Language
English
Publication Date
4-3-2026
Journal
Science Advances
DOI
10.1126/sciadv.aec8684
PMID
41931605
PMCID
PMC13048268
PubMedCentral® Posted Date
4-3-2026
PubMedCentral® Full Text Version
Post-print
Abstract
Systemic neoadjuvant chemotherapy, often combined with immunotherapy, is the standard of care for early-stage, non-breast cancer susceptibility gene (BRCA)-mutant triple negative breast cancer (TNBC). However, up to 70% of patients retain residual disease after treatment, which is linked to recurrence and mortality within 5 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 up-regulated C15ORF48, a paralog of the mitochondrial cytochrome c oxidase associated subunit FA4 (NDUFA4), while exhibiting reciprocal down-regulation of NDUFA4. Functionally, C15ORF48 knockdown sensitized breast cancer cells to AC, increasing reactive oxygen species (ROS) and apoptosis. Thus, the up-regulation 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.
Keywords
Humans, Reactive Oxygen Species, Drug Resistance, Neoplasm, Animals, Mitochondria, Female, Triple Negative Breast Neoplasms, Doxorubicin, Gene Expression Regulation, Neoplastic, Cell Line, Tumor, Mice, Cyclophosphamide, Apoptosis, Xenograft Model Antitumor Assays, Mitochondrial Proteins
Published Open-Access
yes
Recommended Citation
Jiang, Yan; Abdulkareem, Noor M; Rinkenbaugh, Amanda L; et al., "Regulation of Mitochondrial Ros by C15ORF48 in a Basal Cell Subpopulation Contributes to Chemotherapy Resistance in TNBC" (2026). Faculty, Staff and Students Publications. 8022.
https://digitalcommons.library.tmc.edu/baylor_docs/8022