PRECLINICAL EVALUATION OF INTERMEDIATE ENDPOINTS

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Validation of Early Surrogate Biomarkers of Breast, Prostate, Pancreas, and Colon Neoplasia in Animals Fed a Nutritional Stress diet. It has already been established that Western-style stress diets can increase cell proliferation, alter apoptosis, alter cytokeratin expression, modulate acidic mucins, and induce dysplastic changes in colon epithelia in mice without carcinogen treatment (Newmark et all., JNCI 82:491, 1990, Risio et al., Cancer Res. 56:4910, 1996, and Yang, et al. Cancer Res 56:4644, 1996). in addition mouse mammary ductal epithelium is also induced to become hyperplastic when fed similar Western stress diets (Khan et al., Carcinogenesis 15:2645, 1994). The Western-stress diet is high in fat, and low in calcium and vitamin D compared to AIN-76A diet. This project is developing criteria for the quantitation of induced cell proliferation and other SEB by computer-assisted cell image analysis and histochemical methods in breast, prostate, pancreas, and colon ductal epithelial cells under nutritional stress conditions. In mice fed stress diets SEBs in breast, prostate, pancreas and colon epithelial cells are being measured. Specifically alterations in ploidy, nuclear morphometry, and proliferative status of cells using software algorithms are being measured.