Reproductive Steroid Hormones Alter Ovarian Cancer Progression in Mouse Models.

Epidemiological studies have shown that estrogen replacement after menopause increases the risk of developing ovarian cancer, whereas taking oral contraceptives before menopause decreases that risk. Because the majority of ovarian cancers are diagnosed after menopause, and because so many women are exposed to exogenous hormones, it is important to understand how menopause and hormones alter cancer progression. To study the early stages of ovarian cancer, we generated a transgenic mouse model of ovarian cancer that we are now using to determine how steroid hormones and menopausal changes in ovarian phenotype alter disease progression. We hypothesized 1) that estrogen would stimulate cancer progression by altering transcription of genes involved in proliferation, metastasis and angiogenesis and 2) that menopausal ovaries would be more sensitive to exogenous hormone action. In the tgCAG-LS-TAg mouse model, SV40 T antigen is activated, and therefore tumourigenesis is selectively induced, in the ovarian surface epithelium, a primary site of origin for ovarian cancers. T antigen expression was induced in young (3 months) or older mice (8 months) by intrabursal injection of adenovirus expressing Cre recombinase. To model ovarian cancer in a menopausal ovary, we simulated 'menopause' by injecting vinylcyclohexene diepoxide 2 months prior to tumour initiation. Mice were then treated with 60-day pellets releasing 17beta-estradiol (E2), progesterone (P4), or both E2 and P4, and were monitored until a loss of wellness endpoint. Median survival after adenovirus injection tended to be shorter in young (113 days, range of 75-181) vs. older mice (142 days, range of 53-207). The induction of 'menopause' had no effect on survival, but altered tumour histology relative to non-'menopausal' mice. In both age groups, treatment with E2 decreased median survival by 56-68% relative to controls. To differentiate between E2 effects on tumour initiation vs. progression and to investigate the mechanisms underlying the decreased survival caused by E2, we used a xenograft model in which SCID mice were injected with ovarian cancer cells derived from the ascites of a tgCAG-LS-TAg mouse treated with E2 (MASE) or control pellets (MASC). E2 decreased median survival time for both groups, but caused more rapid progression in mice injected with MASE (32 days) compared to MASC cells (48.5 days). Western blotting showed that estrogen receptor (ERα levels were 5-fold higher in the MASE than in the MASC cells, suggesting that increased ERα levels in the MASE cells are responsible for the enhanced responses to E2. Microarray analysis of MASE tumours from mice treated with exogenous E2 showed upregulation of 197 genes and downregulation of 55 genes compared to tumours from placebo-treated mice. In addition to several known ER targets such as Pgr, several novel genes were identified, including genes involved in angiogenesis, cell proliferation and differentiation. These are currently being validated and tested for functional significance. In summary, our results indicate that overall survival is not altered by ovarian pre/post-menopausal status, and that E2 accelerates ovarian cancer progression in both young and older mice. Further characterization of the function of E2-targeted genes will aid the identification of mechanisms by which this hormone increases the risk of ovarian cancer. (poster)

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