Endometrial cancer is one of the most prevalent and invasive gynaecological malignancies of the female reproductive tract, affecting 1 in 75 Australian women by the age of 75. Based on histology and clinical features it can be divided into type I and type II cancers. Type I endometrial cancer is caused by unopposed oestrogen action and constitutes about 90% of all endometrial cancers. 30% of these endometrial cancer cases show nuclear accumulation of β-catenin, which is indicative of the overactivation of Wnt signalling. How oestrogen drives the endometrial carcinoma along with hyperactivation of Wnt signalling is currently unclear.
To study this, we have developed a mouse model with doxycycline regulated cre expression limited to the uterine epithelium. Using this approach we developed a mouse model with hyperactive β-catenin signalling. Analysis of these mice revealed that overexpression of Wnt/ β-catenin signalling in uterine epithelium leads to endometrial hyperplasia and carcinoma in situ, known precursors of endometrial cancer. To understand how steroid hormones affect endometrial carcinogenesis, we ovariectomised mutant mice and allowed them to rest for 14 days to remove traces of circulating hormones. After this rest period, hormonal pellets (E2, E2+P4 and vehicle) were subcutaneously inserted in mice (N=4/group). Examination of uteri from these mice after one month of treatment revealed development of endometrial cancer in E2 treated group. Co-treatment with progesterone suppressed endometrial cancer development. However, cystic growth and hyperplasia were still observed. Uteri from vehicle treated group showed endometrial hyperplasia but no cancer. In summary, we have shown that synergistic action of unopposed oestrogen along with dysregulation of Wnt signalling in uterine epithelium leads to endometrial carcinoma. This explains why human patients with type 1 endometrial cancer harbour activating mutations in the Wnt pathway.