Insulin Resistance Increases TNBC Aggressiveness and Brain Metastasis via Adipocyte-Derived Exosomes

Abstract Patients with triple-negative breast cancer (TNBC) and comorbid type 2 diabetes (T2D), characterized by insulin resistance of adipose tissue, have a higher risk of metastasis and shorter survival. Adipocytes are the main nonmalignant cells of the breast tumor microenvironment (TME). However, adipocyte metabolism is usually ignored in oncology, and the mechanisms that couple T2D to TNBC outcomes are poorly understood. In this study, we hypothesized that exosomes, small vesicles secreted by TME breast adipocytes, drive epithelial-to-mesenchymal transition (EMT) and metastasis in TNBC via miRNAs. Exosomes were purified from conditioned media of 3T3-L1 mature adipocytes, either insulin-sensitive (IS) or insulin-resistant (IR). Murine 4T1 cells, a TNBC model, were treated with exosomes in vitro (72 hours). EMT, proliferation, and angiogenesis were elevated in IR versus control and IS. Brain metastases showed more mesenchymal morphology and EMT enrichment in the IR group. MiR-145a-3p is highly differentially expressed between IS and IR and potentially regulates metastasis. Implications: IR adipocyte exosomes modify the TME, enhance EMT, and promote brain metastasis—likely via miRNA pathways—suggesting that metabolic diseases such as T2D foster a prometastatic TME, reducing survival and warranting close monitoring and potential metabolic interventions in patients with TNBC and T2D.