Epigenetic Regulation of GFRA1 by Extracellular Vesicle lncRNA SOX9‐AS1 Facilitates Breast Cancer Metastasis

Breast cancer (BRCA) metastasis remains a critical clinical challenge, with extracellular vesicles (EVs) playing a significant role in intercellular communication during tumor progression. This study investigates the role of EV-enriched long non-coding RNA (lncRNA) SOX9-AS1 in promoting metastasis in highly metastatic BRCA. Bioinformatics analysis revealed SOX9-AS1 as highly expressed in metastatic BRCA tissues and EVs, correlating with the eIF3d/GFRA1 axis. In vitro, EVs derived from high metastatic BRCA cells transferred SOX9-AS1 to low metastatic BRCA cells, enhancing proliferation and invasion. Silencing SOX9-AS1 in high metastatic BRCA cells suppressed these phenotypes. Mechanistically, SOX9-AS1 recruited eIF3d to the GFRA1 promoter, facilitating its transcription and driving metastasis. In vivo, silencing SOX9-AS1 in EVs reduced tumor growth and metastasis in mouse models. These findings demonstrate that SOX9-AS1 in EVs facilitates BRCA metastasis via epigenetic regulation of GFRA1, providing potential targets for therapeutic intervention in metastatic BRCA.