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

Kerstin W Sinkevicius; Joanna E Burdette; Karolina Woloszyn; Sylvia C Hewitt; Katherine Hamilton; Sonia L Sugg; Karla A Temple; Fredric E Wondisford; Kenneth S Korach; Teresa K Woodruff; Geoffrey L Greene

doi:10.1210/en.2007-1526

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

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

Kerstin W Sinkevicius, Joanna E Burdette, Karolina Woloszyn, Sylvia C Hewitt, Katherine Hamilton, Sonia L Sugg, Karla A Temple, Fredric E Wondisford, Kenneth S Korach, Teresa K Woodruff, …

Endocrinology (Philadelphia), Vol.149(6), pp.2970-2979

06/01/2008

DOI: 10.1210/en.2007-1526

PMCID: PMC2408815

PMID: 18339713

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Abstract

Estrogen-nonresponsive estrogen receptor-α (ERα) knock-in (ENERKI) mice were generated to distinguish between ligand-induced and ligand-independent ER-α actions in vivo. These mice have a mutation [glycine 525 to leucine (G525L)] in the ligand-binding domain of ERα, which significantly reduces ERα 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 ERα 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 ERα ligand-independent pathways were active. In addition, the synthetic ERα selective agonist propyl pyrazole triol (PPT) and ER agonist diethylstilbestrol (DES) were still able to activate ligand-induced G525L ERα 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 ERα 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 ERα pathways and temporal patterns of response. DES did not stimulate an ENERKI uterotrophic response. Because ERβ may modulate ERα activation and have an antiproliferative function in the uterus, we hypothesize that ENERKI animals were particularly sensitive to DES-induced inhibition of ERα due to up-regulated uterine ERβ levels.

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Title: Subtitle: An Estrogen Receptor-α Knock-In Mutation Provides Evidence of Ligand-Independent Signaling and Allows Modulation of Ligand-Induced Pathways in Vivo
Creators: Kerstin W Sinkevicius - The Ben May Department for Cancer Research (K.W.S., K.W., G.L.G.), The University of Chicago, Chicago, Illinois 60637
Joanna E Burdette - Medicinal Chemistry and Pharmacognosy (J.E.B.), University of Illinois at Chicago, Chicago, Illinois 60612
Karolina Woloszyn - The Ben May Department for Cancer Research (K.W.S., K.W., G.L.G.), The University of Chicago, Chicago, Illinois 60637
Sylvia C Hewitt - 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
Katherine Hamilton - 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
Sonia L Sugg - Department of Surgery (S.L.S.), Division of Surgical Oncology and Endocrine Surgery, University of Iowa, Iowa City, Iowa 52242
Karla A Temple - Department of Medicine and Committee on Molecular Metabolism and Nutrition (K.A.T.), The University of Chicago, Chicago, Illinois 60637
Fredric E Wondisford - Metabolism Division (F.E.W.), Departments of Pediatrics, Medicine, and Physiology, Johns Hopkins School of Medicine, Baltimore, Maryland 21287
Kenneth S Korach - 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
Teresa K Woodruff - Institute for Women’s Health Research (T.K.W.), Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611
Geoffrey L Greene - The Ben May Department for Cancer Research (K.W.S., K.W., G.L.G.), The University of Chicago, Chicago, Illinois 60637
Resource Type: Journal article
Publication Details: Endocrinology (Philadelphia), Vol.149(6), pp.2970-2979
DOI: 10.1210/en.2007-1526
PMID: 18339713
PMCID: PMC2408815
ISSN: 0013-7227
eISSN: 1945-7170
Language: English
Date published: 06/01/2008
Academic Unit: Surgery
Record Identifier: 9984051870002771

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