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 (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.