Regulation of mitochondrial ROS by C15ORF48 in a basal cell subpopulation contributes to chemotherapy resistance in triple negative breast cancer

Systemic neoadjuvant chemotherapy, often combined with immunotherapy, is the standard of care for early-stage, non-BRCA-mutant triple negative breast cancer (TNBC). Yet, up to 70% of patients retain residual disease after treatment, which is linked to recurrence and mortality within five years. To define mechanisms of resistance, we performed single-cell RNA sequencing on orthotopic TNBC patient-derived xenografts during a cycle of treatment with doxorubicin and cyclophosphamide (AC). Clustering identified four tumor epithelial cell populations, with basal cells enriched in residual tumors. These basal cells upregulated C15ORF48, a paralog of the mitochondrial cytochrome c oxidase subunit NDUFA4, while exhibiting reciprocal downregulation of NDUFA4. Functionally, C15ORF48 knockdown sensitized breast cancer cells to AC, increasing reactive oxygen species (ROS) and apoptosis. Thus, the upregulation of C15ORF48 blunts ROS accumulation and induces resistance to chemotherapy in the basal cell subpopulations. Our findings identify C15ORF48 as a potential therapeutic target for overcoming AC resistance in TNBC.