title: Stromal estrogen receptors mediate mitogenic effects of estradiol on uterine epithelium.
abstract: Estradiol-17beta (E2) acts through the estrogen receptor (ER) to regulate uterine growth and functional differentiation. To determine whether E2 elicits epithelial mitogenesis through epithelial ER versus indirectly via ER-positive stromal cells, uteri from adult ER-deficient ER knockout (ko) mice and neonatal ER-positive wild-type (wt) BALB/c mice were used to produce the following tissue recombinants containing ER in epithelium (E) and/or stroma (S), or lacking ER altogether: wt-S + wt-E, wt-S + ko-E, ko-S + ko-E, and ko-S + wt-E. Tissue recombinants were grown for 4 weeks as subrenal capsule grafts in intact female nude mice, then the hosts were treated with either E2 or oil a week after ovariectomy. Epithelial labeling index and ER expression were determined by [3H]thymidine autoradiography and immunohistochemistry, respectively. In tissue recombinants containing wt-S (wt-S + wt-E, wt-S + ko-E), E2 induced a similar large increase in epithelial labeling index compared with oil-treated controls in both types of tissue recombinants despite the absence of epithelial ER in wt-S + ko-E tissue recombinants. This proliferative effect was blocked by an ER antagonist, indicating it was mediated through ER. In contrast, in tissue recombinants prepared with ko-S (ko-S + ko-E and ko-S + wt-E), epithelial labeling index was low and not stimulated by E2 despite epithelial ER expression in ko-S + wt-E grafts. In conclusion, these data demonstrate that epithelial ER is neither necessary nor sufficient for E2-induced uterine epithelial proliferation. Instead, E2 induction of epithelial proliferation appears to be a paracrine event mediated by ER-positive stroma. These data in the uterus and similar studies in the prostate suggest that epithelial mitogenesis in both estrogen and androgen target organs are stromally mediated events.
authors.affiliation: Department of Veterinary Biosciences, University of Illinois, Urbana, IL 61801, USA.
authors.forename: P S
authors.initials: PS
authors.lastname: Cooke
authors.forename: D L
authors.initials: DL
authors.lastname: Buchanan
authors.forename: P
authors.initials: P
authors.lastname: Young
authors.forename: T
authors.initials: T
authors.lastname: Setiawan
authors.forename: J
authors.initials: J
authors.lastname: Brody
authors.forename: K S
authors.initials: KS
authors.lastname: Korach
authors.forename: J
authors.initials: J
authors.lastname: Taylor
authors.forename: D B
authors.initials: DB
authors.lastname: Lubahn
authors.forename: G R
authors.initials: GR
authors.lastname: Cunha
mesh_terms: D000375:Aging / Q000502:physiology; D000818:Animals; D000831:Animals, Newborn; D002455:Cell Division / Q000187:drug effects; D004247:DNA / Q000096:biosynthesis; D004847:Epithelial Cells; D004848:Epithelium / Q000187:drug effects / Q000502:physiology; D004958:Estradiol / Q000494:pharmacology*; D005260:Female; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D008954:Models, Biological; D010052:Ovariectomy; D011960:Receptors, Estrogen / Q000172:deficiency* / Q000502:physiology*; D017154:Stromal Cells / Q000187:drug effects / Q000502:physiology; D013936:Thymidine / Q000378:metabolism; D014599:Uterus / Q000166:cytology / Q000187:drug effects / Q000502:physiology*
chemical_list: D011960:Receptors, Estrogen; D004958:Estradiol; D004247:DNA; D013936:Thymidine