Ovarian cancer is a complex disease involving multiple genetic alterations. Some of the lesions involved in neoplastic growth in the ovary include the known dominant and recessive oncogenes. However, the ovary is normally subject to complex signals from both extragonadal (e.g., FSH and LH) and intragonadal peptides (e.g., inhibin, activin, MIS and follistatin). The activities and abundances of these peptides in neoplastic growth will vary widely and may exert positive or negative effects on a focal tumor. These factors make the elucidation of a genetic cascade a necessary step in understanding the loss of growth control in the ovary. Recently, we have generated a mouse with a genetic lesion which is clearly central to ovarian cancer. Using a gene targeting approach, we have generated mice deficient in the gonadal peptide, inhibin, and have shown that inhibin-deficient mice develop gonadal tumors as early as 4 weeks of age. These studies indicate that inhibin is a tumor suppressor protein with gonadal specificity in mice. Furthermore, progression of these gonadal tumors causes cachexia in the inhibin-deficient mice. Thus, inhibin-deficient mice are a major mouse model for ovarian tumor development and cancer cachexia syndrome. The overall goals of this research project are to generate and characterize mouse models for the development of ovarian cancer and its progression.
The aims of this project are: 1) Characterize the development of ovarian tumors in inhibin-deficient mice; 2) Characterize the cancer cachexia syndrome which accompanies ovarian tumor development in inhibin-deficient mice; and 3) Generate mice deficient in multiple genes by interbreeding to evaluate synergy and function in the development of ovarian tumors and cancer cachexia. Studies of these mice will facilitate the understanding of some of the genetic lesions which are important in ovarian cancer.
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