Identifying estrogen receptor target genes

Abstract

The estrogen receptor (ER) is a ligand inducible transcription factor that regulates a large number of target genes. These targets are particularly relevant in breast cancer, where the sensitivity of the tumor to estrogens determines whether the patients can be treated with endocrine therapy such as tamoxifen. Identifying genomic ER targets is a daunting task. Quantifying expression levels of suspected target genes after estradiol stimulation or, more recently, using expression microarrays to this effect will reveal which genes are regulated by estradiol, however, without discriminating between direct and indirect tar- Published by Elsevier B.V. All rights reserved. IntroductionIn 1896 Beatson observed that removing the ovaries could lead to remission of breast cancer (Beatson, 1896). Although at that time hormones were not yet discovered, his experiments were the first to connect estrogens with breast cancer. More than 60 years later it was demonstrated that estrogens were retained in target tissues (Jensen and Jacobson, 1962), laying the foundation for the subsequent identification of steroid receptors. Indeed, in 1968 O'Malley described that changes in gene expression occurred after estrogen stimulation, indicating estrogen receptor (ER) functions as a transcription factor (O'Malley et al., 1968). Soon after, a protein that specifically bound estrogens was found in breast tumors, and its quantity could predict the response of these tumors to endocrine disruption (Jensen et al., 1971;McGuire, 1973). With the cloning of the ER in 1986 (Green et al., 1986;Greene et al., 1986) and subsequent identification of its functional domains the role for the ER as a ligand dependent transcription factor became apparent (Green et al., 1986;Greene et al., 1986;Kumar et al., 1987). The ER is a member of the superfamily of nuclear receptors, which are structurally related ligand-inducible transcription factors, including steroid receptors (SRs), thyroid/ retinoids receptors (TR, RARs and RXRs), vitamin D receptors (VDR), LXR, PPARs, and orphan receptors for which no ligand

Genomic Determinants of Gene Regulation by 1,25-Dihydroxyvitamin D3 during Osteoblast-lineage Cell Differentiation

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Estrogen-regulated STAT1 activation promotes TLR8 expression to facilitate signaling via microRNA-21 in systemic lupus erythematosus

“…While a limited number of genes are known to be regulated by estrogen at present, recent evidence suggests that this list is likely much larger [2]. In lupus mouse models, studies have shown enhanced survival and decreased disease severity with ERα deficiency, while no effect was observed with regard to ERβ [3, 4]; thus supporting other studies also indicating the important role of the ERα receptor subtype in promoting autoimmune-mediated inflammation [5].…”

Diverse Associations between ESR1 Polymorphism and Breast Cancer Development and Progression

“…The phosphorylated and thus activated ERα regulates the transcription of target genes by protein-protein interaction with other transcription factors, such as SP1 (3,7,11). Many proteins encoded by these ERα-regulated genes are involved in regulating the cell cycle, angiogenesis, and survival (3,7,12,13).…”