Grant: CIHR Fellowship

Most breast cancers arise from epithelial cells that form the branched ducts of the mammary gland. Epithelial cells are organized in a distinct fashion where all the cells in the epithelial sheet are polarized to form a top and a bottom. Based on evidences in flies and worms it is conceivable that in order for tumor cells to escape the ducts and spread they have to lose their polarity. Indeed loss of the core polarity protein, Par3 in tumorigenic cells enhances their proliferation and metastasis. Clinically >50% of breast cancers have reduced Par3 expression. However, ablation of Par3 expression in mouse mammary epithelial cells elicit dual signals that cause the cells to either die or hyperproliferate leading to abnormal mammary duct outgrowth in mice, but do not show any signs of hyperplasia or tumor. We postulate that cell death due to Par3-loss alone acts as a barrier to formation of hyperplasia or tumor. Provided cells can overcome the cell death signal, either by gain in mutations in classical oncogenes or other unknown mechanisms, the compensatory proliferative signal wins out. This may then lead to hyperplasia and cells may possibly even leave the mammary fat pad and seed elsewhere in the body, the hallmark of early metastasis. My research goal is to firstly understand the molecular mechanisms underlying the cell death signals caused by loss of Par3 in mammary epithelial cells. Secondly, I will test if blocking cell death by genetic manipulations cause hyperplasia or tumor formation and cause the polarity defective cells to extrude from the epithelium and invade the surrounding tissues. This work therefore proposes to test a novel concept in how early metastasis occurs, which can provide opportunities for early diagnosis and therapeutic interventions to prevent cancer cell dissemination.