Defining the role of aberrant O-linked glycosylation in breast cancer

点击翻译按钮获取中文摘要

Proteins are encoded by genes contained within the DNA of the cell and the pattern of proteins expressed is known as the proteome. However, the vast majority of proteins found on the cell surface and many found within the cell carry sugars known as glycans. These sugars, and sugars carried on other molecules expressed by the cell are known as the glycome. A single protein can be modified by different glycans, which will affect its function and how it interacts with other components in the same cell and on different cells. Thus the glycome plays a key role in many biological processes and can be more complex then the proteome.Glycans play a role in many diseases and in cancer the glycans attached to proteins are often different to those attached to the same protein expressed by normal cells. As this can alter the way proteins and therefore cells function, changes in the glycosylation observed in cancer can influence tumour development and progression.We have been studying one particular type of glycosylation, O-linked, and changes in this type of glycosylation occurs in >90% of breast cancers. We hypothesise that such a common and consistent change plays a role in the development and progression of breast cancer. We have found that the changes in these glycans attached to proteins that occur in breast cancer are due to changes in the expression of enzymes (known as glycosyltransferases) that catalyse the addition of the glycans to the protein. Two particular glycoproteins known as MUC1 and osteopontin are associated with breast cancer and the glycans carried on these proteins are changed when they are expressed by cancer compared to normal cells. MUC1 is a large glycoprotein which can interact with smaller surface proteins for example EGFR, and affect how these molecules signal to the nucleus and so control gene expressionIn this project we aim to establish the mechanism by which a particular glycosyltransferase that is over-expressed in breast cancer can influence the development of mammary cancer. To achieve this aim we will use a murine model developed by us where over-expression of the glycosyltransferase causes mammary tumours to develop earlier than the controls. We will also investigate the role changes in the glycans of MUC1 and osteopontin have on the progression of breast cancer. We will investigate how the O-linked glycans on MUC1 alter its interaction with EGFR and what the consequences are for gene transcription. The O-linked glycans attached to active and inactive osteopontin will be determined. By manipulating the expression of glycosyltransferases we will change the glycans attached to osteopontin and determine the influence on its ability to stimulate metastasis.The data coming from this project should give an insight into some of the mechanisms controlling cancer development and progression and therefore identify new potential therapeutic targets for the treatment of cancer.