Dietary Inorganic Phosphate as a Target for Nutritional intervention in Cancer

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DESCRIPTION (provided by applicant): It is becoming increasingly apparent that diet can have profound effects on functional genomics. However, this area of research has only begun to be exploited for therapeutic benefit. Understanding the role of individual dietary components in promoting health or disease will open new opportunities to intervene in both disease prevention and treatment. Cancer of the prostate is known to be influenced by life style factors such as diet. Our preliminary in vitro results suggest that the concentration of inorganic phosphate that prostate cells are exposed to is an important predisposing factor in the growth potential of cells and alters the expression of transformation and metastasis associated genes such as osteopontin and Egr-1. Inorganic phosphate is also a critical component of cellular energy which raises a number of questions regarding the events associated with excess and/or limited cellular phosphate: Does the amount of available serum phosphate alter the growth properties of the cell in vivo? Does the amount of available phosphate alter the response of the cell in the presence of a transformational pressure? Surprisingly, little is known about the potential positive or negative effects of altered serum levels of inorganic phosphate on cell and tissue behavior related to health and disease. As the amount of phosphate in the American diet continues to rise beyond levels already considered high by the FDA it will be important to understand the long-term health benefits and risks associated with this common dietary element. This application will test the hypothesis that: a reduced inorganic phosphate diet reduces development and/or progression of prostate cancer. To test this hypothesis we will utilize an existing and well defined mouse model, the transgenic adenocarcinoma of the mouse prostate (TRAMP). Specifically, results from this application will determine whether a diet low in inorganic phosphate reduces development and/or progression of prostate cancer in the TRAMP model, relative to a diet high in phosphate. The extent of cancer development and progression will be measured by genitourinary tract weight and graded histology. Based on preliminary results, altered levels of serum inorganic phosphate might influence prostate function by two possible mechanisms; 1) directly affecting cell function by altering the expression of specific genes such as osteopontin and Egr-1, which we will measure by immunohistochemistry and molecular characterization of the neoplasia and/or 2) altering the levels of one or more circulating factors such as vitamin D or osteopontin which we will measure in the serum.