Grant: Operating Grant - Priority Announcement: Breast Cancer Research (AVON)

Breast cancer is not one disease. Some breast cancer cells are more difficult to kill because they do not express on their surface the targets for standard treatments. These stealth breast tumour cells may be more reliant upon an enzyme called aurora kinase A and, thus, more susceptible to new treatments that specifically target aurora kinase A. We would like to know more about when and how aurora kinase A is active in breast cancer cells so that we can use these new treatments against stealth breast tumours. Aurora kinase A is very important during the process of cell division. We have identified a new cell division protein called RHAMM, and shown that it regulates the formation of a cancer-causing complex between aurora kinase A and another protein, called TPX2. This aurora kinase A- TPX2 complex activates the enzyme. We have seen that RHAMM also binds to TPX2, and that the loss of RHAMM releases TPX2 and enables it to activate aurora kinase A. In this project, we will determine exactly how, when, and where RHAMM regulates aurora kinase A activity, and how these proteins control cell division and cancer progression. We will do this by removing the RHAMM protein from cells and replacing it with mutants that lack specific domains and residues. We will find out what domains are necessary for these roles of RHAMM and what other proteins may regulate its action. The findings from the proposed studies will highlight processes in cancer cells that we can target with drugs, and help us optimize the preclinical use of drugs that target aurora kinase A, which may ultimately improve overall cancer survival rates.