TY  - EJOU
AU  - Huang, Yu-Hao 
AU  - Chen, Hao-Yeh 
AU  - Chien, Peng-Ju 
AU  - Chen, Chun-Yu 
AU  - Li, Shao-Ti 
AU  - Lee, Hsueh-Te 
AU  - Lee, Yueh-Chun 
AU  - Chang, Wen-Wei 

TI  - BCL2-Associated Transcription Factor 1 Promotes SRC/Hypoxia-Inducible Factor 1 Subunit α-Mediated Cancer Stemness in Radioresistant Triple-Negative Breast Cancer
T2  - Oncology Research

PY  - 
VL  - 
IS  - 
SN  - 1555-3906

AB  - <b><i>Backgrounds:</i></b> 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 (<i>BCLAF1</i>) is an oncogene in certain cancers, but its role in TNBC is unclear. This study investigated <i>BCLAF1</i>’s involvement in radioresistance and CSC activity in TNBC. <b><i>Methods:</i></b> 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, <i>BCLAF1</i> 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. <b><i>Results:</i></b> Elevated BCLAF1 mRNA levels were associated with advanced pathological and T stages (analysis of variance [ANOVA], <i>p</i> = 1.4 × 10<sup>−3</sup>) and poorer overall survival by Kaplan–Meier analysis (<i>p</i> = 0.021). BCLAF1 expression was positively correlated with SRC signaling pathway-associated genes, including Kirsten rat sarcoma viral oncogene homolog (<i>KRAS</i>), GTPase-activating protein-binding protein 1 (<i>G3BP1</i>), and phosphoinositide-3-kinase regulatory subunit 1 (<i>PIK3R1</i>). Radioresistant cells exhibited higher BCLAF1 expression. SRC overexpression reduced radiosensitivity, while increasing BCLAF1 levels. <i>BCLAF1</i> 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). <i>BCLAF1</i> knockdown diminished nuclear HIF-1α, and HIF-1α inhibition abrogated BCLAF1-induced tumorsphere formation. <b><i>Conclusions:</i></b> 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.
KW  - B-cell lymphoma 2 (BCL2) associated transcription factor 1; SRC kinase; hypoxia-inducing factor 1subunit α; triple negative breast cancer; cancer stemness; radiation response

DO  - 10.32604/or.2026.080978