Loss of Vitamin A Metabolism in Ovarian Oncogenesis

描述（由申请人提供）：我们最近报道了在卵巢癌大鼠模型、人卵巢癌细胞系和微解剖肿瘤组织中，对维生素a稳态重要的蛋白质、细胞视黄醇结合蛋白1 （CRBP1）的持续表达缺失。在乳腺癌和卵巢癌高风险妇女预防性卵巢切除术的各种前体病变中也发现了这种损失。此外，通过HPLC分析发现，相对于正常卵巢表面上皮，卵巢癌细胞中维生素A代谢完全丧失。这种改变在乳腺癌中也有体现。基于这些观察结果，我们假设CRBP1表达和维生素A代谢的缺失通过改变正常卵巢细胞的氧化还原和/或分化能力，从而导致有利于转化的细胞损伤，从而导致卵巢癌的病因。我们的假设将通过实施以下具体目标来检验：

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.