Oestrogen fuels the growth of endometrial hyperplastic lesions initiated by overactive Wnt/β-catenin signalling

Abstract

Unopposed oestrogen is responsible for approximately 80% of all the endometrial cancers. The relationship between unopposed oestrogen and endometrial cancer was indicated by the increase in the number of endometrial cancer cases due to the widespread use of oestrogen replacement therapy. Approximately 30% of the endometrial cancer patients have mutations in the Wnt signalling pathway. How the unbalanced ratios of ovarian hormones and the mutations in Wnt signalling pathway interact to cause endometrial cancer is currently unclear. To study this, we have developed a uterine epithelial cell-specific inducible cre mouse model and used 3D in vitro culture of human endometrial cancer cell lines. We showed that activating mutations in the Wnt signalling pathway for a prolonged period leads to endometrial hyperplasia but not endometrial cancer. Interestingly, unopposed oestrogen and activating mutations in Wnt signalling together drive the progression of endometrial hyperplasia to endometrial cancer. We have provided evidence that progesterone can be used as a targeted therapy against endometrial cancer cases presented with the activating mutations in Wnt signalling pathway.

Wnt Signaling in Gynecologic Malignancies

“…Correct regulation of Wnt/β-catenin signaling in this cyclical fashion is required for normal endometrial function [16,17,95,100], as loss of β-catenin results in squamous metaplasia of the endometrium, while constitutively active β-catenin results in endometrial hyperplasia [16,17]. The addition of unopposed estrogen to the models containing activating β-catenin mutations results in EC, demonstrating the relationship between Wnt/β-catenin signaling and hormonal regulation in the endometrium.…”

“…This relationship is also highlighted by the fact that progesterone-mediated downregulation of Wnt/β-catenin signaling inhibits EC progression [17]. Progesterone's downregulation of Wnt/β-catenin signaling may play a significant mechanistic role in its treatment effects.…”

“…More recently, there is growing research evaluating the role of Wnt signaling in gynecologic malignancies. Specifically, Wnt signaling promotes metastasis and therapy resistance in ovarian cancer, plays a crucial role in tumorigenesis and recurrence in endometrial cancer, and participates in human papillomavirus (HPV) -related tumorigenesis and metastasis in cervical cancer [ 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 ]. For all of these gynecologic malignancies, Wnt signaling is also being evaluated as a possible therapeutic target [ 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 ].…”

Cyclooxygenase-2 and β-Catenin as Potential Diagnostic and Prognostic Markers in Endometrial Cancer

“…In particular, β-catenin is the primary mediator of the oncogenic effect in this signaling pathway (17,21). Almost 30-85% of type I EC cases show nuclear accumulation of β-catenin in the epithelium (43)(44)(45). Thus, it is important to understand the role of wnt/β-catenin signaling in EC.…”

“…Thus, it is important to understand the role of wnt/β-catenin signaling in EC. A recent study reported that wnt/β-catenin pathway dysregulation to be an important factor in young EC patients with poor prognosis (45)(46)(47). Genetic mutations of the wnt/βcatenin signaling pathway members are mostly detected in patients with more aggressive histologic type of EC and are related to worse prognosis and poor overall survival rate (4, 10, 45).…”