title: TGFβ signaling promotes juvenile granulosa cell tumorigenesis by suppressing apoptosis.
abstract: Molecular changes that give rise to granulosa cell tumors of the ovary are not well understood. Previously, we showed that deletion in granulosa cells of the bone morphogenetic protein receptor-signaling transcription factors, Smad1 and Smad5, causes development of metastatic granulosa cell tumors that phenocopy the juvenile form of granulosa cell tumors (JGCTs) in humans. The TGFβ-SMAD2/3 pathway is active in JGCTs, but its role is unknown. We tested the in vivo contribution of TGFβ-SMAD signaling to JGCT development by genetically deleting the common Smad4 from Smad1/5 double knockout mice. Smad1/5/4 triple knockout mice were sterile and had significantly increased survival and delayed tumor development compared to those for the Smad1/5 double knockout mice. The few tumors that did develop were smaller, showed no evidence of metastasis, and had increased apoptosis. In the human JGCT cell line COV434, TGFβ1 increased viability by inhibiting apoptosis through a TGFβ type I receptor-dependent repression of caspase activity and inhibition of poly(ADP-ribose) polymerase cleavage. These data support a tumor-promoting function of TGFβ in JGCTs through its ability to repress apoptosis.
authors.affiliation: Department of Pathology and Immunology (N.M.-A., S.K.T., H.P., M.L.A., K.E., S.A.P.), Department of Obstetrics and Gynecology (M.L.A.), Graduate Program in Molecular and Cell Biology (N.G.), and Department of Molecular and Cellular Biology (S.A.P.), Baylor College of Medicine, Houston, Texas 77030.
authors.forename: Nadéra
authors.initials: N
authors.lastname: Mansouri-Attia
authors.forename: Swamy K
authors.initials: SK
authors.lastname: Tripurani
authors.forename: Nisha
authors.initials: N
authors.lastname: Gokul
authors.forename: Hermann
authors.initials: H
authors.lastname: Piard
authors.forename: Matthew L
authors.initials: ML
authors.lastname: Anderson
authors.forename: Karen
authors.initials: K
authors.lastname: Eldin
authors.forename: Stephanie A
authors.initials: SA
authors.lastname: Pangas
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D063646:Carcinogenesis / Q000235:genetics* / Q000473:pathology; D002470:Cell Survival / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D005260:Female; D006106:Granulosa Cell Tumor / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D006107:Granulosa Cells / Q000378:metabolism* / Q000473:pathology*; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D051785:Smad Proteins / Q000235:genetics / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000235:genetics* / Q000378:metabolism*
chemical_list: D018125:Receptors, Transforming Growth Factor beta; D051785:Smad Proteins; D053773:Transforming Growth Factor beta1; D011065:Poly(ADP-ribose) Polymerases; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I