Loss of Vitamin A Metabolism in Ovarian Oncogenesis

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DESCRIPTION (provided by applicant): We recently reported a consistent loss in expression of a protein important for vitamin A homeostasis, cellular retinol-binding protein 1 (CRBP1), in a rat model of ovarian cancer, human ovarian cancer cell lines and in microdissected tumor tissues. This loss was also found in various precursor lesions in prophylactic oophorectomies from women at high risk for breast and ovarian cancer. Moreover, complete loss of vitamin A metabolism was discovered through HPLC analysis in ovarian cancer cells relative to normal ovarian surface epithelium. Such alterations have also been shown in breast cancer. Based on these observations, we hypothesize that concomitant losses of CRBP1 expression and vitamin A metabolism contribute to the etiology of ovarian carcinoma by altering redox and/or differentiation capacity of normal ovarian cells, thus leading to cellular damage conducive to transformation. Our hypothesis will be tested by implementation of the following Specific Aims: 1) Analyze the impact of altered CRBP1 expression and vitamin A homeostasis on ovarian histology and the initiation of ovarian cancer in genetically engineered mice, 2) Determine the impact of CRBP1 expression alteration on the cancer phenotype and ovarian surface epithelial cell transformation, and 3) Determine the impact of altered CRBP1 expression and vitamin A homeostasis on the redox and differentiation status of the ovarian epithelium. Strategies for addressing the specific aims will focus on in vitro and in vivo evaluation of normal and CRBP1-null mice and then ovarian surface epithelial (MOSE) cells, and CRBP1-inducible human ovarian cell lines. Hopefully, these endeavors will result in a better understanding of ovarian cancer development and progression and provide a basis for more effective prevention of this frequently fatal disease.