The genome landscape of ERα- and ERβ-binding DNA regions

Liu, Yawen; Gao, Hui; Marstrand, Troels; Ström, Anders; Valen, Eivind; Sandelin, Albin; Gustafsson, Jan‐Åke; Dahlman-Wright, Karin

doi:10.1073/pnas.0712085105

Cited by 95 publications

(83 citation statements)

References 29 publications

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“…Monomeric ERs mediate constitutive gene expression without hormone involvement. This is particularly true of ERβ which can directly bind to selectively sensitive sites in EREs in DNA (Liu et al 2008), significantly contributing to bodily development (Słomczyńska 2002). These observations imply that ovarian cells can develop at very low physiological concentrations of E 2 .…”

Section: Discussionmentioning

confidence: 99%

The effect of low-dose experimental zearalenone intoxication on the immunoexpression of estrogen receptors in the ovaries of pre-pubertal bitches

Gajęcka¹

2012

Polish Journal of Veterinary Sciences

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Zearalenone is an estrogenic mycotoxin that often contaminates plant material used in the production of feeds for companion animals. Small daily doses of ingested zearalenone -a competitive substrate modulating the activity of enzymes participating in estrogen biosynthesis at the pre-receptor level -can induce subclinical symptoms of hyperestrogenism in bitches. The objective of this study was to determine the effects of low zearalenone doses on the presence of estrogen receptors in the ovaries of pre-pubertal Beagle bitches. The bitches were divided into three groups of 10 animals each: experimental group I -50 μg zearalenone/kg body weight administered once daily per os; experimental group II -75 μg zearalenone/kg body weight administered once daily per os; control group -placebo containing no ZEN administered per os. The animals were ovariorectomized at the end of the experiment, at 112 days of age. Estrogen receptors were detected in ovarian specimens by immunohistochemical methods. The results revealed an absence of estrogen receptors alpha in all groups. In both experimental groups a decrease in the positive response of estrogen receptors beta in specified structures of ovaries was observed. Very low α-zearalenol levels probably attested to the slowing down (hypostimulation) of the biotransformation process. Overall, zearalenone intoxication led to hyperestrogenism during a specific developmental stage of pre-pubertal bitches. As regards hormesis, the threshold dose of zearalenone (adaptive capability) was exceeded in the ovaries of experimental group II animals. The results obtained in both experimental groups suggest that long-term exposure to low-dose zearalenone intoxication decreased the degree of estrogen receptors beta staining in particular structures of ovaries in the experimental bitches, which initiated epigenetic modification mechanisms that inhibited ovarian development.

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Section: Discussionmentioning

confidence: 99%

The effect of low-dose experimental zearalenone intoxication on the immunoexpression of estrogen receptors in the ovaries of pre-pubertal bitches

Gajęcka¹

2012

Polish Journal of Veterinary Sciences

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“…This result explains the failure of liquiritigenin to activate ER␣, highlighting that receptor dimerization is an essential step that can be regulated to alter transcription. The varied abilities of diverse synthetic and natural estrogenic ligands to induce ER␣ and ER␤ homoand heterodimers are expected to add complexity to ER signaling because ER␣ and ER␤ often coexist in biological contexts, but different dimer pairs are likely to have distinct genomic targets (30).…”

Section: Discussionmentioning

confidence: 99%

Intermolecular interactions identify ligand-selective activity of estrogen receptor α/β dimers

Powell

2008

Proc. Natl. Acad. Sci. U.S.A.

101

119

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Estrogen receptor (ER) dimerization is prerequisite for its activation of target gene transcription. Because the two forms of ER, ER␣ and ER␤, exhibit opposing functions in cell proliferation, the ability of ligands to induce ER␣/␤ heterodimers vs. their respective homodimers is expected to have profound impacts on transcriptional outcomes and cellular growth. However, there is a lack of direct methods to monitor the formation of ER␣/␤ heterodimers in vivo and to distinguish the ability of estrogenic ligands to promote ER homo-vs. heterodimerization. Here, we describe bioluminescence resonance energy transfer (BRET) assays for monitoring the formation of ER␣/␤ heterodimers and their respective homodimers in live cells. We demonstrate that although both partners contribute to heterodimerization, ligand-bound ER␣ plays a dominant role. Furthermore, a bioactive component was found to induce ER␤/␤ homodimers, and ER␣/␤ heterodimers but had minimal activity on ER␣/␣ homodimers, posing a model that compounds promoting ER␣/␤ heterodimer formation might have therapeutic value. Thus, ER homodimer and heterodimer BRET assays are applicable to drug screening for dimer-selective selective ER modulators. Furthermore, this strategy can be used to study other nuclear receptor dimers. bioluminescence resonance energy transfer (BRET) ͉ estrogenic ligands ͉ selective estrogen receptor modulator (SERM) ͉ heterodimer ͉ homodimer T he biological actions of estrogens are mediated by estrogen receptors (ERs), which are ligand-inducible transcription factors. Binding of 17␤-estradiol (E 2 ) and other estrogenic compounds triggers receptor dimerization and subsequent association with estrogen response elements (EREs) in the promoter regions of ER-target genes to control gene transcription. ERs exist in two forms, ER␣ and ER␤, which have opposing roles in regulating estrogen action: ER␣ promotes whereas ER␤ inhibits estrogendependent cell growth (1, 2). It has been shown that the coexpression of ER␤ with ER␣ results in reduced ER␣-mediated proliferation of breast cancer cells. Approximately 60% of all breast tumors coexpress ER␣ and ER␤ (3, 4). Despite the findings that the coexpression of ER␤ has been correlated with a more favorable prognosis (5) and decreased biological aggressiveness compared with tumors expressing ER␣ alone (6, 7), whether ER␤ modulates ER␣ by heterodimerization to mediate growth-inhibitory phenotypes remains elusive. Multiple lines of evidence suggest that ER␣/␤ heterodimers do exist in vivo and may function to regulate distinct estrogen-responsive genes (8-10). However, the coexistence of homodimers has prevented a clear understanding of heterodimer function. Hypothetically, different estrogenic ligands could exert different cellular effects via differential induction of ER␣ homodimerization, ER␤ homodimerization, and ER␣/␤ heterodimerization. The differential regulation of these ER subtypes could be influenced by several factors including ligand-binding selectivity, conformational differences upon dimerization, d...

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“…Both receptors tend to bind to estrogen-response elements with similar affinity due to a high homology of their DNA-binding domains. Remarkably, ERb has the ability to mediate sometimes opposite effects to ERa due to different binding regions (Liu et al 2008) and the existence of different splice variants of ERb. Especially, ERb cx is known to exhibit a dominant-negative activity against ERa (Herynk & Fuqua 2004).…”

Section: Erbmentioning

confidence: 99%

Current and emerging biomarkers in breast cancer: prognosis and prediction

Weigel¹,

Dowsett²

2010

Endocrine-Related Cancer

422

296

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Breast cancer treatment has experienced several changes in the past decades due to the discovery of specific prognostic and predictive biomarkers that enable the application of more individualized therapies to different molecular subgroups. These subgroups show specific differences regarding biological clinical behavior. In addition to the classical clinical prognostic factors of breast cancer, established molecular biomarkers such as estrogen receptor and progesterone receptor have played a significant role in the selection of patients benefiting from endocrine therapy for many years. More recently, the human epidermal growth factor receptor 2 (HER2) has been validated to be not only a prognostic factor, but also a predictor of response to HER2 targeting therapy. The shift toward an earlier diagnosis of breast cancer due to improved imaging methods and screening programs highlights the need for new factors and combinations of biomarkers to quantify the residual risk of patients and to indicate the potential value of additional treatment strategies. The marker of proliferation Ki67 has recently emerged as an important marker due to several applications in neoadjuvant therapy in addition to its moderate prognostic value. With the introduction of high-throughput technologies, numerous multigene signatures have been identified that aim to outperform traditional markers: current prospective clinical trials are seeking evidence for their definitive role in breast cancer. There exist many more factors and approaches that have the potential to become relevant in the near future including the detection of single disseminating and circulating tumor cells in blood and bone marrow as well as of circulating cell-free DNA and microRNA. Careful randomized prospective testing and comparison with existing established factors will be required to select those emerging markers that offer substantial cost-effective benefit and thereby justify their routine use for breast cancer therapy decision-making.

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The genome landscape of ERα- and ERβ-binding DNA regions

Cited by 95 publications

References 29 publications

The effect of low-dose experimental zearalenone intoxication on the immunoexpression of estrogen receptors in the ovaries of pre-pubertal bitches

The effect of low-dose experimental zearalenone intoxication on the immunoexpression of estrogen receptors in the ovaries of pre-pubertal bitches

Intermolecular interactions identify ligand-selective activity of estrogen receptor α/β dimers

Current and emerging biomarkers in breast cancer: prognosis and prediction

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