As a regulatory inhibitor of cell cycle, the retinoblastoma protein (Rb) is central to a tumor suppressive pathway that is frequently disrupted in human cancer. LOH of the retinoblastoma gene (Rb) is one of the most common mutations associated with prostate cancer and through much of the molecular function of Rb is known, it's role in the pathobiology of prostate cancer has not been investigated. Some of the mutation events that occur during the prostate tumorigenesis involve alterations to apoptotic programs present in normal prostate epithelium. Therefore, the ability of prostate epithelial cells to circumvent apoptosis may be important in prostate tumorigenesis. During the first two years of our SPORE-funded research, we develop two cell culture models with which we have demonstrated that apoptosis of prostate epithelial cells is uniquely regulated through the Rb cell cycle control pathway. Additionally, we have shown that activation of the Rb pathway occurs in the rat prostate gland during castration-induced apoptosis. Based on these studies, we hypothesize that the loss of Rb function may facilitate tumor formation by inactivating an Rb-dependent apoptotic mechanism. To elucidate the role of Rb in prostate tumorigenesis we have developed a unique in vivo model system with which to study homozygous deletion of the RB gene in mouse prostate epithelium. We will also determine the efficacy of an Rb adenoviral construct to induce apoptosis of prostate cancer cells. We will pursue these goals by addressing the following specific aims.
Specific Aim 1. To investigate the tumorigenic effects of Rb deletion over time, we will analyze Rb-/-E in the TR system for tumor formation over a period of one year.
Specific Aim 2. To investigate the tumorigenic effect of Rb deletion in the TR system, we will analyze Rb-/- E in the presence of tumor stroma.
Specific Aim 3. To determine if constitutively active Rb, delivered with the adenovirus system will induce apoptosis of prostate cancer cells. We anticipate that the results from this study would be the first to identify a pathobiological role for Rb in prostate tumorigenesis and the first to define a critical component of an androgen-regulated apoptotic program in prostate epithelium in vivo.
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