Loss of Vitamin A Metabolism in Ovarian Oncogenesis

描述(申请人提供)：我们最近报道，在卵巢癌大鼠模型、人卵巢癌细胞系和显微解剖的肿瘤组织中，对维生素A稳态至关重要的蛋白质-细胞视黄醇结合蛋白1(CRBP1)的表达持续丢失。在乳腺癌和卵巢癌高危女性预防性卵巢切除术的各种前驱病变中也发现了这种缺失。此外，通过高效液相分析发现，相对于正常卵巢表面上皮，卵巢癌细胞中的维生素A代谢完全丧失。这种变化在乳腺癌中也有表现。基于这些观察结果，我们推测，CRBP1表达和维生素A代谢的伴随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，从而参与卵巢癌的病因。我们的假设将通过实现以下具体目标来检验： 1)分析CRBP1表达变化和维生素A稳态对卵巢组织学和基因工程小鼠卵巢癌发生的影响， 2)确定CRBP1表达变化对肿瘤表型和卵巢表面上皮细胞转化的影响，以及 3)确定CRBP1表达改变和维生素A稳态对卵巢上皮细胞氧化还原和分化状态的影响。 针对特定目标的策略将集中在对正常和CRBP1缺失小鼠的体外和体内评估，然后是卵巢表面上皮(MOSE)细胞和CRBP1诱导的人卵巢细胞系。希望这些努力将导致更好地了解卵巢癌的发展和进展，并为更有效地预防这种经常致命的疾病提供基础。

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.