Objective: An association between estrogen and the risk of type 1 endometrial carcinoma, which shows frequent mutations in the Pten tumor suppressor gene, has consistently been found in many studies. However, such tumors usually arise in perimenopausal or postmenopausal women with decreased serum estrogen levels. This study aimed to reveal the contributions of estrogen to endometrial carcinogenesis in a mouse model of endometrial carcinoma initiated by conditional targeting of Pten.
Methods: The Cre-loxP system was used to achieve Pten inactivation within mouse endometrial epithelium. We delivered a recombinant adenovirus vector expressing Cre recombinase to the endometrial cavity of the Pten loxP/loxP mice that had been ovariectomized at 10 weeks old. Mice were subcutaneously injected with 17β-estradiol (E2) or vehicle, followed by injection of the adenovirus. Two weeks after adenovirus injection, the entire endometrium was analyzed.
Results: Mice that did not receive E2 injection notably developed endometrial neoplasia, complex atypical hyperplasia, or carcinoma (7/8, 87.5%). In contrast, hyperplastic but nonneoplastic endometrium was observed in E2-treated mice. In these E2-treated mice, immunohistochemistry revealed that Pten-null glandular epithelial cells clonally proliferate among the hyperplastic endometrium.
Conclusions: The results of this study suggest that estrogen clonally proliferates Pten-null epithelial cells together with surrounding cells, and depletion of estrogen induces predominant growth of Pten-null cells with estrogen-independent capabilities, resulting in abnormal structure of the glandular cells and subsequent neoplasia. This phenomenon might explain why the incidence of human endometrial carcinoma increases with perimenopausal or postmenopausal status, which represents declining ovarian function. Our model mice have partially resolved the issue of endometrial Pten- and estrogen-related carcinogenesis and have potential to represent a valuable tool for developing novel therapies against this carcinoma.
- Endometrial carcinoma
- Mouse model
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