Among North American women, breast cancer is the most common type of cancer and the second leading cause of cancer-related deaths. Breast cancer represents a group of diseases that vary in their biology and response to therapy. At least 3 major types of breast cancer have been identified: estrogen receptor (ER) positive, HER2/Neu positive, and basal-like. The basal-like subtype is a newly discovered aggressive form that accounts for 15-20% of all cases and is associated with poor prognosis. These tumors do not express estrogen, progesterone, or Her2/Neu receptors (i.e. ER/PR/Her2/Neu negative). This feature of basal-like breast cancer is significant because drugs that are used to treat ER or HER2/Neu positive tumors (e.g., Tamoxifen and Herceptin, respectively) cannot be used in patients diagnosed with this type of breast cancer. As a result, toxic chemotherapy is the only therapeutic option for these patients. Thus, there is an urgent need to develop more specific and less toxic therapies for the treatment of basal-like breast cancer. To achieve this goal, we need to improve our understanding of the genetic events that lead to the development of type of this aggressive disease.

In recent years, a number of studies have found that the Rb and p53 tumor suppressor genes are frequently mutated in basal-like breast cancer. In normal breast cells, both Rb and p53 restrict cell proliferation and suppress tumor formation. However, when these genes become mutated, they no longer prevent cells from dividing, leading to tumor formation and spread. The major focus of our lab is on the function of Rb in breast cancer. To determine whether Rb plays a direct role in breast cancer, we have recently developed a mouse model that lacks Rb expression in the mammary gland. Excitingly, these mice developed multiple types of breast cancer including a subset that resemble the basal-like subtype. Moreover, the basal-like tumors in our model also contained mutations in the p53 gene. From these data, I hypothesize that combined loss of the Rb and p53 tumor suppressor genes in the mouse mammary gland will lead to the development of mammary tumors that resemble human basal-like breast cancer.

To test this hypothesis, I have created genetically engineered mice that do not express Rb or p53 in the mammary gland, and monitored them for tumor development. Interestingly, I found that Rb/p53 double mutant tumors arose much faster (after 6 months) compared with tumors induced by loss of p53 alone (11 months) or Rb alone (18 months). Moreover, the Rb/p53 double mutant tumors exhibited similar histology as opposed to the heterogeneous histology of tumors from the single mutant tumors. I propose to (1) characterize these tumors using a variety of techniques to determine whether they do indeed represent basal-like tumors, (2) investigate which cell type(s) within the mammary gland is the source of tumor development following mutation of Rb and p53, and (3) utilize a novel screening approach to identify new drug targets for basal-like tumors with mutations in Rb and p53.

The results of these studies have important implications for breast cancer research. Firstly, by analyzing genes that are expressed in the tumors that develop in our mouse model, we may be able to determine the prognosis of patients with basal-like breast cancer. Secondly, if we are able to identify the cell type(s) within the mammary gland that are susceptible to tumor formation, we may be able to develop agents that could be used to treat and prevent breast cancer. Thirdly, by screening Rb/p53 mutant mammary tumor cells for genes that are important for cell survival, we will be able to rapidly identify potential targets that could be manipulated therapeutically to specifically kill tumor cells. With advances in drug development technology, therapies that are effective against basal-like tumor cells could be developed and tested within approximately 5-10 years.

My ultimate career objective is to obtain a faculty position at a Canadian University and establish an independent breast cancer research program. Towards this goal, I am taking advantage of the freedom I have been given to explore my own project ideas, my expertise in breast cancer research, breast cancer stem cells, and targeted therapy, and training undergraduate and graduate students. In addition, the large number of world renowned scientists within TGRI and surrounding institutes (Ontario Cancer Institute, Campbell Family Institute of Cancer Research, Samuel Lunenfeld Research Institute, Hospital for Sick Children, University of Toronto) provides an excellent environment to establish collaborations that will contribute to the success of my postdoctoral training and future career as a breast cancer researcher. Following completion of the proposed work, I will continue to investigate novel approaches towards the identification of new targets for the treatment of aggressive forms of breast cancer.