Gonadotropins & Cox-2 in Ovarian Cancer Prevention

项目总结/摘要 流行病学观察已经确立了卵巢癌的危险因素，如高癌 绝经后妇女的发病率-绝经后年龄和口服避孕药的预防作用。但 这些已经确立的概念的机制仍然模糊不清，实验系统是非常可取的 以获得流行病学调查结果的生物学和机械学理解。 月经期卵巢发生形态学变化，称为“卵巢老化”，这与以下有关： 卵巢癌的高发病率发生在围绝经期和绝经后 时期我们探索了一种生殖细胞缺陷的Wv（白色斑点变体）突变小鼠系，以模拟 更年期生理学对卵巢癌风险增加的影响，该模型也可以让我们测试 预防剂。Wv小鼠在c-Kit中具有点突变，其降低酪氨酸激酶活性， 约1-5%（不是无效突变）。这种突变会导致卵巢生殖细胞和卵泡的过早丧失， 但其他生物表型非常温和，小鼠的寿命接近正常。生殖细胞- Wv缺陷小鼠重演了一些绝经后卵巢形态学的改变， 管状腺瘤此外，增加致癌突变，如p27 kip 1缺失或p53缺失， 将卵巢腺瘤转化为肿瘤。在初步实验中，抑制考克斯-1的表达， 发现除了抑制肿瘤发展外，还可以延缓卵巢滤泡的消耗。在几个 通过对蛋白水解酶的研究，我们发现uPA在Wv卵巢中升高，我们推测uPA 可能是Wv卵巢肿瘤表型的根本原因。 该提案的目标是使用具有额外致癌突变的Wv小鼠模型来研究 绝经期卵巢癌风险增加的机制，并测试几个潜在的 预防方法。首先，我们将进一步研究考克斯-1在卵巢生殖细胞和卵泡中的作用 成熟和存活，以及卵巢肿瘤的发展（目的1）。我们还将研究 使用Wv小鼠模型研究uPA在卵巢肿瘤形成中的作用，以及uPA抑制剂降低卵巢肿瘤形成的能力。 肿瘤发生（目的2）。最后，我们将使用雷公藤红素抑制Wv小鼠的促性腺激素，以验证 卵泡耗竭假说这些实验将揭示卵泡是否减少或增加 促性腺激素是Wv小鼠卵巢肿瘤发生的主要原因（目的3）。 这些研究将阐明卵巢癌病因学的一个基本机制， 因素以及考克斯-1、考克斯-2、uPA和孕激素（口服避孕药）的作用和机制， 卵巢癌的潜在预防靶点/药物。实验的成功完成将进一步 我们对生殖因素对卵巢癌风险的潜在机制的理解， 卵巢癌的可能预防方法的理由。

Project Summary/Abstract Epidemiological observations have established ovarian cancer risk factors, such as high cancer incidence in peri- postmenopausal ages and preventive activity of oral contraceptives. However, the mechanisms for these well-established ideas remain obscure, and experimental systems are highly desirable to gain biological and mechanistic understanding of the epidemiological findings. Menopausal ovaries undergo morphological changes, known as "ovarian aging" which are implicated in the high incidence of ovarian cancer occurring during the peri-menopausal and immediate post-menopausal periods. We explore a germ cell-deficient Wv (white spotting variant) mutant mouse line to model the impact of menopausal physiology on the increased risk of ovarian cancer, and the model may also allow us to test preventive agents. The Wv mice harbor a point mutation in c-Kit that reduces the tyrosine kinase activity to about 1-5% (not a null mutation). The mutation results in a premature loss of ovarian germ cells and follicles, but other biological phenotypes are very mild and the mice have a near normal life span. The germ cell- deficient Wv mice recapitulate some of these post-menopausal alterations in ovarian morphology and develop tubular adenomas. Furthermore, addition of oncogenic mutation such as loss of p27kip1 or loss of p53 converts the ovarian adenomas into neoplastic tumors. In preliminary experiments, suppression of Cox-1 was found to delay ovarian follicle depletion in addition to suppressing tumor development. Among several proteolytic enzymes investigated, we found that uPA was elevated in Wv ovaries, and we speculate that uPA may be the underlying cause of Wv ovarian tumor phenotype. The goal of the proposal is to use the Wv mouse models with additional oncogenic mutation to study the mechanisms responsible for the menopausal increase in ovarian cancer risk and to test several potential preventive approaches. First, we will further study the roles of Cox-1 in ovarian germ cell and follicle maturation and survival, and ovarian tumor development (Aim 1). We also will investigate the importance of uPA in ovarian tumor formation using the Wv mouse models, and the ability of uPA inhibitors to reduce ovarian tumorigenesis (Aim 2). Lastly, we will use progestin to suppress gonadotropins in Wv mice to verify the "follicle depletion hypothesis". The experiments will reveal whether follicle depletion or increased gonadotropins is the principal cause of ovarian tumorigenesis in Wv mice (Aim 3). These studies will address a fundamental mechanism of ovarian cancer etiology related to reproductive factors and the roles and mechanisms of Cox-1, Cox-2, uPA, and progestins (oral contraceptives), which are potential preventive targets/agents for ovarian cancer. Successful completion of the experiments will further our understanding of the underlying mechanism for reproductive factors on ovarian cancer risk and provide rationale for possible preventive approaches for ovarian cancer.