Abstract
Endometrial carcinoma is the most common gynecologic cancer, yet the mechanisms underlying this disease process are poorly understood. We hypothesized that Lef1 is required for endometrial gland formation within the uterus and is overexpressed in endometrial cancer. Using Lef1 knockout (KO) mice, we compared uterine gland development to wild-type (WT) controls, with respect to both morphology and expression of the Lef1 targets, cyclin D1 and MMP7. We characterized the dynamics of Lef1 protein expression during gland development and the mouse estrus cycle, by immunostaining and Western blot. Finally, we investigated the roles of cyclin D1 and MMP7 in gland and cancer formation in the mouse, and assessed the relevance of Lef1 to human cancer by comparing expression levels in cancerous and normal endometrial tissues. Lef1 upregulation in mouse endometrium correlates with the proliferative stages of the estrus cycle and gland development during the neonatal period. WT mice endometrial glands began to develop by day 5 and were easily identified by day 9, whereas Lef1 KO mice endometrial glands had not developed by day 9 although the endometrial lining was intact. We found that during gland development cyclin D1 is elevated and localized to the gland buds, and that this requires the presence of Lef1. We also noted that Lef1 protein was expressed at higher levels in endometrial cancers within mice and humans when compared to normal endometrium. Our loss-of-function data indicate that Lef1 is required for the formation of endometrial glands in the mouse uterus. Lef1 protein elevation corresponds to gland formation during development, and varies cyclically with the mouse estrus cycle, in parallel with gland regeneration. Finally, Lef1 is overexpressed in human and mouse endometrial tumors, consistent with it playing a role in gland proliferation.
Highlights
Endometrial carcinoma is the most common gynecologic malignancy and ranks second as a cause of gynecologic cancer mortality in the United States; in 2012, the American Cancer Society predicts 47,130 new cases and 8,010 deaths in this year alone [1]
In contrast to what has been observed in colon cancer, the uterus normally expresses Lymphoid Enhancing Factor 1 (Lef1) protein both during its initial development and as it cycles through estrus (Fig. 1 & 2)
Lef1 appeared to be precisely regulated during the mouse estrus cycle
Summary
Endometrial carcinoma is the most common gynecologic malignancy and ranks second as a cause of gynecologic cancer mortality in the United States; in 2012, the American Cancer Society predicts 47,130 new cases and 8,010 deaths in this year alone [1]. Most endometrial carcinomas arise from the glands of the endometrium (adenocarcinomas), and the remainder from the supporting stroma (sarcomas). The mechanisms that regulate cyclic turnover of the endometrium, as well as those that control continual regeneration of the glands and supporting stroma during this turnover, are precisely regulated. In other mammals, such as mice, endometrial turnover takes as few as 4 days, but in humans it can last as long as 30 days. Identifying the molecular pathways that govern cyclic turnover of the endometrium and the factors that initiate gland development will help us understand the regulatory defects that give rise to cancer. A more comprehensive understanding of endometrial gland formation will provide insight into: 1) other disorders involving gland dysregulation (e.g., endometriosis, infertility, menstrual irregularities and adenomyosis), and 2) disorders involving hyperproliferation of cells within the endometrial glands, for example complex hyperplasia (with and without atypia) and cancer
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