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.

Public Health Relevance

In this application, we propose to study reproductive factors in ovarian tumor development. Further studies are to focus on Cox-1 and uPA, potential targets for preventive approaches and the use of aspirin, progestins, and WX-UK1 (a uPA inhibitor). These studies will verify the importance of follicle depletion in the development of ovarian neoplasms and provide new understanding of the etiology and tumor biology of ovarian cancer. The results may generate new understanding for the potential to prevent ovarian cancer and the mechanisms of progesterone/progestins in contraceptives and in postmenopausal hormone replacement therapy. Also, the studies will test if Cox and uPA pathways may be useful as targets for prevention of ovarian cancer targets, and provide an understanding of their mechanisms.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
Project #
Application #
Study Section
Chemo/Dietary Prevention Study Section (CDP)
Program Officer
Sathyamoorthy, Neeraja
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Miami School of Medicine
Internal Medicine/Medicine
Schools of Medicine
Coral Gables
United States
Zip Code
Smith, Elizabeth R; Yeasky, Toni; Wei, Jain Qin et al. (2012) White spotting variant mouse as an experimental model for ovarian aging and menopausal biology. Menopause 19:588-96
Capo-chichi, Callinice D; Cai, Kathy Q; Simpkins, Fiona et al. (2011) Nuclear envelope structural defects cause chromosomal numerical instability and aneuploidy in ovarian cancer. BMC Med 9:28
Heiber, Joshua F; Xu, Xiang-Xi; Barber, Glen N (2011) Potential of vesicular stomatitis virus as an oncolytic therapy for recurrent and drug-resistant ovarian cancer. Chin J Cancer 30:805-14
Capo-chichi, Callinice D; Cai, Kathy Q; Smedberg, Jennifer et al. (2011) Loss of A-type lamin expression compromises nuclear envelope integrity in breast cancer. Chin J Cancer 30:415-25
Smith, Elizabeth R; Cai, Kathy Qi; Smedberg, Jennifer L et al. (2010) Nuclear entry of activated MAPK is restricted in primary ovarian and mammary epithelial cells. PLoS One 5:e9295
Capo-chichi, Callinice D; Yeasky, Toni M; Heiber, Joshua F et al. (2010) Explicit targeting of transformed cells by VSV in ovarian epithelial tumor-bearing Wv mouse models. Gynecol Oncol 116:269-75
Yang, Dong-Hua; Smith, Elizabeth R; Cai, Kathy Qi et al. (2009) C-Fos elimination compensates for disabled-2 requirement in mouse extraembryonic endoderm development. Dev Dyn 238:514-23
Cai, Kathy Q; Wu, Hong; Klein-Szanto, Andres J et al. (2009) Acquisition of a second mutation of the Tp53 alleles immediately precedes epithelial morphological transformation in ovarian tumorigenicity. Gynecol Oncol 114:18-25
Cai, Kathy Q; Capo-Chichi, Callinice D; Rula, Malgorzata E et al. (2008) Dynamic GATA6 expression in primitive endoderm formation and maturation in early mouse embryogenesis. Dev Dyn 237:2820-9
Smith, Elizabeth R; Xu, Xiang-Xi (2008) Ovarian ageing, follicle depletion, and cancer: a hypothesis for the aetiology of epithelial ovarian cancer involving follicle depletion. Lancet Oncol 9:1108-11

Showing the most recent 10 out of 17 publications