In humans vitamin A (retinol) is required for the appropriate regulation of the growth and differentiation of many types of cells, including the epithelial cells of the prostate. Data in humans and in animal models indicate that vitamin A (retinol) and related compounds (retinoids) may play important roles in the development, prevention and therapy of human prostate cancer, in part by regulating prostate epithelial cell growth and differentiation. We propose experiments aimed at understanding the molecular basis for the regulation of vitamin A metabolism in human and murine epithelial cells. We have preliminary data that vitamin A is esterified in normal epithelial cells and that this esterification is positively regulated at the transcriptional level by retinoic acid (RA), a biologically active metabolite of vitamin A. In carcinoma cells, including human prostate cancer cells, esterification of vitamin A is greatly reduced; this leads to a state of vitamin A deficiency in the tumor cells. We plan to delineate the molecular basis for the aberrant vitamin A metabolism in cultured human prostate cancer cell lines by employing molecular biological approaches, enzymatic analyses, and human prostate tumor xenograft models in athymic mice. In addition, we plan to utilize the transgenic adenocarcinoma mouse prostate (TRAMP) model, in which expression of the SV4o T Antigen driven by the probasin promoter leads to the development of all stages of prostate cancer from initiation to metastases, to ascertain if vitamin A metabolism becomes altered as the prostate epithelial cells in the TRAMP mice progress from normal to tumorigenic. Genes encoding enzymes involved in vitamin A metabolism will be ectopically expressed in the prostate epithelium of TRAMP mice to determine if this expression alters the progression of prostate cancer and/or markers of differentiation in the TRAMP model. These proposed studies will allow us to explore the role of vitamin A and retinyl ester levels in the etiology of prostate cancer, and to gain a better understanding of the involvement of retinoids in the development and progression of prostate cancer. Moreover, the experiments proposed in this application will clarify the potential use of retinoids as a therapeutic strategy to treat patients with prostate cancer, the second most common cause of cancer deaths in American males, and these studies may also lead to the identification of new therapeutic agents which stimulate vitamin A esterification for the treatment of various stages of prostate cancer.
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