The etiologic factors that are responsible for the development of ovarian granulosa cell tumor (GCTs) are poorly understood. Thus, targeted treatment for these tumors does not exist. Based on clinical and basic science data, the follicle stimulating hormone receptor (FSH-R) pathway may be involved in the pathogenesis of this disorder. We, and others, have examined GCTs for the presence of FSH-R mutations that would impart constitutive activity as well as screened tumors for Gsalpha mutations. Thus far, no mutations have been detected. However, other essential components of this pathway, such as the G protein-coupled receptor kinases (GRKs) and the arrestins have never been examined for abnormalities that might lead to hyperstimulation. In order to test the hypothesis that the FSH-R pathway is involved in GCT pathogenesis, we will utilize a unique mouse model for GCT formation. This proposal represents a new research direction for the principal investigator. The application is designed to generate pilot data to support a more comprehensive R01 application to investigate the pathogenesis of GCTs. In this pilot R03 proposal, we will validate the use of the SWXJ-9/SWR mouse as an appropriate model of GCTs in which detailed analysis of the FSH-R signaling pathway can be studied. This will be accomplished by pursuing three specific aims. First, we will characterize and compare GRK and arrestin expression in normal and malignant mouse granulosa cells. Next, we will compare FSH-R desensitization and internalization in these two cell types and determine which, if any, GRK and arrestin isoforms are essential for FSH-R signaling in normal and pathologic granulosa cells. Finally, we will dissect out the roles of gonadotropins and sex steroids for the development of GCTs, in vivo, using the animal model. Regardless of the outcome, it is anticipated that significant novel data will be generated from completion of this proposal that will direct more extensive future studies. Ultimately, this work has the potential to advance our understanding of the pathogenesis of GCTs, contributing to effective, targeted forms of therapy for this serious disorder of girls and women.
| Zeng, Pingyu; Wagoner, Heather A; Pescovitz, Ora Hirsch et al. (2005) RNA interference (RNAi) for extracellular signal-regulated kinase 1 (ERK1) alone is sufficient to suppress cell viability in ovarian cancer cells. Cancer Biol Ther 4:961-7 |
| Steinmetz, Rosemary; Wagoner, Heather A; Zeng, Pingyu et al. (2004) Mechanisms regulating the constitutive activation of the extracellular signal-regulated kinase (ERK) signaling pathway in ovarian cancer and the effect of ribonucleic acid interference for ERK1/2 on cancer cell proliferation. Mol Endocrinol 18:2570-82 |
| King, Denise Walker; Steinmetz, Rosemary; Wagoner, Heather A et al. (2003) Differential expression of GRK isoforms in nonmalignant and malignant human granulosa cells. Endocrine 22:135-42 |
