Lack of ovarian tumorigenesis in mice expressing elevated FSH levels combined with granulosa cell-specific Brca1 and global p53<sup>+/-</sup> loss. — ASN Events
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  2. SRB Poster Session - Ovary/Follicle Development/Corpus luteum
  3. Lack of ovarian tumorigenesis in mice expressing elevated FSH levels combined with granulosa cell-specific Brca1 and global p53+/- loss.

Lack of ovarian tumorigenesis in mice expressing elevated FSH levels combined with granulosa cell-specific Brca1 and global p53+/- loss. (#249)

Dannielle H Upton 1 , Emily S Fuller 2 , Emily K Colvin 2 , David J Handelsman 1 , Viive M Howell 2 , Charles M Allan 1
  1. Andrology Laboratory, ANZAC Research Institute, Concord, NSW, Australia
  2. Bill Walsh Cancer Research Laboratory, Kolling Institute, St Leonards, NSW, Australia

Follicle stimulating hormone (FSH) is vital for ovarian function. However, elevated FSH is associated with reproductive ageing and implicated in ovarian tumorigenesis. We created transgenic (Tg) mice exhibiting progressively rising FSH levels with age, which caused dose-dependent ovarian dysfunction and premature infertility. Ovarian tumours were not found in TgFSH females up to 18mo, indicating that elevated FSH alone is insufficient for ovarian neoplasia. We predicted that high FSH may act as a trophic effector when combined with other candidates involved in ovarian tumorigenesis, such as loss of BRCA1 and p53. Previously, a TgCre-loxP model was used to inactivate Brca1 in granulosa cells (GC), producing mice exhibiting cystic ovarian and uterine horn tumours, reported to resemble serous cystadenomas1. However, extra-ovarian Brca1 disruption (eg. pituitary) and altered estrous cycling was found in this model2, and the origin and cause of tumours remains unclear. We have used TgAMH.Cre mice with proven GC-specific expression3  to target Brca1 disruption and determine the effects of GC-specific Brca1 loss (Brca1GC-/-). Brca1GC-/- was combined with TgFSH expression and heterozygous p53+/- loss to provide a multi-hit strategy to test potential causes of ovarian tumour development in vivo.

TgFSH or non-Tg mice with  Brca1GC-/- ± p53+/- modification were collected at 6 and 12 mo. Ovarian weights were equivalent in TgFSH and non-Tg groups, and no detectable cystic/neoplastic changes were observed in ovarian-uterine tissue. No significant differences were found in estrous cycle stages. The normal ovarian phenotype in TgAMH.Cre-driven Brca1GC-/- mice suggests extra-ovarian rather than GC-driven defects may have produced cystic tumours in the previous Brca1 disrupted model exhibiting ectopic TgCre expression. Our findings indicate the ovary is resistant to tumorigenic changes, despite elevated FSH and associated loss of BRCA1 and p53, which supports an emerging view of an extra-gonadal origin for ovarian malignancies.

  1. R. Chodankar et al., Current Biology 15, 561 (2005).
  2. H. Hong et al., Cancer Research 70, 221 (2010).
  3. K. A. Walters et al., Biology of Reproduction 87, 151 (2012).
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