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An Estrogen Receptor- Knock-In Mutation Provides Evidence of Ligand-Independent Signaling and Allows Modulation of Ligand-Induced Pathways in Vivo

The Ben May Department for Cancer Research (K.W.S., K.W., G.L.G.), Department of Medicine and Committee on Molecular Metabolism and Nutrition (K.A.T.), The University of Chicago, Chicago, Illinois 60637; Medicinal Chemistry and Pharmacognosy (J.E.B.), University of Illinois at Chicago, Chicago, Illinois 60612; Receptor Biology Section (S.C.H., K.H., K.S.K.), Laboratory of Reproductive and Developmental Toxicology, National Institute of Environmental and Health Sciences, Research Triangle Park, North Carolina 27709; Department of Surgery (S.L.S.), Division of Surgical Oncology and Endocrine Surgery, University of Iowa, Iowa City, Iowa 52242; Metabolism Division (F.E.W.), Departments of Pediatrics, Medicine, and Physiology, Johns Hopkins School of Medicine, Baltimore, Maryland 21287; and Institute for Women’s Health Research (T.K.W.), Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611

Address all correspondence and requests for reprints to: Geoffrey Greene, The University of Chicago, 929 East 57th Street, GCIS W330, Chicago, Illinois 60637. E-mail: ggreene{at}uchicago.edu.

Estrogen-nonresponsive estrogen receptor- (ER) knock-in (ENERKI) mice were generated to distinguish between ligand-induced and ligand-independent ER- actions in vivo. These mice have a mutation [glycine 525 to leucine (G525L)] in the ligand-binding domain of ER, which significantly reduces ER interaction with and response to endogenous estrogens, whereas not affecting growth factor activation of ligand-independent pathways. ENERKI mice had hypoplastic uterine tissues and rudimentary mammary gland ductal trees. Females were infertile due to anovulation, and their ovaries contained hemorrhagic cystic follicles because of chronically elevated levels of LH. The ENERKI phenotype confirmed that ligand-induced activation of ER is crucial in the female reproductive tract and mammary gland development. Growth factor treatments induced uterine epithelial proliferation in ovariectomized ENERKI females, directly demonstrating that ER ligand-independent pathways were active. In addition, the synthetic ER selective agonist propyl pyrazole triol (PPT) and ER agonist diethylstilbestrol (DES) were still able to activate ligand-induced G525L ER pathways in vitro. PPT treatments initiated at puberty stimulated ENERKI uterine development, whereas neonatal treatments were needed to restore mammary gland ductal elongation, indicating that neonatal ligand-induced ER activation may prime mammary ducts to become more responsive to estrogens in adult tissues. This is a useful model for in vivo evaluation of ligand-induced ER pathways and temporal patterns of response. DES did not stimulate an ENERKI uterotrophic response. Because ERβ may modulate ER activation and have an antiproliferative function in the uterus, we hypothesize that ENERKI animals were particularly sensitive to DES-induced inhibition of ER due to up-regulated uterine ERβ levels.

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