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

Abstract

Biological responses to estrogens are dependent on the integrated actions of proteins, including the estrogen receptor (ER)-a, 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 ERa 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 ERa-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 ERa signaling in vivo and further suggest that ERE-BP is a novel target for modulation by selective estrogen receptor modulators.

Original languageEnglish (US)
Pages (from-to)2429-2435
Number of pages7
JournalEndocrinology
Volume150
Issue number5
DOIs
StatePublished - May 2009

ASJC Scopus subject areas

  • Endocrinology

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