PTEN mutations occur frequently in ovarian cancer but in previous experimental studies granulosa cell (GC)-specific Pten inactivation alone was insufficient to cause murine tumors. Follicle stimulating hormone (FSH) is vital for ovarian function with elevated circulating levels associated with reproductive ageing and ovarian tumorigenesis in women. Transgenic FSH (TgFSH) mice exhibit progressively rising FSH levels with ageing causing ovarian dysfunction and premature infertility, but no tumours. We hypothesized that high FSH when combined with ovarian Pten mutations may promote ovarian tumorigenesis in mice.
We used Tg.AMH.Cre to target Pten disruption to GCs (PtenGC) and Tg.Sox2.Cre for global heterozygous Pten mutation (Pten+/-) combiningthem with TgFSH overexpression as a multi-hit strategy to use genetic and hormonal means to induce ovarian tumors. TgFSH ± PtenGC females displayed similar ovary and uterine weights versus controls (±TgFSH) with no detectable tumours at 12 months. TgFSH ± Pten+/- ovary weights remained unchanged (p = 0.5), whereas uterine weights increased due to tumors vs controls (p < 0.001). TgFSH ± Pten+/- females developed tumours in various organs (pituitary, skin, kidneys) but not in the ovary. Estrous cycling and stage lengths were not significantly altered by ovary-specific PtenGC status whereas global Pten+/- mice had reduced estrous cycling (p < 0.001). Corpora lutea (CL) numbers remained unchanged among PtenGC mice vs control (p = 0.99), however Pten+/- significantly increase CL numbers (p < 0.05), indicating increased ovulation rates or persisting CLs by global Pten mutation.
We conclude that specific follicular or global Pten mutations, alone, or combined with TgFSH, were not sufficient to cause ovarian tumors. These findings that the ovary is remarkably resistant to oncogenesis support the newer extra-gonadal origin hypothesis for ovarian tumorigenesis.