SLC6A14 Drives Mitochondrial Fusion and Oxidative Phosphorylation to Promote Cancer Stemness and Early-Onset of Breast Cancer.

Abstract

Early-onset breast cancer (EOBC), diagnosed before the age of 45, is associated with poor therapeutic outcomes and limited survival, yet the underlying mechanisms remain poorly defined. Identifying environmental risk factors and actionable therapeutic targets is an urgent clinical need. Notably, the largest survival gap between younger and older patients occurs in luminal breast cancer, implicating potential endocrine disruption. Here, an association is identified between elevated levels of di(2-ethylhexyl)phthalate (DEHP) in hair, a widely used endocrine-disrupting plasticizer, and earlier age at diagnosis of breast cancer. Mechanistically, DEHP exposure promotes tumor initiation by enhancing cancer stemness through mitochondrial fusion and glutamine-driven oxidative phosphorylation. DEHP upregulates the glutamine transporter SLC6A14 to enhance glutamine uptake, while suppressing mitochondrial fission factor (MFF), which exacerbates mitochondrial fusion. High SLC6A14 expression correlates with cancer stemness signatures and earlier onset in patient cohorts. Inhibition of SLC6A14 reduces stemness, impairs tumor growth, and sensitizes tumors to chemotherapy. Collectively, the findings uncover a novel environmental-metabolic axis linking plasticizer exposure to EOBC and establish SLC6A14 as a promising metabolic vulnerability. These results provide a strong preclinical rationale for targeting SLC6A14 in young breast cancer patients and offer new insights into mitigating the oncogenic impact of environmental pollutants.