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.
Huang et al. (Thu,) studied this question.