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. © 1996 Wiley‐Liss, Inc.

Epidermal Growth Factor and Transforming Growth Factor-α Stimulate the Proliferation of Mouse Uterine Stromal Cells

“…EGF and EGF mRNA levels are increased by estrogen in the mouse uterus (DiAugustine et al, 1988;Falck and Forsberg, 1996). The TGF-α mRNA level is also increased by estrogen in the adult ovariectomized rat uterus (Borgundvaag et al, 1992) and in the immature mouse uterus (Nelson et al, 1992).…”

“…Immunoreactive EGF has been localized in the neonatal and adult mouse uterine stromal cells (Falck and Forsberg, 1996). TGF-α and its mRNA are also detected in both uterine epithelial cells and stromal cells (Tamada et al, 1991).…”

Effect of diethylstilbestrol on cell proliferation and expression of epidermal growth factor in the developing female rat reproductive tract

“…EGF and insulin-like growth factor (IGF)-I stimulate cell proliferation in immature mouse uterine and vaginal epithelial cells in vitro (Tomooka et al 1986, Iguchi et al 1987, Shiraga et al 1997. Because estrogen stimulates uterine epithelial cell proliferation (McCormack & Glasser 1980, Quarmby & Korach 1984 and expression of EGF, IGF-I, heparin-binding EGF-like growth factor, transforming growth factor (TGF)-and EGF-R in the reproductive tracts of mice and rats, these growth factors may mediate the estrogen-induced proliferative and differentiative responses in rodent reproductive tracts (Murphy et al 1987, DiAugustine et al 1988, Nelson et al 1991, Beck & Garner 1992, Ignar-Trowbridge et al 1992, Kapur et al 1992, Das et al 1994, Sahlin et al 1994, Zhang et al 1994, Falck & Forsberg 1996, Hom et al 1998. In the fetal reproductive tract, expression of EGF-R in mice (Bossert et al 1990), and EGF, TGFand IGF-I in rats (Koike & Noumura 1993, Kanno et al 1994, Gu et al 1999) was reported.…”

Neonatal estrogenic exposure suppresses PTEN-related endometrial carcinogenesis in recombinant mice

“…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. [57][58][59] Although further studies will be required, neonatal estrogenic exposure might affect such genes, and induce carcinomas independently of surrounding stromal cells in adult mice.…”