Estradiol and tamoxifen mediate rescue of the dominant-negative effects of estrogen response element-binding protein in vivo and in vitro

Hong Chen, Thomas L Clemens, Martin Hewison, John S Adams

Research output: Contribution to journalArticlepeer-review

8 Citations (Scopus)


Biological responses to estrogens are dependent on the integrated actions of proteins, including the estrogen receptor (ER)-alpha, 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 (E(2)) 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 ERalpha ligand. To test this hypothesis, wild-type and ERE-BP-expressing female mice were implanted with capsules containing E(2), 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 E(2) (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 E(2) (1000 nM) restored normal ERalpha-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 ERalpha signaling in vivo and further suggest that ERE-BP is a novel target for modulation by selective estrogen receptor modulators.

Original languageEnglish
Pages (from-to)2429-35
Number of pages7
Issue number5
Publication statusPublished - May 2009


  • Animals
  • Estradiol
  • Estrogen Receptor alpha
  • Female
  • Genes, Dominant
  • Humans
  • Mammary Glands, Animal
  • Matrix Attachment Region Binding Proteins
  • Mice
  • Mice, Transgenic
  • Nuclear Matrix-Associated Proteins
  • Receptors, Estrogen
  • Selective Estrogen Receptor Modulators
  • Tamoxifen
  • Tumor Cells, Cultured


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