Global or Granulosa Cell-Specific Pten Mutations in Combination with Elevated FSH Levels Fail to Cause Ovarian
Dannielle H Upton1, Kirsty A Walters2, Rachel E Allavena3
1ANZAC Research Institute, University of Sydney, Concord Hospital, Sydney, NSW, 2139, Australia. dannielle.upton@sydney.edu.au.
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 (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.
Insights
Phosphatase and tensin homologue (PTEN) loss causes tumors elsewhere but not in the ovary. Ovarian Pten disruption or elevated follicle-stimulating hormone (FSH) did not induce ovarian tumors, suggesting ovarian resistance.
Area of Science:
- Oncology
- Endocrinology
- Genetics
Background:
- Phosphatase and tensin homologue (PTEN) is a critical tumor suppressor.
- Understanding PTEN's role in ovarian cancer is crucial for developing targeted therapies.
Purpose of the Study:
- To investigate the role of PTEN in ovarian tumorigenesis using genetically modified mouse models.
- To assess the combined effects of PTEN disruption and elevated follicle-stimulating hormone (FSH) on ovarian tumor development.
Main Methods:
- Utilized transgenic SOX2.Cre and AMH.Cre mouse models for global and ovary-specific Pten disruption (Pten+/- and PtenGC).
- Combined Pten mutant models with transgenic FSH (TgFSH) to evaluate combined genetic and endocrine modifications.
- Monitored tumor development, survival rates, ovarian morphology, and estrous cycling.
Main Results:
- Global Pten haploinsufficiency (Pten+/-) led to extra-ovarian tumors (uterine, mammary) and reduced survival, but no ovarian tumors.
- Ovary-specific Pten disruption (PtenGC) did not result in ovarian or uterine tumors.
- Combined Pten+/- and TgFSH did not induce ovarian tumors, though early survival was reduced; PtenGC +/- TgFSH mice showed no tumors and unchanged estrous cycling.
Conclusions:
- Ovarian tissue exhibits remarkable resistance to Pten-induced tumorigenesis, even with concurrent extra-ovarian cancers.
- Multi-hit genetic mutations, potentially involving both ovarian and extra-ovarian tissues, are likely necessary for initiating ovarian tumors.
- Elevated FSH may negatively impact early cancer survival but does not appear to drive ovarian tumorigenesis in the absence of other critical genetic events.
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