Follicle stimulating hormone (FSH) is vital for ovarian function with elevated levels associated with reproductive ageing and putative role in ovarian tumorigenesis. FSH transgenic (TgFSH) mice expressing human dimeric FSH exhibit progressively rising FSH levels with age causing dose-dependent ovarian dysfunction and premature infertility, but no ovarian tumours suggesting that elevated FSH alone is insufficient to cause murine ovarian cancer. We hypothesized that high FSH may promote ovarian tumours when combined with genetic mutations in ovarian tumour suppressor genes such as loss of Brca1, Tp53 and Pten.
Previously, inactivation of Brca1 in murine granulosa cells (GC) produced cystic ovarian and uterine tumours (1,2); however, this model also featured confounding effects of extra-ovarian Brca1 disruption (eg.pituitary) and altered estrous cycling (1,2) clouding interpretation of the pathogenesis of these tumours. We used an AMH.Cre mouse line with proven GC-specific expression (3) to produce 2 models: targeted GC-specific Brca1 loss(± global Tp53+/-) or Pten disruption, both combined with TgFSH expression to provide a multi-hit strategy to assess ovarian tumour development in vivo.
At 6 and 12 month of age, TgFSH and non-TgFSH control mice (n=3-12/group) with GC modifications displayed similar or higher ovary weights but no ovarian or uterine tumours. Estrous stage cycling was unaffected in all genotypes, but there was a decrease in corpus luteum numbers in all Brca1(±TgFSH± global Tp53+/-)vs Control(0-0.5±0-0.9 v s3.5±0.5, p=0.002) at both ages. The absence of ovarian tumours with high FSH and AMH.Cre-driven inactivation of Brca1±Tp53 or Pten suggests extra-ovarian rather than GC-driven defects are responsible for cystic tumours in the previously reported Brca1 disrupted model. Our findings that the ovary is remarkably resistant to tumorigenic changes despite elevated FSH and associated loss of Brca1, Tp53 and Pten for up to 12 months, supports an emerging view of an extra-gonadal origin for apparently “ovarian” cancers.