NDUFS1 promotes malignant breast cancer behaviors through enhancement of mitochondrial respiration and PROX1/c-Myc signaling

Cancer cells exploit oxidative phosphorylation (OXPHOS) for growth and metastasis. NDUFS1, the largest subunit of the electron transport chain complex I, is a promising therapeutic target in cancer but has a context-dependent role. Here, we elucidate the function of NDUFS1 in breast cancer. Elevated NDUFS1 expression was associated with advanced breast cancer stage and poor survival outcomes. In vitro experiments showed that NDUFS1 knockdown inhibited breast cancer cell proliferation, invasion, and stemness-associated properties, whereas NDUFS1 overexpression enhanced these phenotypes. Moreover, NDUFS1 directly regulated mitochondrial respiratory function in breast cancer cells and increased c-Myc expression via PROX1. In a mouse model of breast cancer, NDUFS1 knockdown in injected mammary carcinoma cells or OXPHOS inhibition decreased tumor growth and PROX1 and c-Myc expression. Our study highlights the role of the NDUFS1-PROX1-c-Myc axis in breast cancer progression, paving the way for new therapies targeting breast cancer mitochondrial OXPHOS.