Although prostate cancer (PCa) remains one of the leading causes of death from cancer in American men, the specific nutritional factors affecting disease progression and their potential mechanisms of action are largely unknown. This project tests the hypothesis that serum cholesterol and membrane cholesterol, through their roles in regulating the size and complexity of lipid raft membrane domains, affect parameters of PCa progression in vitro and in vivo. This application responds to the RFA by directly evaluating the effect of dietary cholesterol on prostate tumor progression and the ability of membrane cholesterol to regulate the ErbB/PI3K/Akt anti-apoptotic signaling axis, a critical cell survival pathways operating constitutively in prostate tumor cells. In these studies we will examine the role of cholesterol-rich lipid raft signaling complexes in orchestrating and regulating ErbB receptor family distribution, dimerization and activation, PI3 kinase distribution and activation, and Akt isoform distribution and activation. We will determine the effect of membrane cholesterol modulation on these signaling molecules and on prostate tumor cell survival. We will study the effect of dietary cholesterol on prostate tumor progression in vivo using a murine model of human tumor cell progression, as well as two autochthonous PCa mouse models. We will test whether high levels of dietary cholesterol cause PIN to convert to frank cancer, to accelerate the growth of prostate tumors and to promote metastasis. We will determine whether high levels of dietary cholesterol cause cholesterol accumulation in prostate tumors and affect the form and function of lipid raft domains. These hypothesis driven, mechanistic studies on the role of dietary and membrane cholesterol on PCa disease progression may suggest new therapies for the treatment and management of the disease, such as the use of HMG-CoA reductase inhibitor drugs or the use of low cholesterol diets. Further, these studies also have the potential to identify new drug targets.