Targeting the Extracellular Signal-Regulated Kinase 5-Cellular Jun-Vimentin Axis to Inhibit Epithelial-Mesenchymal Transition and Metastasis in Patients with Triple-Negative Breast Cancer.

Abstract

Breast cancer is the second most common cancer worldwide and remains the leading cause of cancer-related deaths among women. Triple-negative breast cancer (TNBC) represents approximately 15-20% of all breast cancer cases and is characterized by an aggressive clinical course and a high risk of metastasis. Extracellular signal-regulated kinase 5 (ERK5) is a critical biomarker that promotes tumor progression through mechanisms involving cell proliferation, invasion, and metastasis; however, its precise role in epithelial-mesenchymal transition (EMT) in TNBC remains unclear. In this study, we analyzed data from 117 patients with TNBC and found that high ERK5 expression was significantly associated with tumor progression, shorter progression-free survival, and shorter overall survival. RNA sequencing of a highly metastatic TNBC cell line revealed that ERK5 knockdown modulated the expression of various gene clusters, particularly those associated with DNA repair, G2/M checkpoint regulation, and angiogenesis. In addition, ERK5 knockdown in a mouse xenograft model significantly suppressed tumor proliferation and lung metastasis, inhibited tumor cell migration, and reduced the expression of EMT-related proteins. Mechanistically, our data further demonstrated that ERK5 regulates the interaction between cellular JUN (c-JUN) and the vimentin promoter, thereby modulating vimentin expression and downstream signaling pathways. A significant positive correlation between ERK5 and vimentin expression in human TNBC tissue specimens further supported this regulatory association. These findings suggest that ERK5 mediates the recruitment of c-JUN to regulate vimentin expression, thereby promoting EMT and metastasis. Thus, the ERK5/c-JUN/vimentin axis may be a potential therapeutic target to improve clinical outcomes in patients with TNBC.