Regulation of mitochondrial ROS by C15ORF48 in a basal cell subpopulation contributes to chemotherapy resistance in TNBC

  • Sci Adv. 2026 Apr 3;12(14):eaec8684. doi: 10.1126/sciadv.aec8684.
Yan Jiang  1 ,  Noor M Abdulkareem  1 ,  Amanda L Rinkenbaugh  1 ,  Yuan Qi  1  2 ,  Steven W Wall  3 ,  Xiaomei Zhang  1 ,  Jiansu Shao  1 ,  Sabrina Jeter-Jones  1 ,  Shirong Cai  1 ,  Faiza Baameur Hancock  1 ,  Gloria V Echeverria  3 ,  Jeffrey T Chang  2  4 ,  Helen Piwnica-Worms  1
Affiliations
  • 1. Department of Experimental Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • 2. Department of Bioinformatics and Computational Biology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • 3. Lester and Sue Smith Breast Cancer Center and Department of Medicine, Baylor College of Medicine, Houston, TX, USA.
  • 4. Department of Integrative Biology and Pharmacology, University of Texas Health Science Center, Houston, TX, USA.
PMID: 41931605 DOI: 10.1126/sciadv.aec8684
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.

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