Keele Research Repository

Breast cancer is the most common malignant tumour among females world-wide. The complexity of the pathogenesis of the disease and its heterogeneous clinical presentation, with an increasing incidence of the development of chemotherapeutic resistant cases, make its treatment challenging.

This report describes the analysis of the role of the catalytic subunit of PP4 (PP4c) in controlling survival and death of breast cancer cells. These investigations suggested that PP4c regulates both apoptosis and proliferation in human breast cancer cells and have shown that the level of PP4c has a strong influence on the cell cycle and on the anchorage-dependent growth of these cells. This wide variety in the functions of PP4 enzyme is likely to be related to its interacting proteins which determine the location and the functions of the PP4 holoenzyme. This work has identified the effects of modulating the expression level of some of the PP4c-regulatory subunits on the function of PP4c in breast cancer cells. This study has also highlighted a novel PP4c-PEA15 signalling axis in the control of breast cancer cell survival. This study has showed that modulation in the endogenous expression level of PP4c changes the phosphorylation status of important proteins in the Akt-mTOR signalling pathway. Most of these proteins are implicated in the regulation of a variety of cellular functions including cell survival, proliferation, apoptosis and protein translation. Furthermore, this study has revealed important differences between hormone positive and triple negative breast cancer cells in the term of changes in phosphorylation status of some of downstream proteins in the Akt-mTOR pathway as a result of modulating endogenous expression of PP4c. These differences may partly explain the different behaviour of these cell lines and require further investigation in the future which may open up new opportunities for developing therapeutic approaches to breast cancer.