GENE EXPRESSION IN DIET INDUCED PROSTATE CANCER

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Epidemiological studies suggest that a high fat diet for more than one generation is associated with an increased risk of prostate cancer. A more complete understanding of the molecular basis for prostate cancer initiation, promotion and progression by dietary fat is essential for the design of rational programs for prostate cancer prevention and treatment. We have maintained ACI rats on a high beef fat diet (22.52% by weight) for two generations (mothers and male pups) and observed that 2nd-generation male rats develop prostatic neoplasia at a higher incidence, and earlier in life, than rats on a control, 5% fat diet. It is significant that rats on the high beef fat diet developed neoplasia in the dorsal lobes of the prostate, as the dorsal lobe of the rat prostate is homologous to the peripheral zone of the human prostate, where prostate cancer is most prevalent. All animal studies and histological analyses have been completed and we have prepared RNA from dorsal prostates of 6, 12 and 18-month-old 2nd-generation rats. We now propose to analyze the molecular differences in the dorsal prostates of rats maintained on a high fat diet, compared to rats on a control diet to follow gene expression through the progressive molecular stages of diet-induced prostatic neoplasia. We propose to use Affymetrix microarrays (approximately 7000 genes) to identify differences in mRNA expression profiles in the dorsal prostates of rats on high beef fat and control diets. Further we propose to use northern blots and immunohistochemistry to confirm data obtained using microarrays and to identify the cell types differentially expressing the genes in question. The successful completion of these experiments will contribute to our understanding of the molecular basis of diet-associated prostate cancer. Further, it can potentially identify intermediate biomarkers that are modulated by diet and are relevant to human prostate cancer.