title: Global or Granulosa Cell-Specific Pten Mutations in Combination with Elevated FSH Levels Fail to Cause Ovarian Tumours in Mice.
abstract: Phosphatase and tensin homologue (PTEN) is a known tumour suppressor. To explore the role of Pten in ovarian tumorigenesis, we used transgenic (Tg) SOX2. Cre and AMH. Cre mouse models to direct global Pten haploinsufficiency (Pten+/-) or ovary-specific granulosa cell (GC) Pten disruption (PtenGC). Pten mutant models were combined with progressively rising Tg-follicle-stimulating hormone (TgFSH) levels to study the tumorigenic potential of combined genetic/endocrine modification in vivo. Global Pten+/-mice exhibited grossly detectable tumours in multiple organs including uterine and mammary tissue and displayed reduced survival. Despite extra-ovarian tumorigenesis, Pten+/-females had no detectable ovarian tumours, although elevated corpus luteum numbers increased ovary size and estrous cycling was altered. Combined TgFSH/Pten+/-mice also had no ovarian tumours, but early survival was reduced in the presence of TgFSH. Ovary-specific PtenGC± TgFSH females exhibited no detectable ovarian or uterine tumours, and corpus luteum numbers and estrous cycling remained unchanged. The non-tumorigenic ovarian phenotypes in Pten+/-and PtenGC± TgFSH mice support the proposal that multi-hit genetic mutations (including ovarian and extra-ovarian tissue) initiate ovarian tumours. Our findings suggest that elevated FSH may reduce early cancer survival; however, the ovary remains remarkably resistant to Pten-induced tumorigenic changes even in the presence of uterine and reproductive cancers.
authors: ANZAC Research Institute, University of Sydney, Concord Hospital, Sydney, NSW, 2139, Australia. dannielle.upton@sydney.edu.au.
authors: Dannielle H
authors: DH
authors: Upton
authors: ANZAC Research Institute, University of Sydney, Concord Hospital, Sydney, NSW, 2139, Australia.
authors: Kirsty A
authors: KA
authors: Walters
authors: School of Veterinary Science, University of Queensland, QLD, Gatton, 4343, Australia.
authors: Rachel E
authors: RE
authors: Allavena
authors: ANZAC Research Institute, University of Sydney, Concord Hospital, Sydney, NSW, 2139, Australia.
authors: Mark
authors: M
authors: Jimenez
authors: ANZAC Research Institute, University of Sydney, Concord Hospital, Sydney, NSW, 2139, Australia.
authors: Reena
authors: R
authors: Desai
authors: ANZAC Research Institute, University of Sydney, Concord Hospital, Sydney, NSW, 2139, Australia.
authors: David J
authors: DJ
authors: Handelsman
authors: ANZAC Research Institute, University of Sydney, Concord Hospital, Sydney, NSW, 2139, Australia.
authors: Charles M
authors: CM
authors: Allan
mesh_terms: D000818:Animals; D005260:Female; D005640:Follicle Stimulating Hormone / Q000378:metabolism*; D006107:Granulosa Cells / Q000378:metabolism*; D015674:Mammary Neoplasms, Animal / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D009929:Organ Size; D010051:Ovarian Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology* / Q000662:veterinary*; D051059:PTEN Phosphohydrolase / Q000235:genetics* / Q000378:metabolism; D055748:SOXB1 Transcription Factors / Q000235:genetics*; D016019:Survival Analysis; D014594:Uterine Neoplasms / Q000235:genetics
chemical_list: D055748:SOXB1 Transcription Factors; C527783:Sox2 protein, mouse; D005640:Follicle Stimulating Hormone; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse