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

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

Research output: Contribution to journalArticle

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
Externally publishedYes

Fingerprint

Response Elements
Tamoxifen
Estradiol
Carrier Proteins
Estrogens
Selective Estrogen Receptor Modulators
Human Mammary Glands
Transgenic Mice
In Vitro Techniques
Breast
Placebos
Estrogen Antagonists
MCF-7 Cells
Cell Communication
Chromatin
Capsules
Lactic Acid
Ligands

ASJC Scopus subject areas

  • Endocrinology

Cite this

Estradiol and tamoxifen mediate rescue of the dominant-negative effects of estrogen response element-binding protein in vivo and in vitro. / Chen, Hong; Clemens, Thomas; Hewison, Martin; Adams, John S.

In: Endocrinology, Vol. 150, No. 5, 05.2009, p. 2429-2435.

Research output: Contribution to journalArticle

@article{0d4e48b74af04c318b8156c93fe8836a,
title = "Estradiol and tamoxifen mediate rescue of the dominant-negative effects of estrogen response element-binding protein in vivo and in vitro",
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.",
author = "Hong Chen and Thomas Clemens and Martin Hewison and Adams, {John S.}",
year = "2009",
month = "5",
doi = "10.1210/en.2008-1148",
language = "English (US)",
volume = "150",
pages = "2429--2435",
journal = "Endocrinology",
issn = "0013-7227",
publisher = "The Endocrine Society",
number = "5",

}

TY - JOUR

T1 - Estradiol and tamoxifen mediate rescue of the dominant-negative effects of estrogen response element-binding protein in vivo and in vitro

AU - Chen, Hong

AU - Clemens, Thomas

AU - Hewison, Martin

AU - Adams, John S.

PY - 2009/5

Y1 - 2009/5

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=66449089620&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=66449089620&partnerID=8YFLogxK

U2 - 10.1210/en.2008-1148

DO - 10.1210/en.2008-1148

M3 - Article

C2 - 19106221

AN - SCOPUS:66449089620

VL - 150

SP - 2429

EP - 2435

JO - Endocrinology

JF - Endocrinology

SN - 0013-7227

IS - 5

ER -