scholarly journals Estrogen-dependent downregulation of hairy and enhancer of split homolog-1 gene expression in breast cancer cells is mediated via a 3′ distal element

2008 ◽  
Vol 200 (3) ◽  
pp. 311-319 ◽  
Author(s):  
Patrick Müller ◽  
Kenneth W Merrell ◽  
Justin D Crofts ◽  
Caroline Rönnlund ◽  
Chin-Yo Lin ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Retinoic Acid ◽  
Binding Site ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Regulatory Elements ◽  
Estrogen Response Element ◽  
Response Element ◽  
Estrogen Response ◽  
Enhancer Of Split

Regulation of hairy and enhancer of split homologue-1 (HES-1) by estradiol and all-trans retinoic acid affects proliferation of human breast cancer cells. Here, we identify and characterize cis-regulatory elements involved in HES-1 regulation. In the distal 5′ promoter of the HES-1 gene, we found a retinoic acid response element and in the distal 3′ region, an estrogen receptor α(ER)α binding site. The ERα binding site, composed of an estrogen response element (ERE) and an ERE half-site, is important for both ERα binding and transcriptional regulation. Chromatin immunoprecipitation assays revealed that ERα is recruited to the ERE and associates with the HES-1 promoter. We also show recruitment of nuclear receptor co-regulators to the ERE in response to estradiol, followed by a decrease in histone acetylation and RNA polymerase II docking in the HES-1 promoter region. Our findings are consistent with a novel type of repressive estrogen response element in the distal 3′ region of the HES-1 gene.

scholarly journals A retinoic acid response element that overlaps an estrogen response element mediates multihormonal sensitivity in transcriptional activation of the lactoferrin gene.

1995 ◽  
Vol 15 (8) ◽  
pp. 4194-4207 ◽  
Author(s):  
M O Lee ◽  
Y Liu ◽  
X K Zhang
Keyword(s):  
Breast Cancer ◽  
Retinoic Acid ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Orphan Receptor ◽  
Human Leukemia ◽  
Response Element ◽  
Retinoic Acid Response Element ◽  
Gel Retardation ◽  
Lactoferrin Gene

The lactoferrin gene is highly expressed in many different tissues, and its expression is controlled by different regulators. In this report, we have defined a retinoic acid response element (RARE) in the 5'-flanking region of the lactoferrin gene promoter. The lactoferrin-RARE is composed of two AGGTCA-like motifs arranged as a direct repeat with 1-bp spacing (DR-1). A gel retardation assay demonstrated that it bound strongly with retinoid X receptor (RXR) homodimers and RXR-retinoic acid receptor (RAR) heterodimers as well as chicken ovalbumin upstream promoter transcription factor (COUP-TF) orphan receptor. In CV-1 cells, the lactoferrin-RARE linked with a heterologous thymidine kinase promoter was strongly activated by RXR homodimers in response to 9-cis-retinoic acid (9-cis-RA) but not to all-trans-RA. When the COUP-TF orphan receptor was cotransfected, the 9-cis-RA-induced RXR homodimer activity was strongly repressed. A unique feature of the lactoferrin-RARE is that it has an AGGTCA-like motif in common with an estrogen-responsive element (ERE). The composite RARE/ERE contributes to the functional interaction between retinoid receptors and the estrogen receptor (ER) and their ligands. In CV-1 cells, cotransfection of the retinoid and estrogen receptors led to mutual inhibition of the other's activity, while an RA-dependent inhibition of ER activity was observed in breast cancer cells. Furthermore, the lactoferrin-RARE/ERE showed differential transactivation activity in different cell types. RAs could activate the lactoferrin-RARE/ERE in human leukemia HL-60 cells and U937 cells but not in human breast cancer cells. By gel retardation analyses, we demonstrated that strong binding of the endogenous COUP-TF in breast cancer cells to the composite element contributed to diminished RA response in these cells. Thus, the lactoferrin-RARE/ERE functions as a signaling switch module that mediates multihormonal responsiveness in the regulation of lactoferrin gene expression.

scholarly journals Synergistic Up-Regulation of Prostaglandin E Synthase Expression in Breast Cancer Cells by 17β-Estradiol and Proinflammatory Cytokines

Endocrinology ◽  
2008 ◽  
Vol 149 (12) ◽  
pp. 6272-6279 ◽  
Author(s):  
Jonna Frasor ◽  
Aisha E. Weaver ◽  
Madhumita Pradhan ◽  
Kinnari Mehta
Keyword(s):  
Breast Cancer ◽  
Prostaglandin E2 ◽  
Cancer Cells ◽  
Proinflammatory Cytokines ◽  
Breast Cancer Cells ◽  
Prostaglandin E ◽  
Estrogen Response Element ◽  
Prostaglandin E Synthase ◽  
Estrogen Response ◽  
17Β Estradiol

Inflammatory mediators, such as cytokines and prostaglandins, play a fundamental role in estrogen-dependent breast cancer through their ability to up-regulate aromatase expression and subsequent local production of estrogens in the breast. To study the link between estrogens and inflammation further, we examined the regulation of prostaglandin E synthase (PTGES), a key enzyme in the production of prostaglandin E2. We found that 17β-estradiol (E2) rapidly and robustly up-regulates PTGES mRNA and protein levels in estrogen receptor (ER)-positive breast cancer cells through ER recruitment to an essential estrogen response element located in the 5′ flanking region of the PTGES gene. PTGES is also up-regulated by the proinflammatory cytokines TNFα or IL-1β. Surprisingly, the combination of E2 and cytokines leads to a synergistic up-regulation of PTGES in an ER and nuclear factor-κB (NFκB)-dependent manner. This is in contrast to the mutual transrepression between ER and NFκB that has been well characterized in other cell types. Furthermore, we found enhanced recruitment of ERα as well as the NFκB family member, p65, to the PTGES estrogen response element by the combination of E2 and TNFα compared with either E2 or TNFα alone. The synergistic up-regulation of PTGES may result in enhanced prostaglandin E2 production, which in turn may further enhance aromatase expression and production of local estrogens. Our findings suggest that a finely tuned positive feedback mechanism between estrogens and inflammatory factors may exist in the breast and contribute to hormone-dependent breast cancer growth and progression.

scholarly journals Identification of transcriptional regulatory elements in the human somatostatin receptor sst2 promoter and regions including estrogen response element half-site for estrogen activation

2007 ◽  
Vol 40 (2) ◽  
pp. 75-91 ◽  
Author(s):  
Nobuko Kimura ◽  
Nobuko Takamatsu ◽  
Yoshio Yaoita ◽  
R Yoshiyuki Osamura ◽  
Narimichi Kimura
Keyword(s):  
Breast Cancer ◽  
Transcriptional Regulation ◽  
Somatostatin Receptor ◽  
Regulatory Elements ◽  
Upstream Region ◽  
Receptor Subtype ◽  
Estrogen Response Element ◽  
Response Element ◽  
Estrogen Response ◽  
Half Site

The somatostatin receptor subtype 2 (sst2) mediates inhibition of hormone secretion and cell proliferation, and modulates neurotransmission. Its expression is widespread in various normal tissues and many malignant cells, and is up-regulated by estrogen in breast cancer cells. This study was undertaken to investigate molecular mechanism of transcriptional regulation of the human sst2 gene, for which an additional exon (exon 1) in the 5′-untranslated region was recently found. Transient transfection and mutational analysis showed that the immediate 5′-upstream region containing two Sp1 (−54/−45 and −88/−79) and an ATF/CRE (−69/−62) sites provided full promoter activity. An EMSA together with transfection analysis in Sp1-deficient Drosophila Schneider line (SL2) cells showed that Sp1 acted on the proximal Sp1 site, whereas Sp3, Sp1, and Sp2 did on the distal Sp1 site. Activating transcription factor-2 (ATF)-2, c-Jun, and cyclic AMP response element-binding protein (CREB) interacted with the ATF/CRE site. Transcriptional activation by estrogen occurred through two different regions; one included these proximal elements and the other existed in the upstream region containing estrogen response element (ERE) half-site (−348/−344) and GC-rich sequence (−447/−414). This upstream estrogen responsiveness was observed in a human breast cancer T47D cell, but not in GH3 or estrogen receptor α (ERα) -expressing HeLa cells, and was potentiated by overexpression of ERα or ERβ, whose binding to the ERE half-site was verified by EMSAs. A chromatin immunoprecipitation assay suggested that ERα was recruited to the ERE half-site after estrogen treatment in T47D cells. The present results should provide a molecular basis for transcriptional regulation in a variety of physiological and pathological contexts of sst2-expressing tissues.

Retinoic acid receptor α1 isoform is induced by estradiol and confers retinoic acid sensitivity in human breast cancer cells

1995 ◽  
Vol 109 (1) ◽  
pp. 77-86 ◽  
Author(s):  
Bas-jan M. van der Leede ◽  
Gert E. Folkers ◽  
Christina E. van den Brink ◽  
Paul T. van der Saag ◽  
Bart van der Burg
Keyword(s):  
Breast Cancer ◽  
Retinoic Acid ◽  
Cancer Cells ◽  
Human Breast Cancer ◽  
Breast Cancer Cells ◽  
Retinoic Acid Receptor ◽  
Human Breast Cancer Cells ◽  
Human Breast ◽  
Acid Sensitivity ◽  
Acid Receptor
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