Abstract
Endometrioid endometrial carcinomas (EECs) carry multiple driver mutations even when they are low grade. However, the biological significance of these concurrent mutations is unknown. We explored the interactions among three signature EEC mutations: loss-of-function (LOF) mutations in PTEN, gain-of-function (GOF) mutations of phosphoinositide 3-kinase (PI3K), and CTNNB1 exon 3 mutations, utilizing in vivo mutagenesis of the mouse uterine epithelium. While epithelial cells with a monoallelic mutation in any one of three genes failed to propagate in the endometrium, any combination of two or more mutant alleles promoted the growth of epithelium, causing simple hyperplasia, in a dose-dependent manner. Notably, Ctnnb1 exon 3 deletion significantly increased the size of hyperplastic lesions by promoting the growth of PTEN LOF and/or PI3K GOF mutant cells through the activation of neoadenogenesis pathways. Although these three mutations were insufficient to cause EEC in intact female mice, castration triggered malignant transformation, leading to myometrial invasion and serosal metastasis. Treatment of castrated mice with progesterone or estradiol attenuated the neoplastic transformation. This study demonstrates that multiple driver mutations are required for premalignant cells to break the growth-repressing field effect of normal endometrium maintained by ovarian steroids and that CTNNB1 exon 3 mutations play critical roles in the growth of preneoplastic cells within the endometrium of premenopausal women and in the myometrial invasion of EECs in menopausal women.
Highlights
Endometrioid endometrial carcinomas (EECs) carry multiple driver mutations even when they are low grade
This study demonstrates that multiple driver mutations are required for premalignant cells to break the growth-repressing field effect of normal endometrium maintained by ovarian steroids and that CTNNB1 exon 3 mutations play critical roles in the growth of preneoplastic cells within the endometrium of premenopausal women and in the myometrial invasion of EECs in menopausal women
We developed a mouse EEC model, in which multiple driver mutations are introduced into a small fraction of fully differentiated uterine epithelial cells
Summary
Endometrioid endometrial carcinomas (EECs) carry multiple driver mutations even when they are low grade. Ctnnb exon 3 deletion significantly increased the size of hyperplastic lesions by promoting the growth of PTEN LOF and/or PI3K GOF mutant cells through the activation of neoadenogenesis pathways. These three mutations were insufficient to cause EEC in intact female mice, castration triggered malignant transformation, leading to myometrial invasion and serosal metastasis. Recent large-scale comprehensive genomic analysis by The Cancer Genome Atlas (TCGA) proposed the classification of EC subtypes by unique molecular features: POLE ultramutated, microsatellite instability (MSI) hypermutated, copy-number-low (CL; endometrioid), and copy-number-high (CH; serous-like) EC subtypes [2]. In the absence of estradiol and progesterone, a CTNNB1 mutation drives myometrial invasion and metastasis of ECs
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