Role of Wnt signalling in endometrial homeostasis and cancer

Several Wnt signalling pathway members are known to contribute to the development of the uterus. Dysregulation of the Wnt signalling pathway has been found in approximately 30-50% of endometrial cancer cases. It is presently unknown how the Wnt signalling pathway regulates uterine development and contributes to endometrial pathologies such as endometrial cancer. In this thesis, we have shown that epithelial Wnt signalling plays an important role in uterine development, function, and initiation of endometrial cancer. Using a Wnt reporter mouse model we tracked the real-time expression of Wnt/β-catenin signalling in the mouse uterus. Thick uterine sections from Wnt reporter mice taken at time points across the duration of gland formation (dpn3-dpn21) showed high Wnt signalling activity in the uterine epithelium towards the antimesometrial side of the uterus. Interestingly, the uterine glands were also restricted towards the antimesometrial side. In situ hybridization analysis revealed expression of Dkk2, a Wnt inhibitor, in the stroma towards the mesometrial side of the uterus. This finding emphasised the role of Wnt signalling in regulating uterine development and restriction of uterine glands towards the antimesometrial side of the uterus. To further dissect the role of epithelial Wnt signalling we developed two triple transgenic mouse models having uterine epithelium-specific cre expression. Interestingly, in prepubertal mice, constitutive activation of epithelial Wnt signalling lead to development of glands towards both antimesometrial and mesometrial sides of the uterus whereas lack of epithelial Wnt signalling in the uterus resulted in absence of gland development. These results strongly indicate the role of Wnt signalling in regulating adenogenesis. We have also shown that epithelial Wnt signalling was dispensable for postpartum gland formation, however, it was essential for maintaining fertility. Furthermore, we found that sustained activation of Wnt signalling in the uterine epithelium leads to endometrial hyperplasia, a precursor to endometrial cancer. However, constitutive activation of Wnt signalling alone for chronic periods was unable to progress endometrial hyperplasia to endometrial cancer. Interestingly, type 1 endometrial cancer is associated with unopposed oestrogen. Our findings suggest that hyperactivated Wnt signalling together with unopposed oestrogen fuels the growth of endometrial cancer from endometrial cancer initiating lesions. Using mouse models and 3D human endometrial cancer cell culture, we have demonstrated that progesterone inhibits endometrial cancer by suppressing Wnt signalling. In conclusion, we have shown that balanced Wnt signalling is essential for uterine development and function. Furthermore, we have provided evidence that progesterone can be used as a targeted therapy for endometrial cancer driven by activating mutations in Wnt signalling.