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

Sep 22, 2026

Uploaded by Kyle

Systemic neoadjuvant chemotherapy with or without immunotherapy remains standard care for early-stage TNBC, yet up to 70% of patients show residual disease after treatment, driving recurrence and mortality within 5 years. Using single-cell RNA sequencing of orthotopic TNBC patient-derived xenografts treated with doxorubicin and cyclophosphamide, basal cell clusters enriched in residual tumors up-regulated C15ORF48 and reciprocally down-regulated NDUFA4. C15ORF48 knockdown sensitized cells to AC by increasing ROS and apoptosis, indicating C15ORF48-mediated blunting of ROS as a driver of chemotherapy resistance and a potential therapeutic target.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages17

Reading Time43 min

AccessFree to download

Introduction

Triple negative breast cancer and treatment resistance

Oxidative stress and ROS-based mechanisms

Role of drug-tolerant phenotypic states and mitochondrial dependencies

Corresponding author information

CANCER Regulation of mitochondrial ROS by C15ORF48 in a basal cell subpopulation contributes to chemotherapy resistance inTNBC Yan Jiang1, Noor M. Abdulkareem1, Amanda L. Rinkenbaugh1, Yuan Qi1,2, Steven W. Wall3, Xiaomei Zhang1, Jiansu Shao1, Sabrina Jeter-Jones1, Shirong Cai1, Faiza Baameur Hancock1, Gloria V. Echeverria3, Jeffrey T. Chang2,4, Helen Piwnica-Worms1* Systemic neoadjuvant chemotherapy, often combined with immunotherapy, is the standard of care for earlystage, 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 patientderived 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 ofthe 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 inTNBC. copyright © 2026 the Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. no claim to original U.S. Government Works. distributed under a creative commons Attribution noncommercial license 4.0 (cc BY-nc) . INTRODUCTION Breast cancer is the most common cancer diagnosis in females in the United States and the leading cause of cancer death in females worldwide (1). Triple negative breast cancer (TNBC) comprises 10 to 15% of all breast cancers and has a more aggressive clinical course than other subtypes of breast cancer (2). TNBC is a heterogeneous group of distinct diseases, each with unique genomic, phenotypic, histologic, and immunologic characteristics (3). These tumors are grouped together under the moniker ofTNBC because they lack expression of estrogen and progesterone receptors and do not overexpress the epidermal growth factor receptor 2 (HER2) (4), which make them unresponsive to many targeted therapies that are effective in other breast cancer subtypes. TNBC tumors have highly complex genomes, marked by numerous gene copy number gains and losses, as well as a relatively high mutation burden compared to other breast cancer subtypes. Despite this genetic complexity, TNBCs exhibit a limited number of recurrently mutated genes. TP53 is the most frequently mutated gene, with alterations found in over 80% of cases, followed by 10 to 15% PIK3CA (4). As a result, few targeted therapies are available to effectively treat the heterogeneous array of distinct diseases encompassed within non–breast cancer susceptibility gene 1/2 (BRCA1/2)-mutant TNBC. Therefore, systemic neoadjuvant chemotherapy (NACT) combined with immune checkpoint inhibitors is the standard of care for most patients with early-stage TNBC (5). However, a substantial fraction of patients with TNBC experience recurrence within 2 to 3 years (6). Therefore, it is critical to identify mechanisms underlying chemotherapy resistance in TNBC and develop strategies to overcome it. 1department of experimental Radiation Oncology, University of texas Md Anderson cancer center, houston, tX, USA. 2department of Bioinformatics and computational Biology, University of texas Md Anderson cancer center, houston, tX, USA. 3lester and Sue Smith Breast cancer center and department of Medicine, Baylor college of Medicine, houston, tX, USA. 4department of integrative Biology and Pharmacology, University of

FAQs

Why does residual disease after neoadjuvant chemotherapy matter in TNBC?

Up to 70% of patients retain residual disease after treatment, and this residual disease is linked to recurrence and mortality within 5 years.

What did single-cell RNA sequencing reveal about basal cells in residual TNBC tumors?

Single-cell clustering identified basal cell populations enriched in residual tumors that up-regulated C15ORF48 while showing reciprocal down-regulation of NDUFA4.

How does C15ORF48 affect chemotherapy response to doxorubicin and cyclophosphamide?

C15ORF48 knockdown sensitized breast cancer cells to AC by increasing reactive oxygen species and triggering apoptosis, indicating that C15ORF48 helps blunt ROS accumulation and promotes resistance.

Sep 22, 2026

Uploaded by Kyle