The cancer cell arises from normal precursors through a step-wise accumulation of genetic mutations. These oncogenic alterations endow malignant cells with the ability to grow without restraint, to ignore normal tissue boundaries, to recruit a supply of nutrients, and to metastaize. Although the study of cancer cells derived from patients has elucidated many fundamental principles of oncology, the critical changes that initiate cancer have been difficult to define with his approach. Additional progress in the diagnosis and treatment of cancer requires a more detailed and precise understanding of the subtle alterations that transform normal cells into cancer cells. As a postdoctoral fellow I have elucidated the role of telomerase activity is required for the continued growth of cancer. Manipulating telomerase, oncogenes, and tumor suppressors, I have converted normal human cells to tumorigenicity, thereby creating human tumor cells with a defined genetic constitution for the first time. These observations form the foundation for the studies presented in this application to use telomerase as an important component of new model systems of human cancer. I propose to create new cell-based models of the common epithelial including breast, prostate, and lung cancer and to use these model systems to define the critical pathways that convert normal cells into cancer. I will use these model systems to study the molecular systems with information derived from patient samples and clinical outcome data to generate the foundations of a new approach to the molecular staging of cancer. Taken together, these studies will permit me to identify the crucial intracellular pathways that initiate cancer and to validate molecular targets to which to develop new anti-neoplastic agents. A Mentored Research Scientist Development Award will provide me the opportunity to take advantage of the mentorship of Dr. Robert Weinberg and the unique resources of the Whitehead Institute to develop these new systems and to broaden my research experiences as I make the crucial transition to an independent investigator.