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 L.
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 -