancer.© 2023. The Author(s).