Neonatal estrogenic exposure suppresses PTEN-related endometrial carcinogenesis in recombinant mice.
Human endometrial carcinomas, as well as complex atypical hyperplasias (CAH), are estrogen related and frequently have mutations in the PTEN gene. However, the mutual contribution of estrogen and PTEN mutations to endometrial carcinogenesis in vivo is unknown. To address this issue, we investigated whether neonatal estrogenic treatments augment the incidence of CAH and carcinomas in murine PTEN (mPTEN) heterozygous (+/-) mutant mice, an animal model for endometrial carcinoma. Low doses of diethylstilbestrol (1 ng/g/day), genistein (50 microg/g/day) in phytoestrogens, estriol (E(3)) (4 microg/g/day), and vehicle (ethanol and corn oil) were administered subcutaneously daily to neonatal pups from the 1st to 5th day after birth. At 52 weeks of age, the morphological changes in the endometrium, and uterine expression of Hoxa 10 and Hoxa 11, were evaluated. These Hoxa genes are abdominal B-type homeobox genes, which normally regulate differentiation of the Müllerian duct. The incidence of CAH and adenocarcinomas of the endometrium was significantly decreased by the neonatal estrogenic treatments in the mPTEN+/- mice. Coincidentally, all treatments significantly decreased the stromal cell density, and CAH and adenocarcinomas rarely developed in the epithelium adjacent to the affected endometrial stroma. Moreover, the uterine expression of Hoxa 10 in mice with neonatal genistein and E(3) treatments, and that of Hoxa 11 in mice with all treatments, was significantly lower when compared with vehicle alone. Taken together, neonatal estrogenic exposure induced stromal atrophy and/or hyalinization accompanied by repressed expression of Hoxa 10 and Hoxa 11, and exerted an inhibitory effect on PTEN-related tumorigenesis. These findings provide new insight into the interaction between endometrial epithelium and stroma in endometrial carcinogenesis in vivo.
Begum
Monjura
M
Department of Reproductive Medicine and Surgery, Faculty of Medical and Pharmaceutical Sciences, Kumamoto University, Honjo, Kumamoto City, Kumamoto, Japan.
Tashiro
Hironori
H
Katabuchi
Hidetaka
H
Suzuki
Akira
A
Kurman
Robert J
RJ
Okamura
Hitoshi
H
D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D000818:Animals; D000831:Animals, Newborn; D004195:Disease Models, Animal; D016889:Endometrial Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D000080905:Homeobox A10 Proteins; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009929:Organ Size / Q000187:drug effects; D051059:PTEN Phosphohydrolase / Q000235:genetics* / Q000378:metabolism; D048789:Phytoestrogens / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D011995:Recombination, Genetic; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014599:Uterus / Q000378:metabolism / Q000473:pathology
D000080905:Homeobox A10 Proteins; D018398:Homeodomain Proteins; C094041:Hoxa11 protein, mouse; D048789:Phytoestrogens; D012333:RNA, Messenger; C092119:Hoxa10 protein, mouse; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse