Isolated lateropulsion by a lesion of the dorsal spinocerebellar tract.

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.