BCL2-Associated Transcription Factor 1 Promotes SRC/Hypoxia-Inducible Factor 1 Subunit α-Mediated Cancer Stemness in...

Area of Science:

• Oncology
• Molecular Biology
• Cancer Research

Background:

• Triple-negative breast cancer (TNBC) is aggressive, radioresistant, and associated with poor outcomes due to cancer stem cell (CSC) properties.
• The role of B-cell lymphoma 2 (BCL2) associated transcription factor 1 (BCLAF1) in TNBC, particularly its contribution to radioresistance and CSC activity, remains unclear.

Purpose of the Study:

• To investigate the involvement of BCLAF1 in radioresistance and CSC activity within TNBC.
• To elucidate the regulatory mechanisms underlying BCLAF1's function in TNBC.

Main Methods:

• Analyzed BCLAF1 expression and clinical significance using The Cancer Genome Atlas (TCGA) dataset.
• Utilized radioresistant MDA-MB-231 cells to study BCLAF1 function.
• Employed SRC overexpression, BCLAF1 knockdown, dasatinib treatment, and HIF-1α inhibition to explore regulatory pathways.
• Assessed CSC activity via tumorsphere formation assays.

Main Results:

• Elevated BCLAF1 mRNA levels correlated with advanced TNBC stages and poorer overall survival.
• BCLAF1 expression positively associated with SRC signaling pathway genes (KRAS, G3BP1, PIK3R1).
• BCLAF1 knockdown suppressed tumorsphere formation, while BCLAF1 overexpression enhanced radioresistance.
• Dasatinib treatment reduced BCLAF1, HIF-1α, and stemness markers (OCT-4, NICD, c-Myc).
• BCLAF1 knockdown diminished nuclear HIF-1α; HIF-1α inhibition abrogated BCLAF1-induced tumorsphere formation.

Conclusions:

• BCLAF1 significantly enhances radioresistance and CSC properties in TNBC.
• The SRC-HIF-1α signaling pathway mediates BCLAF1's effects in TNBC.
• BCLAF1 represents a potential therapeutic target for overcoming radioresistance in TNBC.