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Estradiol and Tamoxifen Mediate Rescue of the Dominant-Negative Effects of Estrogen Response Element-Binding Protein in Vivo and in Vitro

Division of Endocrinology, Metabolism, and Lipids (H.C.), Department of Medicine, Emory University School of Medicine, Atlanta, Georgia 30322; Division of Molecular and Cellular Pathology (T.L.C.), Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama 35294; and Department of Orthopaedic Surgery (M.H., J.S.A.), University of California, Los Angeles-Orthopaedic Hospital, Los Angeles, California 90095

Address all correspondence and requests for reprints to: John Adams, M.D., University of California, Los Angeles-Orthopaedic Hospital Department of Orthopaedic Surgery, 615 Charles E. Young Drive South, Room 410, Los Angeles, California 90095. E-mail: jsadams{at}mednet.ucla.edu.

Biological responses to estrogens are dependent on the integrated actions of proteins, including the estrogen receptor (ER)-, that regulate the transcription of estrogen response element (ERE)-containing target genes. We have identified a naturally occurring ERE antagonist, termed an ERE-binding protein (BP). To verify that ERE-BP can induce estradiol (E₂) resistance in vivo, we generated transgenic mice that overexpress this protein in breast tissue. Female transgenic mice with high levels of ERE-BP were unable to lactate, and we hypothesized that this effect was dependent on the relative levels of ERE-BP and ER ligand. To test this hypothesis, wild-type and ERE-BP-expressing female mice were implanted with capsules containing E₂, the selective estrogen receptor modulator tamoxifen, or placebo. Histological analysis of nonlactating mammary glands showed a 4.5-fold increase in gland branch number and 3.7-fold increase in ducts in ERE-BP mice treated with E₂ (7.5 mg, 21 d) compared with placebo-treated ERE-BP mice. Wild-type mice showed a 5.3-fold increase in branches and 1.4-fold increase in ducts under the same conditions. Similar results were obtained with tissue from lactating mice, in which tamoxifen also increased mammary gland branch number. Studies using ERE-BP-expressing MCF-7 breast cells showed that high doses of E₂ (1000 nM) restored normal ER-chromatin interaction in these cells, whereas tamoxifen was able to achieve this effect at a dose of 10 nM. These data highlight the importance of ERE-BP as an attenuator of normal ER signaling in vivo and further suggest that ERE-BP is a novel target for modulation by selective estrogen receptor modulators.