Open Access
ARTICLE
BCL2-Associated Transcription Factor 1 Promotes SRC/Hypoxia-Inducible Factor 1 Subunit α-Mediated Cancer Stemness in Radioresistant Triple-Negative Breast Cancer
Yu-Hao Huang1,#, Hao-Yeh Chen2,#, Peng-Ju Chien1, Chun-Yu Chen2,3, Shao-Ti Li4, Hsueh-Te Lee5, Yueh-Chun Lee4,6,*, Wen-Wei Chang1,7,*
1 Department of Biomedical Sciences, Chung Shan Medical University, Taichung, Taiwan
2 Department of Emergency Medicine, Tungs’ Taichung MetroHarbor Hospital, Taichung, Taiwan
3 Post-Baccalaureate Medicine, National Chung Hsing University, Taichung, Taiwan
4 Department of Radiation Oncology, Chung Shan Medical University Hospital, Taichung, Taiwan
5 Institute of Anatomy & Cell Biology, College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
6 School of Medicine, Chung Shan Medical University, Taichung, Taiwan
7 Department of Medical Research, Chung Shan Medical University Hospital, Taichung, Taiwan
* Corresponding Author: Yueh-Chun Lee. Email: 
; Wen-Wei Chang. Email: 
# These authors contributed equally to this work
Oncology Research https://doi.org/10.32604/or.2026.080978
Received 20 February 2026; Accepted 22 April 2026; Published online 12 May 2026
Abstract
Backgrounds: Triple-negative breast cancer (TNBC) is highly aggressive, insensitive to radiotherapy, and exhibits increased cancer stem cell (CSC) properties, contributing to poor patient outcomes. B-cell lymphoma 2 (BCL2) associated transcription factor 1 (BCLAF1) is an oncogene in certain cancers, but its role in TNBC is unclear. This study investigated BCLAF1’s involvement in radioresistance and CSC activity in TNBC. Methods: BCLAF1 expression and clinical significance were analyzed using The Cancer Genome Atlas (TCGA) breast cancer dataset. Radioresistant MDA-MB-231 cells were used to examine BCLAF1’s function. Proto-oncogene SRC (SRC) overexpression, BCLAF1 knockdown, dasatinib treatment, and hypoxia inducible factor 1 subunit α (HIF-1α) inhibition were employed to elucidate regulatory mechanisms. CSC activity was assessed using tumorsphere formation assays. Results: Elevated BCLAF1 mRNA levels were associated with advanced pathological and T stages (analysis of variance [ANOVA], p = 1.4 × 10−3) and poorer overall survival by Kaplan–Meier analysis (p = 0.021). BCLAF1 expression was positively correlated with SRC signaling pathway-associated genes, including Kirsten rat sarcoma viral oncogene homolog (KRAS), GTPase-activating protein-binding protein 1 (G3BP1), and phosphoinositide-3-kinase regulatory subunit 1 (PIK3R1). Radioresistant cells exhibited higher BCLAF1 expression. SRC overexpression reduced radiosensitivity, while increasing BCLAF1 levels. BCLAF1 knockdown suppressed tumorsphere formation. Dasatinib decreased BCLAF1, HIF-1α, and stemness proteins, including octamer-binding transcription factor 4 (OCT-4), Notch intracellular domain (NICD), and cellular myelocytomatosis oncogene (c-Myc). BCLAF1 knockdown diminished nuclear HIF-1α, and HIF-1α inhibition abrogated BCLAF1-induced tumorsphere formation. Conclusions: BCLAF1 enhances radioresistance and CSC properties in TNBC via SRC-HIF-1α signaling, suggesting that BCLAF1 is a potential therapeutic target to overcome radioresistance in TNBC.
Keywords
B-cell lymphoma 2 (BCL2) associated transcription factor 1; SRC kinase; hypoxia-inducing factor 1subunit α; triple negative breast cancer; cancer stemness; radiation response
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