Global or Granulosa Cell-Specific Pten Mutations in Combination with Elevated FSH Levels Fail to Cause Ovarian Tumours in Mice

• Published in: Hormones & cancer 2016-12, Vol.7 (5-6), p.316-326
• Main Authors: Upton, Dannielle H., Walters, Kirsty A., Allavena, Rachel E., Jimenez, Mark, Desai, Reena, Handelsman, David J., Allan, Charles M.
• Format: Article
• Language: English
• Subjects: Animals; Cell Biology; Endocrinology; Female; Follicle Stimulating Hormone - metabolism; Granulosa Cells - metabolism; Internal Medicine; Mammary Neoplasms, Animal - genetics; Medicine; Medicine & Public Health; Mice; Mice, Transgenic; Microbiology; Mutation; Oncology; Organ Size; Original Paper; Ovarian Neoplasms - genetics; Ovarian Neoplasms - metabolism; Ovarian Neoplasms - pathology; Ovarian Neoplasms - veterinary; PTEN Phosphohydrolase - genetics; PTEN Phosphohydrolase - metabolism; SOXB1 Transcription Factors - genetics; Survival Analysis; Systems Biology; Uterine Neoplasms - genetics
• ISSN: 1868-8497; 1868-8500
• DOI: 10.1007/s12672-016-0272-3

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 ( Pten GC ). 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 Pten GC  ± 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 Pten GC  ± 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.