The extracellular-regulated protein kinase 5 (ERK5) enhances metastatic burden in triple-negative breast cancer through focal adhesion protein kinase (FAK)-mediated regulation of cell adhesion

Qiuping Xu,Emanuele Giurisato,Katherine G Finegan,Cathy Tournier,Hao Zhang,Jingwei Zhang,Fuhui Chen,Ahmet Ucar,Adam J Pearson,Nisha Ali,Wei Zhang,Blanca Risa,Brian A Telfer

doi:10.1038/s41388-021-01798-2

Abstract

There is overwhelming clinical evidence that the extracellular-regulated protein kinase 5 (ERK5) is significantly dysregulated in human breast cancer. However, there is no definite understanding of the requirement of ERK5 in tumor growth and metastasis due to very limited characterization of the pathway in disease models. In this study, we report that a high level of ERK5 is a predictive marker of metastatic breast cancer. Mechanistically, our in vitro data revealed that ERK5 was critical for maintaining the invasive capability of triple-negative breast cancer (TNBC) cells through focal adhesion protein kinase (FAK) activation. Specifically, we found that phosphorylation of FAK at Tyr397 was controlled by a kinase-independent function of ERK5. Accordingly, silencing ERK5 in mammary tumor grafts impaired FAK phosphorylation at Tyr397 and suppressed TNBC cell metastasis to the lung without preventing tumor growth. Collectively, these results establish a functional relationship between ERK5 and FAK signaling in promoting malignancy. Thus, targeting the oncogenic ERK5-FAK axis represents a promising therapeutic strategy for breast cancer exhibiting aggressive clinical behavior.

Highlights

We found that the level of extracellular-regulated protein kinase 5 (ERK5) expression inversely correlated with distant metastasis-free survival across all subtypes
We have demonstrated for the first time that induced ERK5 silencing in small triple-negative breast cancer (TNBC) grafts accelerated the dynamic of tumor growth, suggesting that ERK5 could antagonize mitogenic signaling to maintain cancer cell survival in established tumors
This hypothesis contradicts previous reports that demonstrated that ERK5 knockdown did not affect the growth of primary triple-negative mammary tumors [8,9,10, 13]

Summary

Introduction

Patterns of expression of the estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) constitute effective predictive markers for potential responses to endocrine treatment, the humanized monoclonal anti-HER2 antibody trastuzumab (Herceptin®) and the small protein tyrosine kinase inhibitor lapatinib [2, 3]. In spite of these marked therapeutic advances, the most aggressive basal-like tumors, which largely overlap with the triple ER, PR and HER2 negative subtype of breast cancer (TNBC), continue to present a significant clinical challenge due to the limited availability of treatment options [2, 3]. The identification of relevant biomarkers has become of paramount importance for guiding the future development of efficacious targeted therapies to improve TNBC patient outcome

Methods

Results

Conclusion