Mitochondria Pathway Signature Predicts Prognosis and Therapeutic Response and Identifies REXO2 as a Crucial Regulator in Breast Cancer

BACKGROUND: Mitochondrial-related pathways (MRPs) play a crucial role in cancer metabolism and progression; however, their prognostic value in breast cancer (BC) is still poorly understood. METHODS: We integrated multiomics data to investigate the landscape of MRPs in BC. A mitochondria pathways-associated signature (MPAS) was established using multimachine learning framework and interpreted by SHAP analysis across independent BC cohorts. Additionally, a series of functional experiments were employed to explore the role of RNA exonuclease 2 (REXO2) in BC cells. RESULTS: MRPs are extensively activated in BC at multiomics level. MPAS demonstrates outstanding predictive performance across multiple BC cohorts, with high scores indicating poor clinical outcomes. Moreover, it was observed that high MPAS scores are closely associated with immunosuppressive states and inflammatory microenvironments. SHAP analysis identified REXO2 as a hub factor of MPAS. Cell-based work confirmed that silencing REXO2 greatly inhibited cell proliferation and induced apoptosis in BC. CONCLUSIONS: Our proposed MPAS could effectively evaluate the prognosis and treatment response of BC patients, providing new reference for clinical decision-making. Furthermore, REXO2 regulates cell proliferation and apoptosis, making it a promising potential therapeutic target for inhibiting BC progression.