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

Abstract

Background: The final target cell response to estrogen is dependent not only on the estrogen receptor, but also on autocrine/paracrine interactions with growth factors (e.g., EGF) and proto-oncogenes (e.g., c-fos). Because neonatal estrogen treatment results in permanent changes in the female mouse genital tract (permanent vaginal cornification, cervical adenosis and tumors, changed growth control mechanisms in uterus), it was of interest to study possible acute and permanent effects of such treatment on distribution and levels of EGF, its receptor (EGF-r), and c-fos and to relate such changes to morphological development and appearance of epithelial abnormalities.

Methods: Immunohistochemical techniques using frozen sections from the uterus and vagina of neonatal and adult (ovariectomized, estradiol-treated) females, treated with olive oil or diethylstilbestrol in neonatal life.

Results: A difference in stromal-epithelial distribution of EGF was demonstrated with respect to region studied (uterus, vagina) and age (neonatal, adult). EGF was localized mainly in the uterine stroma but in both vaginal epithelium and stroma (with a different pattern compared to uterus). In neonatal females, EGF occurred in both tissue components in both regions, and the distribution pattern was quite different from that in adult females. The EGF level was increased by estrogen in adult but not in neonatal females. EGF-r and c-fos occurred in both uterine epithelium and stroma and in the vaginal epithelium; levels and distribution pattern were affected by estrogen. Neonatal estrogen treatment increased the levels of uterine EGF and c-fos in adult life.

Conclusions: There are distinct developmental changes in the distribution and estrogen sensitivity of EGF. Only further studies can prove or disprove the association between the earlier reported disturbed growth control mechanisms in the uterus of adult but neonatally estrogen-treated females and the increased levels of uterine EGF and c-fos. The present results do not seem to explain mechanisms involved in the origin of neonatally estrogen-induced cervicovaginal epithelial abnormalities, nor do they explain the earlier described difference in estrogen-induced proliferative response between the uterine cervix and uterus proper.