Distinct alterations in gene expression following neonatal DES exposure have been reported for EGF, EGF receptor, c-fos, c-jun, c-myc, bax, and bcl-2.
- Exposure to diethylstilbestrol during a critical developmental period of the mouse reproductive tract leads to persistent induction of two estrogen-regulated genes.
- Immunohistochemical studies on the expression and estrogen dependency of EGF and its receptor and c-fos proto-oncogene in the uterus and vagina of normal and neonatally estrogen-treated mice.
- Neonatal diethylstilbestrol treatment alters the estrogen-regulated expression of both cell proliferation and apoptosis-related proto-oncogenes (c-jun, c-fos, c-myc, bax, bcl-2, and bcl-x) in the hamster uterus.
Although further studies will be required, neonatal estrogenic exposure might affect such genes, and induce carcinomas independently of surrounding stromal cells in adult mice.
Taken together, neonatal estrogenic treatments exerted an inhibitory, rather than stimulatory, effect on PTEN-related carcinogenesis via stromal alterations. CAH and carcinomas rarely occurred in the atrophic and/or hyalinized stroma, resulting from an irreversible repression of Hoxa 10 and Hoxa 11 through these neonatal estrogenic exposures. This study can be expected to provide new insight into the interaction between the endometrial epithelium and stroma in endometrial carcinogenesis in vivo.
Neonatal estrogenic exposure suppresses PTEN-related endometrial carcinogenesis in recombinant mice
2006 Study 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 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.
Sources and more information
- Full study (free access) Neonatal estrogenic exposure suppresses PTEN-related endometrial carcinogenesis in recombinant mice, Laboratory investigation; a journal of technical methods and pathology, NCBI PubMed PMID: 16402032, 2006 Mar.
- PTEN (gene) featured image credit wikipedia.
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