title: Smad1-Smad5 ovarian conditional knockout mice develop a disease profile similar to the juvenile form of human granulosa cell tumors.
abstract: Granulosa cell tumors (GCTs) of the ovary are rare sex cord stromal tumors. Although generally indolent, GCTs recur, and if not diagnosed and treated in early stages, survival rates are significantly shortened. Very little is known regarding GCT etiology. Because of the low incidence of cases and lack of standard diagnostics, mouse models for granulosa cell tumors are a valuable tool for studying GCTs and provide models for developing diagnostic and treatment strategies. We recently developed a novel mouse model of metastatic granulosa cell tumors by genetic deletion of the bone morphogenetic protein signaling transcription factors (SMADs) in granulosa cells of the ovary. Histological and serum hormone analyses reveal that this mouse model most closely resembles the juvenile form of GCT. We further analyzed samples of human juvenile GCT (JGCT) for expression of anti-Müllerian hormone and activation of two major signaling pathways: TGFbeta/SMAD2/3 and wingless-related mouse mammary tumor virus integration site (Wnt)/beta-catenin. The TGFbeta family is active in mouse Smad1-Smad5 double knockout tumors, and here we show that this pathway, but not the beta-catenin pathway, is activated in samples of human JGCT. These data suggest that the SMAD family, possibly through disruption of SMAD1/5 or activation of SMAD2/3 may contribute to the pathogenesis of JGCT in humans.
authors.affiliation: Department of Pathology, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Brooke S
authors.initials: BS
authors.lastname: Middlebrook
authors.forename: Karen
authors.initials: K
authors.lastname: Eldin
authors.forename: Xiaohui
authors.initials: X
authors.lastname: Li
authors.forename: Sujatha
authors.initials: S
authors.lastname: Shivasankaran
authors.forename: Stephanie A
authors.initials: SA
authors.lastname: Pangas
mesh_terms: D000293:Adolescent; D000818:Animals; D054304:Anti-Mullerian Hormone / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D004195:Disease Models, Animal; D005260:Female; D006106:Granulosa Cell Tumor / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D007223:Infant; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D010051:Ovarian Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D010053:Ovary / Q000378:metabolism* / Q000473:pathology; D051898:Smad1 Protein / Q000235:genetics / Q000378:metabolism*; D051899:Smad2 Protein / Q000378:metabolism; D051900:Smad3 Protein / Q000378:metabolism; D051902:Smad5 Protein / Q000235:genetics / Q000378:metabolism*; D016019:Survival Analysis
chemical_list: D051898:Smad1 Protein; D051899:Smad2 Protein; D051900:Smad3 Protein; D051902:Smad5 Protein; D054304:Anti-Mullerian Hormone