Targeting mitochondrial EGFR by CTAB in triple-negative breast cancer

Abstract EGFR is an oncogenic factor highly expressed in multiple tumor types. While previous research has primarily focused on plasma membrane-localized EGFR, the role of its mitochondrial localization (mitoEGFR) in breast cancer remains poorly understood. This study reveals that EGFR is enriched in mitochondria in triple-negative breast cancer (TNBC), with high mitoEGFR expression closely associated with aggressive phenotypes. Through small-molecule compound screening, we identified cetrimonium bromide (CTAB) as an effective inhibitor of mitoEGFR. CTAB induces mitochondrial morphological abnormalities, disrupts reactive oxygen species (ROS) homeostasis, and activates mitophagy, thereby significantly suppressing proliferation, stemness maintenance, and migration capabilities of TNBC cells. This research not only demonstrates the critical role of mitoEGFR in TNBC progression but also elucidates the mechanism by which CTAB, as a mitoEGFR inhibitor, suppresses tumor growth by inducing mitochondrial dysfunction and autophagy. These findings provide both a novel therapeutic target and a translationally promising compound for TNBC treatment.