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Creation of Estrogen Resistance in Vivo by Transgenic Overexpression of the Heterogeneous Nuclear Ribonucleoprotein-Related Estrogen Response Element Binding Protein

Burns and Allen Research Institute and Division of Endocrinology, Diabetes, and Metabolism (H.C., L.N., G.H., J.S.A.) and Department of Pathology (B.H.), Cedars-Sinai Medical Center, David Geffen School of Medicine at the University of California, Los Angeles, Los Angeles, California 90048; Department of Surgery (W.S.), The University of Cincinnati College of Medicine, Cincinnati, Ohio 45267; and Department of Pathology (T.L.C.), University of Alabama at Birmingham, Birmingham, Alabama 35294

Address all correspondence and requests for reprints to: Hong Chen, Division of Endocrinology, Diabetes, and Metabolism, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Room B-131, Los Angeles, California 90048. E-mail: chenh{at}cshs.org.

Estrogen unresponsiveness among primate species can result from overexpression of a heterogeneous nuclear ribonucleoprotein (hnRNP) that competes with estrogen receptor (ER) for binding to the estrogen-response element (ERE). This hnRNP has been coined the "ERE-binding protein" (ERE-BP). The ERE-BP is a member of the hnRNP C-like subfamily of hnRNPs, traditionally considered to be single-strand RNA binding proteins designed for the stabilization and handling of pre-mRNA. To verify in vivo the dominant-negative actions of the ERE-BP to inhibit ER-ERE-directed transactivation and to avoid the potential for lethality from global overexpression of an hnRNP, we generated transgenic mice that overexpressed ERE-BP in breast tissue under the control of a whey acidic protein gene promoter. Graded overexpression of ERE-BP in transgenic mice was established. Founders were viable and fertile. Female transgenics in all lines gave birth to pups, but their ability to nurse was dependent on the level of ERE-BP expression in breast; high-ERE-BP expressors were unable to lactate. A gradient of impaired breast pheno(histo)type, from near normal to failed ductal development and lactational capacity, correlated with the relative level of transgene expression. ERE-BP, expressed either endogenously as a transgene or after transfection, colocalized with ER in the nucleus of target cells. This work confirms that tissue-targeted overexpression of the ERE-BP can effectively block estrogen-ER-ERE-directed action in vivo.

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				H. Chen, T. L. Clemens, M. Hewison, and J. S. Adams Estradiol and Tamoxifen Mediate Rescue of the Dominant-Negative Effects of Estrogen Response Element-Binding Protein in Vivo and in Vitro Endocrinology, May 1, 2009; 150(5): 2429 - 2435. [Abstract] [Full Text] [PDF]

				H. Chen, M. Hewison, and J. S. Adams Control of Estradiol-Directed Gene Transactivation by an Intracellular Estrogen-Binding Protein and an Estrogen Response Element-Binding Protein Mol. Endocrinol., March 1, 2008; 22(3): 559 - 569. [Abstract] [Full Text] [PDF]