STROMAL ESTROGEN-RECEPTORS MEDIATE MITOGENIC EFFECTS OF ESTRADIOL ON UTERINE EPITHELIUM

Estradiol-17 beta (E-2) acts through the estrogen receptor (ER) to reg ulate uterine growth and functional differentiation. To determine whet her E-2 elicits epithelial mitogenesis through epithelial ER versus in directly via ER-positive stromal cells, uteri from adult ER-deficient ER knockout (ko) mice and neonatal ER-positive wild-type (wt) BALB/c m ice 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 recombinant s were grown for 4 weeks as subrenal capsule grafts in intact female n ude mice, then the hosts were treated with either E-2 or oil a week af ter ovariectomy, Epithelial labeling index and ER expression were dete rmined by [H-3] thymidine autoradiography and immunohistochemistry, re spectively, In tissue recombinants containing wt S (wt-S + wt-E, wt-S + ko-E), E-2 induced a similar large increase in epithelial labeling i ndex compared with oil-treated controls in both types of tissue recomb inants despite the absence of epithelial ER in wt-S + ko-E tissue reco mbinants, This proliferative effect was blocked by an ER antagonist, i ndicating it was mediated through ER, In contrast, in tissue recombina nts prepared with ko-S (ko-S + ko-E and ko-S + wt-E), epithelial label ing index was low and not stimulated by E-2 despite epithelial ER expr ession in ko-S + wt-E grafts, In conclusion, these data demonstrate th at epithelial ER is neither necessary nor sufficient for E-2-induced u terine epithelial proliferation, Instead, E-2 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 s uggest that epithelial mitogenesis in both estrogen and androgen targe t organs are stromally mediated events.