Transcription factor TFAP2A drives the growth and metastasis and blocks ferroptosis of triple-negative breast cancer by activating PRAME transcription.

Triple-negative breast cancer (TNBC) is the subtype of breast cancer with the highest rates of recurrence and mortality. Transcription factor AP-2 alpha (TFAP2A) plays a key role in modulating the expression of various genes, affecting multiple biological processes such as ferroptosis, and driving the initiation and progression of tumors, including breast cancer. Furthermore, preferentially expressed antigen in melanoma (PRAME), an inhibitor of retinoic acid signaling, was reported to promote TNBC cell migration and invasion. This study aims to explore the effects of TFAP2A and PRAME in TNBC. TFAP2A and PRAME mRNA levels were detected by real-time quantitative polymerase chain reaction (RT-qPCR). TFAP2A, solute carrier family 7 member 11 (SLC7A11), glutathione peroxidase 4 (GPX4), and PRAME protein levels were determined using western blot. Cell invasion, migration, proliferation, and apoptosis were assessed using Transwell, wound healing, colony formation, and flow cytometry. Malondialdehyde (MDA), Fe level, glutathione (GSH), and reactive oxygen species (ROS) levels were determined using corresponding kits. After bioinformatics JASPAR analysis, the binding between TFAP2A and PRAME promoter was predicted and then verified using chromatin immunoprecipitation (ChIP) and dual-luciferase reporter assays. A xenograft model was applied to analyze the effects of TFAP2A on TNBC cell growth in vivo. TFAP2A and PRAME were highly expressed in TNBC tissues (n = 43) and TNBC cell lines compared with paracancerous non-tumor tissues (n = 43) and human non-tumorigenic breast epithelial cell line (MCF10A). Furthermore, the deficiency of TFAP2A by sh-TFAP2A inhibited TNBC cell invasion, migration, proliferation, and induced apoptosis and ferroptosis in vitro. At the molecular level, TFAP2A was a transcription factor of PRAME and increased the transcriptional activity of PRAME via binding to its promoter region. TFAP2A knockdown could repress TNBC tumor growth in xenograft mode in vivo. TFAP2A-activated PRAME promoted TNBC cell malignant behavior and constrained ferroptosis, which provided a promising therapeutic target in TNBC.