Gonadotropins & Cox-2 in Ovarian Cancer Prevention

促性腺激素

• 批准号: 8447386
• 负责人: XiangXi Mike Xu
• 金额: $ 35.35万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-05-01 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8447386
• 关键词: Accounting; Address; Age; Aging; Apoptosis; Aspirin; Basement membrane; Benign; Biological; Biology; Cancer Etiology; Cancer Model; Chemicals; Contraceptive Agents; Development; Devices; Dose; Enzymes; Epidemiology; Epithelial Cells; Etiology; Funding; Gene Dosage; Genetic; Genotype; Germ Cells; Goals; Gonadotropins; Growth; Hormones; Implant; Incidence; Infusion procedures; Investigation; Knock-out; Knowledge; Lead; Longevity; Malignant Neoplasms; Malignant neoplasm of ovary; Mediating; Menopause; Modeling; Morphology; Mus; Mutant Strains Mice; Mutation; Oncogenic; Oral Contraceptives; Organ Culture Techniques; Ovarian; Ovarian Follicle; Ovary; Pathway interactions; Peptide Hydrolases; Phenotype; Physiology; Point Mutation; Post-Menopausal Hormone Replacement Therapy; Postmenopause; Prevention strategy; Preventive; Progesterone; Progestins; Protein Tyrosine Kinase; Proto-Oncogene Protein c-kit; Reagent; Reproductive History; Risk; Risk Factors; Role; Study models; Surface; System; Testing; Translating; Tubular Adenoma; Tumor Biology; Variant; White Spots; abstracting; adenoma; base; cancer risk; design; follow-up; inhibitor/antagonist; mouse model; mutant mouse model; neoplastic; null mutation; ovarian cancer prevention; ovarian neoplasm; practical application; premature; prevent; reproductive; research study; tumor; tumorigenesis

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.

项目总结/文摘