Gonadotropins & Cox-2 in Ovarian Cancer Prevention

项目摘要/摘要 流行病学观察已经确定了卵巢癌的危险因素，如高癌症 围绝经期年龄发病率与口服避孕药的预防效果。然而， 这些成熟想法的机制仍然不清楚，实验系统是非常可取的。 以获得对流行病学结果的生物学和机械学理解。 更年期卵巢会发生形态变化，即所谓的“卵巢老化”，这与 围绝经期和绝经后即刻卵巢癌的高发 句号。我们探索了一个生殖细胞缺陷的WV(白点突变)突变小鼠品系，以模拟 更年期生理学对卵巢癌风险的增加，而这一模型也可能让我们检验 防范剂。WV小鼠在c-Kit中存在点突变，该突变使酪氨酸激酶活性降低到 大约1-5%(非零突变)。这种突变会导致卵巢生殖细胞和卵泡过早丧失， 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基因缺陷的小鼠在绝经后卵巢形态上的一些变化和发育 管状腺瘤。此外，添加致癌突变，如丢失p27kip1或丢失p53 将卵巢腺瘤转化为肿瘤。在初步实验中，COX-1的抑制是 除了抑制肿瘤的发展外，还被发现可以延缓卵泡的枯竭。在几个 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卵巢肿瘤表型的潜在原因。 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 绝经后卵巢癌风险增加的机制和几个潜在的检验 采取预防性的方法。首先，我们将进一步研究COX-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(目标1)。我们还将调查以下问题的重要性 利用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的能力 肿瘤发生(目标2)。最后，我们将使用孕激素抑制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耗尽还是增加 促性腺激素是WV小鼠卵巢肿瘤发生的主要原因(目标3)。 这些研究将解决与生殖有关的卵巢癌病因学的基本机制 COX-1、COX-2、uPA和孕激素(口服避孕药)的因素及其作用和机制 卵巢癌的潜在预防靶点/制剂。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和提供 卵巢癌可能的预防方法的基本原理。

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.