Spontaneous malignant ovarian granulosa cell (GC) tumors develop during pubertal maturation in SWR but not in SJL mice - two closely Swiss inbred strains. The same tumors occur in 3 of 14 SWXJ Recombinant Inbred strains derived from SWR and SJL progenitor matings. Furthermore, GC tumors can be induced in four previously tumor-free SWXJ strains by feeding dehydroepiandrosterone (DHEA), a precursor of sex steroid hormones. Testosterone feeding promotes tumorigenesis, whereas estradiol completely suppresses spontaneous tumorigenesis. Discovery of roles for sex steroids in the tumor incidence pattern among strains has led to formulation of a two gene model for the mechanism of GC tumorigenesis. One gene is proposed to regulate androgen metabolism. Strains that are susceptible to spontaneous tumors, androgen-induced tumors, or are tumor-resistant will be compared to ascertain whether genetically determined differences in sex steroid metabolism lead to tumorigenesis through alteration in androgen hormones during the critical prepubertal period of ovarian development. the second gene is proposed to be a viral or cellular oncogene. The same spontaneous, androgen-inducible, and tumor-resistant strains described above will be investigated to determine if viral or cellular oncogene activation is correlated with GC tumorigenesis. Studies in vivo and in vitro will utilize radioimmunoassays of gonadotropin and steroid hormones, steroid treatments of SWR, SJL, and SWXJ mice, steroid receptor analyses, light and electron microscopy for morphological analyses, organ and primary granulosa cell cultures, steroid metabolizing enzyme analyses, ovarian graft studies, XC plaque and reverse transcriptase assays for infectious virus, and DNA transfection assays with NIH 3T3 cells to detect transforming gene activity. The availability of closely related inbred strains of mice that carry genes permissive or resistant to GC tumorigenesis, coupled with those genes segregated in recombinant inbred strains, offers an unparalleled opportunity for genetic and physiologic studies of mechanisms leading to a malignant cancer. The knowledge gained will point to directions for investigations of GC tumorigenesis in women.
