Investigating the Combined Effect of Brca1 Loss and Estradiol Increase on Ovarian Tumourigenesis

Abstract

The mechanism of how BRCA1 mutation exclusively increases susceptibility to breast and ovarian cancer is unknown, however evidence suggests that Brca1 loss upregulates aromatase, the enzyme that produces estradiol, and that increased estradiol promotes tumourigenesis. To investigate these processes, Brca1 was inactivated in the ovarian surface epithelium (OSE) of mice that were then exposed to placebo or estradiol for 60 days. Ovaries were examined histologically at time points up to one year. Estradiol did not induce tumourigenesis of the OSE, but did increase preneoplastic morphological changes. Inactivation of Brca1 in OSE and granulosa cells (GCs) in vitro did not upregulate aromatase or increase estradiol production. An in vivo model of Brca1 inactivation in GCs and OSE that enables monitoring of aromatase, estradiol levels and tumourigenesis remains desirable, as elucidation of the relationship between Brca1 and aromatase could impact understanding of the pathways responsible for ovarian tumour initiation and early progression.