Historically, the process of tumorigenesis in humans is considered to result from the sequential accumulation of inherited and/or somatic mutations within a given cell, that together contribute to the phenotypic hallmarks of cancer: uncontrolled cell growth, resistance to apoptosis, increased cell motility, genetic instability, clonality, and evasion of the immunological defense network. Although it is a widely accepted notion that mutations must accumulate within a single cell, the 'tumor cell', it is also becoming quite clear that tumor biogenesis results from a series of complex interactions between the tumor cell and the surrounding cellular microenvironment. The different cell types within the microenvironment are thought to provide the appropriate milieu that is conducive for tumor growth and metastasis. Although much of the cellular biology of the tumor "microenvironment" has been described over the last twenty years, the molecular mechanisms by which different cell types within the microenvironment promote tumor growth is poorly understood. The long-term goals of our current projects are to study, at the molecular level, the mesenchymal-epithelial interactions which impact on the control of the cell cycle, apoptosis and cellular proliferation of tumor cells. By disrupting specific signaling pathways within each of these two cellular compartments, we hope to develop relevant in vivo models to study these vital interactions during mammary carcinogenesis. To this end, we have embarked on a comprehensive approach that applies Cre-LoxP gene knock-out technology and the Tet-off inducible system, in a combined strategy to disrupt the RbIE2F and p53 tumor suppressor pathways in different cell compartments of the mammary gland in a temporal regulated manner. These studies will begin to explore the mechanisms of how cells 'cross talk" within physiologically relevant settings, and how alterations in the cross talk between cells can promote the initiation and progression of cancer.