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

Breast cancer is the most prevalent cancer among women. Previous studies demonstrated that adipose-derived stem cells (ADSCs) co-cultured with resistin promote malignant behaviors in breast cancer cells. This study explores the roles of ADSCs and the adipocytokine resistin within the breast tumor microenvironment, emphasizing their contributions to metabolic reprogramming and cancer progression. RNA sequencing analysis of metabolic reprogramming pathways revealed that breast cancer cells in co-culture with resistin-treated ADSCs exhibited elevated expression of NDUFS1, the largest subunit of mitochondrial complex I. Knockdown of NDUFS1 inhibited breast cancer cell proliferation and tumorsphere formation, whereas its overexpression enhanced these effects through mitochondrial metabolism-mediated PROX1/c-Myc signaling pathway. Furthermore, treatment with metformin, an inhibitor of NDUFS1-activated mitochondrial metabolism, reduced Myc and PROX1 expression and diminished breast cancer cell proliferation. Syngeneic orthotopic mouse model showed that NDUFS1 downregulation significantly inhibited mammary tumor growth alongside decreased expression of PROX1 and c-Myc. Also, mitochondrial metabolism inhibitors metformin and rotenone demonstrated a therapeutic effect on NDUFS1-expressing breast tumor. Collectively, this research establishes a novel mechanistic framework linking metabolic adaptations and breast cancer, paving the way for innovative therapeutic strategies aimed at targeting NDUFS1 signaling.