The role of LEF1 in endometrial gland formation and carcinogenesis.
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.
Department of Obstetrics and Gynecology, Holden Comprehensive Cancer Center, The University of Iowa Hospitals and Clinics, Iowa City, Iowa, United States of America.
Dawne N
DN
Shelton
Hubert
H
Fornalik
Traci
T
Neff
Soo Yeun
SY
Park
David
D
Bender
Koen
K
DeGeest
Xiaoming
X
Liu
Weiliang
W
Xie
David K
DK
Meyerholz
John F
JF
Engelhardt
Michael J
MJ
Goodheart
D000230:Adenocarcinoma / Q000139:chemically induced / Q000378:metabolism*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism; D016889:Endometrial Neoplasms / Q000139:chemically induced / Q000378:metabolism*; D004717:Endometrium / Q000254:growth & development* / Q000378:metabolism / Q000473:pathology; D030762:Estrous Cycle / Q000378:metabolism; D005260:Female; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D051821:Lymphoid Enhancer-Binding Factor 1 / Q000235:genetics / Q000378:metabolism* / Q000502:physiology*; D008297:Male; D008770:Methylnitrosourea; D051379:Mice; D008810:Mice, Inbred C57BL; D008813:Mice, Inbred ICR; D018345:Mice, Knockout; D008875:Middle Aged
C530105:Ccnd1 protein, mouse; C497573:LEF1 protein, human; C497574:Lef1 protein, mouse; D051821:Lymphoid Enhancer-Binding Factor 1; D019938:Cyclin D1; D008770:Methylnitrosourea