MEK/ERK/RSK2 positive feedback loop modulates EMT to promote migration and invasion of triple-negative breast cancer through regulating GALNT5 mRNA stability.

Triple-negative breast cancer (TNBC) is the most aggressive type of breast cancer, which is difficult to diagnose and treat due to lack of biomarkers, high metastasis, and recurrence. Ribosomal protein S6 kinase (RSK2) is frequently overexpressed and hyperactivated, thereby regulating proliferation and metastasis in many solid cancers, including breast cancer. However, the underlying mechanisms of RSK2 in TNBC metastasis are poorly understood. Here, we explored the role of RSK2 in the migration and invasion of TNBC. Our findings revealed that overexpression of RSK2 promoted Epithelial-mesenchymal transition (EMT) to induce migration and invasion of TNBC cells MDA-MB-231 and 4T1, whereas RSK2 knockdown decreased them. Mechanically, our results showed that RSK2 positively regulated the MEK/ERK pathway and enhanced GALNT5 mRNA expression and stability by RNA-seq analysis and experimental validation. Furthermore, knockdown of GALNT5 attenuated the MEK/ERK pathway. Finally, the in vivo results found that RSK2 promoted growth and EMT of TNBC. Collectively, our findings indicated that the MEK/ERK/RSK2 positive feedback loop promoted EMT to induce migration and invasion of TNBC via enhancing GALNT5 mRNA stability, and it was suggested that RSK2 may provide a novel therapeutic target for TNBC patients.