On the Therapeutic Potential of ERK4 in Triple-Negative Breast Cancer

SIMPLE SUMMARY: Patients with triple-negative breast cancer have a poor outcome owing to the clinically aggressive behavior of the disease and the lack of hormonal or targeted therapies. Identification of new actionable targets to guide the development of effective treatments remains a critical clinical need. It has been recently suggested that the protein kinase ERK4 has oncogenic signaling activity in triple-negative breast cancer cells and represents a promising novel therapeutic target. However, we raise questions about the experimental approaches used to validate the oncogenic function of ERK4 in breast cancer. ABSTRACT: ERK3 and ERK4 define a distinct and understudied subfamily of mitogen-activated protein kinases (MAPKs). Little is known about the physiological roles of these atypical MAPKs and their association with human diseases. Interestingly, accumulating evidence points towards a role for ERK3 and ERK4 signaling in the initiation and progression of various types of cancer. Notably, a recent study reported that ERK4 is expressed in a subset of triple-negative breast cancer (TNBC) cell lines and that this expression is critical for AKT activation and for sustaining TNBC cell proliferation in vitro and tumor growth in mice. The authors also showed that depletion of ERK4 sensitizes TNBC cells to phosphatidylinositol-3-kinase (PI3K) inhibitors. They concluded that ERK4 is a promising therapeutic target for TNBC and has potential for combination therapy with PI3K inhibitors. Here, we raise concerns about the cellular models and experimental approaches used in this study, which compromise the conclusions on the oncogenic role of ERK4 in TNBC.