Department of Obstetrics and Gynecology, Holden Comprehensive Cancer Center, The University of Iowa Hospitals and Clinics, Iowa City, Iowa, United States of America.
PLoS One. 2012;7(7):e40312. doi: 10.1371/journal.pone.0040312. Epub 2012 Jul 6.
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.
子宫内膜癌是最常见的妇科癌症，但这种疾病的发生机制尚不清楚。我们假设 Lef1 是子宫内子宫内膜腺形成所必需的，并且在子宫内膜癌中过度表达。我们使用 Lef1 敲除（KO）小鼠，比较了 Lef1 靶标 cyclin D1 和 MMP7 的形态和表达，以研究子宫腺的发育。我们通过免疫染色和 Western blot 研究了 Lef1 蛋白在腺发育和小鼠动情周期中的表达动态。最后，我们研究了 cyclin D1 和 MMP7 在小鼠腺和癌症形成中的作用，并通过比较癌症和正常子宫内膜组织中的表达水平来评估 Lef1 对人类癌症的相关性。Lef1 在小鼠子宫内膜中的上调与动情周期的增殖阶段和新生儿期的腺发育相关。WT 小鼠的子宫内膜腺在第 5 天开始发育，在第 9 天很容易识别，而 Lef1 KO 小鼠的子宫内膜腺在第 9 天仍未发育，尽管子宫内膜层完整。我们发现，在腺发育过程中 cyclin D1 升高并定位于腺芽，并且这需要 Lef1 的存在。我们还注意到，与正常子宫内膜相比，Lef1 蛋白在小鼠和人类的子宫内膜癌中表达水平更高。我们的功能丧失数据表明 Lef1 是小鼠子宫内子宫内膜腺形成所必需的。Lef1 蛋白的升高与发育过程中的腺形成相对应，并且与小鼠动情周期周期性变化，与腺再生平行。最后，Lef1 在人类和小鼠子宫内膜肿瘤中过度表达，表明它在腺增殖中起作用。
