Ovarian insufficiency and CTNNB1 mutations drive malignant transformation of endometrial hyperplasia with altered PTEN/PI3K activities

Significance Our mouse model of endometrial cancer (EC) reveals the mechanism underlying the presence of multiple driver mutations in early EC along with the menopause-associated risk in endometrial carcinogenesis. Human ECs carry multiple driver mutations even when they are low grade, whereas a single driver mutation caused EC in previous mouse studies. Our study established that multiple driver mutations are essential for clonal expansion of preneoplastic epithelial cells within the anticancer environment of the normal endometrium. The tumor-suppressing activity of normal endometrium is maintained by estradiol and progesterone, indicating that menopause itself can promote ECs. In the absence of estradiol and progesterone, a CTNNB1 mutation drives myometrial invasion and metastasis of ECs.