CDCA4 Promotes Lipid Metabolism in Triple-Negative Breast Cancer Through Activation of the SESN2/mTOR/SREBP1 Pathway.

Triple-negative breast cancer (TNBC) is an aggressive subtype lacking effective targeted therapies. The molecular drivers of its progression and metabolic reprogramming remain unclear. Here, we identify cell division cycle-associated 4 (CDCA4) as a novel oncogenic driver in TNBC. Analysis of the TCGA-BRCA dataset, including 1085 breast cancer tissues and 112 normal tissues, showed that CDCA4 expression was significantly upregulated in breast cancer tissues. Subgroup analysis of TCGA-BRCA samples further showed higher CDCA4 expression (fold change = 1.707) in TNBC than in non-TNBC samples [TNBC, n = 116; non-TNBC, n = 984]. Survival analysis demonstrated that high CDCA4 expression was associated with poorer overall survival, with a hazard ratio of 1.54 (log-rank p = 0.0053). Functional assays demonstrated that CDCA4 knockdown suppresses proliferation, migration, invasion, and tumor growth in vitro and in vivo, whereas overexpression exerts opposite effects. RNA-sequencing revealed that CDCA4-regulated genes are enriched in lipid metabolism and mTOR signaling pathways. Mechanistically, CDCA4 depletion reduces intracellular lipids and the expression of lipogenic enzymes (FASN, ACC1). We show that CDCA4 activates mTOR and increases the nuclear active form of SREBP1, enhancing its promoter occupancy. Pharmacological mTOR inhibition reverses CDCA4-induced malignancy and metabolic alterations. Furthermore, Our findings suggest that SESN2 may contribute to CDCA4-mediated activation of mTOR signalling. SESN2 knockdown attenuates mTOR signaling and negates the pro-tumorigenic effects of CDCA4 overexpression. Collectively, these findings demonstrate that CDCA4 drives TNBC progression and lipid reprogramming via the SESN2/mTOR/SREBP1 axis, positioning CDCA4 as a potential prognostic biomarker and therapeutic target.