My Career Goals: As a medical oncologist, I know the feeling of dread that comes with having to tell a patient that she has developed metastatic breast cancer. Metastasis is perhaps the single most important tipping point in a patient's care, heralding the transition from potential cure to a battle against time. The lethal consequences of metastasis, and the substantial morbidity that it causes my patients, motivate me to deeply understand and combat this problem.

My long-term goal is to understand tumor invasion and metastasis through an independent career in laboratory research. The proposed research will require the development of expertise in several new areas of study including tumor invasion and metastasis, the molecular genetics of breast cancer, and time-lapse microscopy, imparting training that will be essential to an independent career. My two co-mentors, Andrew Ewald and Sara Sukamar, will provide expertise in these areas and are committed to my intellectual growth. This training program will provide a convergence of my training as a medical oncologist with training as a cancer biologist, to study a complex problem, tumor invasion. Through this training grant, I will investigate a potentially important set of molecular targets and develop the skills required to pursue an independent career in breast cancer research.

Scientific Objective and Rationale: The process by which cancer escapes from its primary site, disseminates into blood vessels and lymph nodes, and colonizes distant organs like brain, liver, and lung is known as metastasis. A critical step in this process is tumor invasion and escape into the surrounding microenvironment. How cancers achieve this critical step remains poorly understood.

The Ewald laboratory has developed innovative techniques for the live cell imaging of tumor fragments in 3D microenvironments that enable observation of tumor invasion in real time. My preliminary experiments using these techniques have identified a highly invasive subpopulation of tumor that move collectively as groups of cells. These cancer cells are characterized by expression of p63 and P-cadherin, which are normally expressed in basal/myoepithelial cells and also enriched in basal breast cancers. p63 is a central regulator of epithelial development and has been implicated in cell cell adhesion, the molecular glue that holds cells together. The central hypothesis of this grant is that p63 and its downstream target P-cadherin regulate the collective movement of cancer cells. The aims of this grant are as follows:

Aim 1: To identify leader cell dynamics of tumor cells positive and negative for K14, a marker of basal/myoepithelial cells, by time-lapse confocal microscopy.

Aim 2: To test the requirement for p63 and its downstream target P-cadherin in mediating collective breast cancer invasion.

Aim 3: To test the hypothesis that inhibition of p63 and P-cadherin will reduce dissemination and metastasis in a hyperplasia transplant model of metastatic progression

Contributions of This Study to Breast Cancer Research: Metastasis is the number one cause of death in patients with breast cancer. Tumor invasion is a crucial step in this process, yet remains poorly understood. The microscopy techniques developed by the primary mentor, Dr. Ewald, open a window into tumor invasion and create a platform for studying the molecules that are required for this process. p63 and P-cadherin are associated with poor risk breast cancers. These studies may help us understand why by defining functions for these genes in invading and metastasizing tumors.