There is substantial molecular data demonstrating that ERK5 is implicated in oncogenic signalling. Additionally, there are compelling clinical evidences that elevated ERK5 signalling in a variety of human tumours correlates with poor prognosis. To investigate the potential therapeutic implication of these findings, I tested the requirement of ERK5 in controlling characteristic hallmarks of epithelial cancer cells. Initially, my work focused on breast cancer. Analysis of ERK5 in several HER2+ cell lines indicated that ERK5 was constitutively active in these cells. Furthermore, ERK5 was overexpressed in epithelial tumour cells of patients with HER2+ tumours, but not in the normal adjacent tissue. These results, corroborated previously published reports that have identified ERK5 overexpression and activation in HER2+ breast tumour samples. Additionally, I used published gene expression datasets from the Kaplan-Meier Plotter to confirm that HER2+ breast cancer patients exhibiting high ERK5 expression presented a significantly decreased relapse free survival. Furthermore, pharmacological inhibition of ERK5 reduced the viability of HER2+ breast cancer cells and enhanced the toxic effect of therapies aimed at blocking HER2 signalling. Together, these results provided further evidence that targeting ERK5 in combination with HER2 constituted a viable clinical strategy for breast cancer patients. In the second part of my work, I examined the phenotypic response of the skin to ERK5 hyperactivation by using a novel knock in mouse model that allowed induced expression of a constitutive active (ca) form of MEK5, namely MEK5D, in epidermal keratinocytes. I found that epidermal hyperactivation of ERK5 sensitised the skin to inflammation. Specifically, induced MEK5D expression accelerated the recruitment of neutrophils and mast cells and increased the production of inflammatory mediators. The ability of MEK5D-expressing epithelial cells to remodel the inflammatory microenvironment coincided with acceleration of tumour development and increased tumour burden and bigger tumours in mice exposed to the DMBA/TPA carcinogenesis protocol. Overall, these results demonstrated that hyperactivation of ERK5 accelerated the development of malignant skin cancer and metastasis progression. This is important considering that inflammation is one of the most influential components of most tumours. Therefore, ERK5 has the potential to become an effective therapeutic target in combination with conventional chemotherapy and immune-based therapies.
|Date of Award||1 Aug 2020|
- The University of Manchester
|Supervisor||Andrew Gilmore (Supervisor) & Cathy Tournier (Supervisor)|
The role of ERK5 signalling in epithelial tumours
Risa Ebri, B. (Author). 1 Aug 2020
Student thesis: Phd