2005 Fiscal Year Final Research Report Summary
Influence of endocrine disturbance in endometrial carcinogenesis in recombinant PTEN mice.
| Project/Area Number |
15591764
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Obstetrics and gynecology
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| Research Institution | Kumamoto University |
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Principal Investigator |
TASHIRO Hironori Kumamoto University, University Hospital, Assistant Professor, 医学部附属病院, 講師 (70304996)
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| Co-Investigator(Kenkyū-buntansha) |
KATABUCHI Hidetaka Kumamoto University, Faculty of Medical and pharmaceutical Sciences, Professor, 大学院・医学薬学研究部, 教授 (90224451)
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| Project Period (FY) |
2003 – 2005
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| Keywords | PTEN recombinant mice / Endometrial carcinoma / Endometrial stroma / Hoxa 10 gene / Hoxa 11 gene / Hyalinization of stroma / Atrophic stroma / 内膜間質萎縮 |
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| Research Abstract |
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 mPTEN heterozygous (+/-) mutant mice, an animal model for endometrial carcinoma. Low doses of diethylstilbestrol (1 ng/g/day), genistein (50 μg/g/day) in phytoestrogens, estriol (E_3) (4 μg/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 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 mullerian 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.
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