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This version published online on March 13, 2008
Endocrinology, doi:10.1210/en.2007-1526
A more recent version of this article appeared on June 1, 2008
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Submitted on November 6, 2007
Accepted on March 3, 2008

An estrogen receptor {alpha} 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, and Geoffrey L. Greene*

The Ben May Department for Cancer Research, The University of Chicago, Chicago, IL, 60637; Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago, Chicago, IL 60612; Receptor Biology Section, Laboratory of Reproductive and Developmental Toxicology, National Institute of Environmental and Health Sciences, Research Triangle Park, NC 27709; Department of Surgery, Division of Surgical Oncology and Endocrine Surgery, University of Iowa, Iowa City, Iowa 52242; Department of Medicine and Committee on Molecular Metabolism and Nutrition, The University of Chicago, Chicago, IL 60637; Metabolism Division, Departments of Pediatrics, Medicine, and Physiology, Johns Hopkins School of Medicine, Baltimore, Maryland 21287; Institute for Women's Health Research, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611

* To whom correspondence should be addressed. E-mail: ggreene{at}uchicago.edu.

Estrogen non-responsive estrogen receptor {alpha} (ER{alpha}) knock-in (ENERKI) mice were generated to distinguish between ligand-induced and ligand-independent ER{alpha} actions in vivo. These mice have a mutation (glycine 525 to leucine, G525L) in the ligand-binding domain of ER{alpha}, which significantly reduces ER{alpha} interaction with and response to endogenous estrogens, while not affecting growth factor activation of ligand-independent pathways. ENERKI mice had hypoplastic uterine tissues and rudimentary mammary gland ductal trees. Female were infertile due to anovulation and their ovaries contained hemorrhagic cystic follicles because of chronically elevated levels of luteinizing hormone (LH). The ENERKI phenotype confirmed ligand-induced activation of ER{alpha} is crucial in female reproductive tract and mammary gland development. Growth factor treatments induced uterine epithelial proliferation in ovariectomized ENERKI females, directly demonstrating ER{alpha} ligand-independent pathways were active. In addition, the synthetic ER{alpha} selective agonist propyl pyrazole triol (PPT) and ER agonist diethylstilbestrol (DES) were still able to activate ligand-induced G525L ER{alpha} pathways in vitro. PPT treatments initiated at puberty stimulated ENERKI uterine development, while neonatal treatments were needed to restore mammary gland ductal elongation, indicating neonatal ligand-induced ER{alpha} 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{alpha} pathways and temporal patterns of response. DES did not stimulate an ENERKI uterotrophic response. Since ER{beta} may modulate ER{alpha} activation and have an antiproliferative function in the uterus, we hypothesize ENERKI animals were particularly sensitive to DES-induced inhibition of ER{alpha} due to upregulated uterine ER{beta} levels.
Key words: estrogen receptor • female reproductive tract • knock-in mouse models




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