Grant: Operating Grant

Recent technological advances have allowed us to identify a plethora of gene mutations present in tumours from breast cancer patients. Certain mutations are thought to be responsible for disease progression, and are the targets of anti-cancer drugs. We have recently observed that, as aggressive cancer tumours evolve over time, many additional mutations develop, making the cancer drug-resistant and impossible to treat. New methodologies are desperately required that will allow researchers to better understand, diagnose and treat this deadly disease. Tumours are not mutationally uniform or static. They are, in fact, mosaic -- constantly evolving, much like an ecosystem. The goal of the proposed project is to extend current analyses of genetic mutations in aggressive breast cancer tumours to characterize this mosaicism at the single cell level. We will identify tumour mutations as they arise by grafting human cancer cells into mice, a technique previously performed by our group. We will also determine the effect(s) of anti-cancer drugs on the introduction of specific mutations within this system. Next, we will undertake single cell analysis to determine the identities and hierarchies of genetic mutations within individual tumour cells. The results of these studies will also allow us to refine current computational methods for characterizing tumour mutations as they develop. Finally, in collaboration with other research groups, we will address these questions using samples from a variety of human tumour specimens. As it stands, the details of how genetic mutations in tumours from breast cancer patients develop/evolve are poorly understood. Our proposed studies have the potential to answer specific questions about how breast cancer arises, progresses and becomes resistant to treatment. These findings will have a global impact within the cancer research community, both in terms of our understanding of this deadly disease, as well as in the diagnosis/treatment thereof.