Role of Rb and E2Fs in Regulating Stromal/Epithelial

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While historically, the process of tumorigenesis in humans was considered to result from the sequential accumulation of inherited and/or somatic mutations within the 'tumor cell '(71),it is clear that the stroma is an integral part of the tumor and that it contributes to some of the most destructive characteristics of malignant cells. Understanding the genetic aberrations that occur in both tumor cells and stromal cells, and elucidating the details of the molecular pathways that are altered as a result of these aberrations, will be key to our overall understanding of human cancer. Uncontrolled cell proliferation is one of the hallmarks of cancer, and both epithelial tumor cells and stromal fibroblast cells have acquired genetic and/or epigenetic changes to genes that directly regulate their cell cycles. Entry into the cell cycle and stimulation of cell proliferation involves the induction of immediate early gene products such as Myc as well as the activation of the Rb pathway that is critical for G1 to S phase progression. Our recent studies demonstrate that E2F1, E2F2 and E2F3 mediate Rb function in vivo and that these three activities are essential components in the Myc pathway that controls cell proliferation and cell fate decisions of both epithelial and stromal fibroblasts. We entertain the hypothesis that the microenvironment of a given tissue is strongly influenced by the function of Rb, and inactivation of this tumor suppressor pathway within stromal fibroblasts contributes strongly to the evolution of neoplasm. The proposed studied will employ transgenic and conditional gene knock-out strategies in order to address the following three specific aims: Specific Aim 1: To examine the role of tumor suppressor and oncogenic pathways, operating within mammary stromal fibroblasts, on the proliferation of normal epithelial cells. Specific Aim 2: To examine the role of tumor suppressor and oncogenic pathways, operating within mammary stromal fibroblasts, in moderating the tumorigenicity of oncogene-primed epithelial cells. Specific Aim 3: To assess in vivo the contributions made by Rb within mammary stromal fibroblasts, towards the development of Myc-induced mammary epithelial tumors