The Involvement of Extracellular-regulated Protein Kinase 5 in Triple Negative Breast Cancer Cell Invasion and Metastasis

Abstract

Breast cancer is the most common cancer in the UK. Recent work has revealed a role for extracellular-regulated protein kinase 5 (ERK5) in breast cancer progression. Likewise, the online breast cancer database was utilized to demonstrated that high ERK5 levels were linked to low metastasis free survival. Nevertheless, the mechanism by which how ERK5 regulates breast cancer cell fate remains obscure. Researchers have demonstrated controversial perspectives in terms of whether ERK5 involved in cancer proliferation and/or metastasis. This is due to the limited characterization of the pathway in disease models. In this study, TNBC cell lines were generated enabling the fine modulation of ERK5 levels using a lentiviral based system, and the transplantation of these cells in immunocompromised mice successfully exhibited xenograft tumour growth. Next, it is reported that ERK5 promoted TNBC cells invasion through focal adhesion kinase (FAK) activation. The in vitro data suggested that the downregulation of ERK5 significantly impaired the TNBC cells adhering to the extracellular Matrigel (ECM), which is further validated by the fact that phospho-FAK(Y397) was blocked in ERK5 silencing cells. Accordingly, knockdown of ERK5 in mice xenograft suppressed FAK phosphorylation at Try397 and metastasis to the lung, without preventing primary tumour growth. Moreover, confocal microscopy showed the colocalization of ERK5 and phospho-FAK(Y397) at focal adhesion sites. Above all, these findings provide fundamental insights into ERK5-FAK signalling, which indicates a potential therapeutic strategy for breast cancer metastasis.

Date of Award	31 Dec 2020
Original language	English
Awarding Institution	The University of Manchester
Supervisor	Andrew Sharrocks (Supervisor) & Cathy Tournier (Supervisor)