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‣ 17b-estradiol aumenta a expressão de Slc2a4/GLUT4 em adipócitos 3T3-L1 via ESR1.; 17b-estradiol increases Slc2a4/GLUT4 expression in 3T3-L1 adipocytes via ESR1.

Campello, Raquel Saldanha
Fonte: Biblioteca Digitais de Teses e Dissertações da USP Publicador: Biblioteca Digitais de Teses e Dissertações da USP
Tipo: Tese de Doutorado Formato: application/pdf
Publicado em 07/12/2012 Português
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O GLUT4 (gene Slc2a4) é responsável pela captação de glicose sob estímulo insulínico, e alterações na sua expressão se relacionam à resistência à insulina (RI). Variações na concentração de estradiol (E2) estão relacionadas a RI e menor expressão deste transportador, mecanismo que pode ser mediado pelo fator transcricional NFk-B, um repressor de Slc2a4. Avaliou-se em células 3T3-L1 a regulação da expressão de Slc2a4/GLUT4, a atividade de ligação de NFk-B e a captação de glicose pelo E2 e o papel de ESR1 (isoforma 1 do receptor de E2) nesta regulação. Tratou-se as células por 1 dia com E2 e PPT (agonista de ESR1). O PPT aumentou a expressão de Slc2a4/GLUT4 na ausência ou presença de E2 bem como a captação de glicose e diminuiu a atividade de ligação de NFk-B. Os resultados apresentados demonstram que o E2, atuando via ESR1 aumenta a expressão de Slc2a4/GLUT4, efeitos estes parcialmente mediados por NFk-B, resultando em alteração na captação de glicose.; GLUT4 (gene Slc2a4) is responsible by insulin-induced glucose uptake and alterations in its expression are related to insulin resistance (IR). Variability in estradiol levels (E2) is related with IR and lower glucose transporter expression and this mechanism can be mediated by transcriptional factor NFk-B...

‣ Overexpression of Arabidopsis ESR1 Induces Initiation of Shoot Regeneration

Banno, Hiroharu; Ikeda, Yoshihisa; Niu, Qi-Wen; Chua, Nam-Hai
Fonte: American Society of Plant Biologists Publicador: American Society of Plant Biologists
Tipo: Artigo de Revista Científica
Publicado em /12/2001 Português
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Functional screening of an Arabidopsis cDNA library enabled the identification of a novel cDNA, ESR1 (for Enhancer of Shoot Regeneration), that can confer cytokinin-independent shoot formation when overexpressed in Arabidopsis root explants. Neither callus induction nor root formation was affected by ESR1 overexpression. ESR1 encodes a putative transcription factor with an AP2/EREBP domain. Surprisingly, ESR1 overexpression also greatly increased the efficiency of shoot regeneration from root explants in the presence of cytokinin, with a shift in the optimal cytokinin concentration required for this process. The effects of ESR1 overexpression on shoot regeneration are synergistic with those of cytokinin. Overexpression of ESR1 cannot induce callus formation or root formation, suggesting that its effects are specific to shoot formation. In wild-type Arabidopsis plants, ESR1 expression was induced by cytokinin. ESR1 transcript levels also increased transiently during shoot regeneration from root explants, most probably in response to cytokinin in the shoot-inducing medium. This transient increase occurred after the acquisition of competence for regeneration and before shoot formation, which is consistent with the physiological effects of ESR1 overexpression. Our results suggest that ESR1 may regulate the induction of shoot regeneration after the acquisition of competence for organogenesis.

‣ An essential gene, ESR1, is required for mitotic cell growth, DNA repair and meiotic recombination in Saccharomyces cerevisiae.

Kato, R; Ogawa, H
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em 11/08/1994 Português
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A new mutant, which was sensitive to both methyl-methanesulfonate (MMS) and ultra-violet light (UV) and defective in meiotic recombination, was isolated from Saccharomyces cerevisiae. The gene, ESR1, was cloned by complementation of the MMS sensitivity of the mutant and found to be essential for cell growth, as the deleted haploid strain was lethal. The ESR1 gene was adjacent to the CKS1 gene on chromosome II and encoded a putative 2368-amino acid protein with a molecular weight of 273 k. The ESR1 transcript was 8.0 kb long and was induced during meiosis. The predicted Esr1 protein had a mosaic structure composed of homologous regions and showed amino acid sequence similarities to Schizosaccharomyces pombe rad3+ protein, which monitors completion of DNA repair synthesis, and cut1+ protein, which is required for spindle pole body (SPB) duplication. The Esr1 protein was also similar to phosphatidylinositol (PI) 3-kinases, including Saccharomyces cerevisiae TOR2 (and DRR1), which are involved in G1 progression. These results suggest that ESR1 is multi-functional throughout mitosis and meiosis.

‣ Estrogen Receptor-1 (Esr1) and -2 (Esr2) Regulate the Severity of Clinical Experimental Allergic Encephalomyelitis in Male Mice

Polanczyk, Magdalena; Yellayi, Srikanth; Zamora, Alex; Subramanian, Sandhya; Tovey, Micah; Vandenbark, Arthur A.; Offner, Halina; Zachary, James F.; Fillmore, Parley D.; Blankenhorn, Elizabeth P.; Gustafsson, Jan-Åke; Teuscher, Cory
Fonte: American Society for Investigative Pathology Publicador: American Society for Investigative Pathology
Tipo: Artigo de Revista Científica
Publicado em /06/2004 Português
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Estrogens and estrogen-receptor signaling function in establishing and regulating the female immune system and it is becoming increasingly evident that they may play a similar role in males. We report that B10.PL/SnJ male mice with a disrupted estrogen receptor-1 (α) gene (Esr1−/−) develop less severe clinical experimental allergic encephalomyelitis (EAE) compared to either Esr1+/− or wild-type (Esr1+/+) controls when immunized with myelin basic protein peptide Ac1-11 (MBPAc1-11). In contrast, the disease course in B10.PL/SnJ male mice with a disrupted estrogen receptor-2 (β) gene (Esr2−/−) does not differ from that of wild-type (Esr2+/+) mice. However, Esr2+/− mice do develop more severe clinical disease with an earlier onset indicating that heterosis at Esr2 plays a significant role in regulating EAE in males. No significant differences in central nervous system histopathology or MBPAc1-11-specific T-cell responses as assessed by proliferation and interleukin-2 production were observed as a function of either Esr1 or Esr2 genotype. An analysis of cytokine/chemokine secretion by MBPAc1-11-specific T cells revealed unique Esr1 and Esr2 genotype-dependent regulation. Interferon-γ secretion was found to be negatively regulated by Esr1 whereas interleukin-6 and tumor necrosis factor-α secretion exhibited classical Esr2 gene dose responses. Interestingly...

‣ Association with litter size of new polymorphisms on ESR1 and ESR2 genes in a Chinese-European pig line

Muñoz, Gloria; Ovilo, Cristina; Estellé, Jordi; Silió, Luis; Fernández, Almudena; Rodriguez, Carmen
Fonte: BioMed Central Publicador: BioMed Central
Tipo: Artigo de Revista Científica
Publicado em 17/02/2007 Português
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The objective of this study was to search for polymorphisms in the coding region of the estrogen receptors 1 and 2 (ESR1 and ESR2 )and to analyze the effects of these variants and the well known intronic ESR1 Pvu II polymorphism on litter size in a Chinese-European pig line. We identified five silent single nucleotide polymorphisms (SNP) in the ESR1 cDNA: c.669T > C (exon 3), c.1227C > T (exon 5), c.1452C > T (exon 7), c.1665T > C and c.1755A > G (exon 8). One pair of these SNP (c.1665T > C and c.1755A > G) co-segregated in the analyzed line, and the SNP c.669T > C showed the same segregation pattern as the Pvu II polymorphism. These polymorphisms were tested in this study, although the c.1452C > T SNP within exon 7 was not analyzed due to its low informativeness. In the ESR2 cDNA, one missense SNP was found within exon 5, which caused an amino acid substitution in the coded protein: "c.949G > A (p.Val317Met)" and was tested on sow litter size. Information on 1622 litter records from 408 genotyped sows was analyzed to determine whether these SNP influenced the total number of piglets born (TNB) or the number of born alive (NBA). The polymorphisms ESR1: [Pvu II; c.669T > C], ESR1: [c.1665T > C; c.1755A > G] and ESR2: c.949G > A showed no statistically significant association with litter size. However...

‣ DNA Hypermethylation of ESR1 and PGR in Breast Cancer: Pathologic and Epidemiologic Associations

Gaudet, Mia M.; Campan, Mihaela; Figueroa, Jonine D.; Yang, Xiaohong R.; Lissowska, Jolanta; Peplonska, Beata; Brinton, Louise A.; Rimm, David L.; Laird, Peter W.; Garcia-Closas, Montserrat; Sherman, Mark E.
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
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Improved understanding of the etiology of ERα-negative and PR-negative breast cancers may permit improved risk prediction. In vitro studies implicate DNA hypermethylation of the ERα and PR promoters in the pathogenesis of ERα-negative and PR- negative tumors, but results are not definitive. We evaluated 200 invasive breast cancers selected from a population-based case-control study. DNA extracted from fixed tumor tissue cores was tested using MethyLight to assess DNA methylation at 4 CpG islands: ESR1 promoter A and B; PGR promoter A and B; and a CpG shore, ESR1 promoter C. DNA methylation results were compared to levels of ERα, PR, tumor characteristics, and breast cancer risk factors. We observed mild to moderate DNA methylation levels in most tumors for ESR1 promoters A and B and PGR promoter B, and a few tumors showed mild methylation in PGR promoter A. In contrast, ESR1 promoter C showed a wide range of methylation and was weakly correlated with lower expression levels of ERα (β=−0.26; p<0.0001) and PR (β=−0.25; p<0.0001). The percentage of tumors with methylated PGR promoters A and B was significantly higher for tumors with low ERα (A, Fisher’s test p=0.0001; B, p=0.033) and PR levels (A, p=0.0006; B, p=0.001). Our data suggest that the relationships between DNA methylation of ESR1 and PGR promoters and protein expression are weak and unlikely to represent a predominant mechanism of receptor silencing. In contrast to CpG-islands...

‣ MYCN-regulated microRNAs repress estrogen receptor-α (ESR1) expression and neuronal differentiation in human neuroblastoma

Lovén, Jakob; Zinin, Nikolay; Wahlström, Therese; Müller, Inga; Brodin, Petter; Fredlund, Erik; Ribacke, Ulf; Pivarcsi, Andor; Påhlman, Sven; Henriksson, Marie
Fonte: National Academy of Sciences Publicador: National Academy of Sciences
Tipo: Artigo de Revista Científica
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MYCN, a proto-oncogene normally expressed in the migrating neural crest, is in its amplified state a key factor in the genesis of human neuroblastoma (NB). However, the mechanisms underlying MYCN-mediated NB progression are poorly understood. Here, we present a MYCN-induced miRNA signature in human NB involving the activation and transrepression of several miRNA genes from paralogous clusters. Several family members derived from the miR-17∼92 cluster, including miR-18a and miR-19a, were among the up-regulated miRNAs. Expression analysis of these miRNAs in NB tumors confirmed increased levels in MYCN-amplified samples. Specifically, we show that miR-18a and miR-19a target and repress the expression of estrogen receptor-α (ESR1), a ligand-inducible transcription factor implicated in neuronal differentiation. Immunohistochemical staining demonstrated ESR1 expression in human fetal sympathetic ganglia, suggesting a role for ESR1 during sympathetic nervous system development. Concordantly, lentiviral restoration of ESR1 in NB cells resulted in growth arrest and neuronal differentiation. Moreover, lentiviral-mediated inhibition of miR-18a in NB cells led to severe growth retardation, outgrowth of varicosity-containing neurites, and induction of neuronal sympathetic differentiation markers. Bioinformatic analyses of microarray data from NB tumors revealed that high ESR1 expression correlates with increased event-free survival in NB patients and favorable disease outcome. Thus...

‣ Estrogen Receptor 1 Gene (ESR1) is Associated with Restrictive Anorexia Nervosa

Versini, Audrey; Ramoz, Nicolas; Le Strat, Yann; Scherag, Susann; Ehrlich, Stefan; Boni, Claudette; Hinney, Anke; Hebebrand, Johannes; Romo, Lucia; Guelfi, Julien-Daniel; Gorwood, Philip
Fonte: Nature Publishing Group Publicador: Nature Publishing Group
Tipo: Artigo de Revista Científica
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Anorexia nervosa (AN) is a highly heritable young-onset psychiatric illness the etiology of which remains unknown. Estrogen alpha and beta receptors, encoded by ESR1 and ESR2 genes, are involved in food intake regulation and eating behavior, and may have a potential role in AN. We performed a family-based association study of 17 single-nucleotide polymorphisms (SNPs) encompassing ESR1 and ESR2 genes in a cohort of 321 French AN families. We attempted to replicate this finding in a cohort of 41 restrictive AN (RAN) families and in a population-based study of 693 young women. Using the transmission disequilibrium test, a significant over-transmission was detected between AN and ESR1 rs726281 and rs2295193. These SNPs and another among ESR1 were more specifically associated with the RAN subtype (rs726281, p=0.005, odds ratio (OR)=2.1, 95% confidence interval (95% CI)=1.2–3.6; rs3798577, p=0.021, OR=1.6, 95% CI=1.1–2.3; and rs2295193, p=0.007, OR=1.7, 95% CI=1.2–2.5). A large eight-SNPs haplotype of ESR1 gene was also associated with AN (p<0.0001, OR=3.1, 95% CI=1.8–5.1). Association of ESR1 SNPs and RAN was driven by paternal over-transmissions (p<0.0001, OR=3.7, 95% CI=1.9–7.3). Furthermore, we confirmed the preferential paternal over-transmission of the ESR1 rs726281 on the independent German sample of 41 RAN trios (p=0.025...

‣ Association between ESR1 rs1884051 polymorphism and dietary total energy and plant protein intake on obesity in Korean men

Doo, Miae; Kim, Yangha
Fonte: The Korean Nutrition Society and the Korean Society of Community Nutrition Publicador: The Korean Nutrition Society and the Korean Society of Community Nutrition
Tipo: Artigo de Revista Científica
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ESR1 has been listed in the Human Obesity Gene Map as candidate gene associated with obesity. Thus, in this study, we investigated the effect of the ESR1 rs1884051 polymorphism on obesity-related variables, together with their modulations by dietary intake in Korean men. The obesity-related variables and dietary intake of 3,039 Korean men aged 40-59 years from KoGES database were analyzed. Body weight (P = 0.007), BMI (P = 0.003), waist-hip ratio (= 0.011), fat body mass (P = 0.010), and body fat percentage (P = 0.040) were significantly lower in subjects with the minor T allele of ESR1 rs1884051 than in subjects carrying the C allele. Moreover, the rs1884051 T allele was associated with a decreased risk of obesity prevalence (P = 0.040). Among the subjects whose total energy intake was below the median, carrier of the minor T allele of ESR1 rs1884051 had a lower BMI (P = 0.003) when compared with subjects carrying the C allele. In addition, among subjects whose plant protein intake was above the median, carrier of the minor T allele of ESR1 rs1884051 had a lower BMI (P = 0.044) compared with subjects carrying the C allele. Our findings demonstrate that there is a significant association between the ESR1 rs1884051 variant and obesity-related variables and this association can be potentially modified by dietary energy and plant protein intake.

‣ Reconstruction of nuclear receptor network reveals that NR2E3 is a novel upstream regulator of ESR1 in breast cancer

Park, Yun-Yong; Kim, Kyounghyun; Kim, Sang-Bae; Hennessy, Bryan T; Kim, Soo Mi; Park, Eun Sung; Lim, Jae Yun; Li, Jane; Lu, Yiling; Gonzalez-Angulo, Ana Maria; Jeong, Woojin; Mills, Gordon B; Safe, Stephen; Lee, Ju-Seog
Fonte: WILEY-VCH Verlag Publicador: WILEY-VCH Verlag
Tipo: Artigo de Revista Científica
Publicado em /01/2012 Português
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ESR1 is one of the most important transcription factors and therapeutic targets in breast cancer. By applying systems-level re-analysis of publicly available gene expression data, we uncovered a potential regulator of ESR1. We demonstrated that orphan nuclear receptor NR2E3 regulates ESR1 via direct binding to the ESR1 promoter with concomitant recruitment of PIAS3 to the promoter in breast cancer cells, and is essential for physiological cellular activity of ESR1 in estrogen receptor (ER)-positive breast cancer cells. Moreover, expression of NR2E3 was significantly associated with recurrence-free survival and a favourable response to tamoxifen treatment in women with ER-positive breast cancer. Our results provide mechanistic insights on the regulation of ESR1 by NR2E3 and the clinical relevance of NR2E3 in breast cancer.

‣ GATA3 acts upstream of FOXA1 in mediating ESR1 binding by shaping enhancer accessibility

Theodorou, Vasiliki; Stark, Rory; Menon, Suraj; Carroll, Jason S.
Fonte: Cold Spring Harbor Laboratory Press Publicador: Cold Spring Harbor Laboratory Press
Tipo: Artigo de Revista Científica
Publicado em /01/2013 Português
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Estrogen receptor (ESR1) drives growth in the majority of human breast cancers by binding to regulatory elements and inducing transcription events that promote tumor growth. Differences in enhancer occupancy by ESR1 contribute to the diverse expression profiles and clinical outcome observed in breast cancer patients. GATA3 is an ESR1-cooperating transcription factor mutated in breast tumors; however, its genomic properties are not fully defined. In order to investigate the composition of enhancers involved in estrogen-induced transcription and the potential role of GATA3, we performed extensive ChIP-sequencing in unstimulated breast cancer cells and following estrogen treatment. We find that GATA3 is pivotal in mediating enhancer accessibility at regulatory regions involved in ESR1-mediated transcription. GATA3 silencing resulted in a global redistribution of cofactors and active histone marks prior to estrogen stimulation. These global genomic changes altered the ESR1-binding profile that subsequently occurred following estrogen, with events exhibiting both loss and gain in binding affinity, implying a GATA3-mediated redistribution of ESR1 binding. The GATA3-mediated redistributed ESR1 profile correlated with changes in gene expression...

‣ ESR1 single nucleotide polymorphisms predict breast cancer susceptibility in the central European Caucasian population

Lipphardt, Mark F; Deryal, Mustafa; Ong, Mei Fang; Schmidt, Werner; Mahlknecht, Ulrich
Fonte: e-Century Publishing Corporation Publicador: e-Century Publishing Corporation
Tipo: Artigo de Revista Científica
Publicado em 12/04/2013 Português
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Estrogen and progesterone hormones are key regulators of a wide variety of biological processes. In addition to their influence on reproduction, cell differentiation and apoptosis, they affect inflammatory response, cell metabolism and most importantly, they regulate physiological breast tissue proliferation and differentiation as well as the development and progression of breast cancer. In order to assess whether genetic variants in the steroid hormone receptor gene ESR1 (estrogen receptor alpha) had an effect on sporadic breast cancer susceptibility, we assessed 7 ESR1 single nucleotide polymorphisms (SNPs) for associations with breast cancer susceptibility and clinical parameters in 221 breast cancer patients and 221 controls, respectively. We identified ESR1 intron SNP +2464 C/T (rs3020314) and ESR1 intron SNP -4576 A/C (rs1514348) to correlate with breast cancer susceptibility and progesterone receptor expression status. Patients genotyped CT for ESR1 intron SNP +2464 (rs3020314) (p ≤ 0.045) or genotyped AC for ESR1 intron SNP -4576 (rs1514348) (p ≤ 0.000026) were identified to carry a significant risk as to the development of breast cancer in the Central European Caucasian population (both together: p ≤ 0.000488). Our study could confirm previous associations and revealed new associations of SNP rs1514348 with susceptibility to breast cancer and clinical outcome...

‣ ESR1 Amplification in Breast Cancer by Optimized RNase FISH: Frequent but Low-Level and Heterogeneous

Moelans, Cathy B.; Holst, Frederik; Hellwinkel, Olaf; Simon, Ronald; van Diest, Paul J.
Fonte: Public Library of Science Publicador: Public Library of Science
Tipo: Artigo de Revista Científica
Publicado em 18/12/2013 Português
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Prevalence of ESR1 amplification in breast cancer is highly disputed and discrepancies have been related to different technical protocols and different scoring approaches. In addition, pre-mRNA artifacts have been proposed to influence outcome of ESR1 FISH analysis. We analyzed ESR1 gene copy number status combining an improved RNase FISH protocol with multiplex ligation-dependent probe amplification (MLPA) after laser microdissection. FISH showed a high prevalence of ESR1 gains and amplifications despite RNase treatment but MLPA did not confirm ESR1 copy number increases detected by FISH in more than half of cases. We suggest that the combination of the ESR1-specific intra-tumor heterogeneity and low-level copy number increase accounts for these discrepancies.

‣ Generation of Esr1-Knockout Rats Using Zinc Finger Nuclease-Mediated Genome Editing

Rumi, M. A. Karim; Dhakal, Pramod; Kubota, Kaiyu; Chakraborty, Damayanti; Lei, Tianhua; Larson, Melissa A.; Wolfe, Michael W.; Roby, Katherine F.; Vivian, Jay L.; Soares, Michael J.
Fonte: Endocrine Society Publicador: Endocrine Society
Tipo: Artigo de Revista Científica
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Estrogens play pivotal roles in development and function of many organ systems, including the reproductive system. We have generated estrogen receptor 1 (Esr1)-knockout rats using zinc finger nuclease (ZFN) genome targeting. mRNAs encoding ZFNs targeted to exon 3 of Esr1 were microinjected into single-cell rat embryos and transferred to pseudopregnant recipients. Of 17 live births, 5 had biallelic and 1 had monoallelic Esr1 mutations. A founder with monoallelic mutations was backcrossed to a wild-type rat. Offspring possessed only wild-type Esr1 alleles or wild-type alleles and Esr1 alleles containing either 482 bp (Δ482) or 223 bp (Δ223) deletions, indicating mosaicism in the founder. These heterozygous mutants were bred for colony expansion, generation of homozygous mutants, and phenotypic characterization. The Δ482 Esr1 allele yielded altered transcript processing, including the absence of exon 3, aberrant splicing of exon 2 and 4, and a frameshift that generated premature stop codons located immediately after the codon for Thr157. ESR1 protein was not detected in homozygous Δ482 mutant uteri. ESR1 disruption affected sexually dimorphic postnatal growth patterns and serum levels of gonadotropins and sex steroid hormones. Both male and female Esr1-null rats were infertile. Esr1-null males had small testes with distended and dysplastic seminiferous tubules...

‣ Lack of Association between ESR1 and CYP1A1 Gene Polymorphisms and Susceptibility to Uterine Leiomyoma in Female Patients of Iranian Descent

Taghizade Mortezaee, Fatemeh; Tabatabaiefar, Mohammad Amin; Hashemzadeh Chaleshtori, Morteza; Miraj, Sepideh
Fonte: Royan Institute Publicador: Royan Institute
Tipo: Artigo de Revista Científica
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Uterine leiomyoma (UL) is the most common benign smooth muscle cell tumor with as yet unknown etiology and pathogenesis. This study was carried out to investigate the association of ESR1-351 A>G, ESR1 -397 T>C and CYP1A1 (Ile462Val) polymorphisms with UL in female patients of Iranian origin. In this case-control study, 276 patients with UL and 156 healthy women were recruited. The genetic polymorphisms ESR1-351 A>G, ESR1-397 T>C and CYP1A1 (Ile462Val) were genotyped by polymerase chain reaction- restriction fragment length polymorphism (PCR-RFLP). No significant difference were found in frequencies of both genotypes and alleles of ESR1-351 A>G, ESR1-397 T>C and CYP1A1 (Ile462Val) polymorphisms between the two groups (p>0.05). Our findings indicated that these ESR1 and CYP1A1 polymorphisms were not associated with the development of UL in the cases reported here.

‣ Endothelial Function and Insulin Resistance in Early Postmenopausal Women with Cardiovascular Risk Factors: Importance of ESR1 and NOS3 Polymorphisms

Clapauch, Ruth; Mourão, André Felipe; Mecenas, Anete S.; Maranhão, Priscila A.; Rossini, Ana; Bouskela, Eliete
Fonte: Public Library of Science Publicador: Public Library of Science
Tipo: Artigo de Revista Científica
Publicado em 31/07/2014 Português
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Cardiovascular benefits from estradiol activation of nitric oxide endothelial production may depend on vascular wall and on estrogen receptor alpha (ESR1) and nitric oxide synthase (NOS3) polymorphisms. We have evaluated the microcirculation in vivo through nailfold videocapillaroscopy, before and after acute nasal estradiol administration at baseline and after increased sheer stress (postocclusive reactive hyperemia response) in 100 postmenopausal women, being 70 controls (healthy) and 30 simultaneously hypertensive and diabetic (HD), correlating their responses to PvuII and XbaI ESR1 polymorphisms and to VNTR, T-786C and G894T NOS3 variants. In HD women, C variant allele of ESR1 Pvull was associated to higher vasodilatation after estradiol (1.72 vs 1.64 mm/s, p = 0.01 compared to TT homozygotes) while G894T and T-786C NOS3 polymorphisms were connected to lower increment after shear stress (15% among wild type and 10% among variant alleles, p = 0.02 and 0.04). The G variant allele of ESR1 XbaI polymorphism was associated to higher HOMA-IR (3.54 vs. 1.64, p = 0.01) in HD and higher glucose levels in healthy women (91.8 vs. 87.1 mg/dl, p = 0.01), in which increased waist and HOMA-IR were also related to the G allele in NOS3 G894T (waist 93.5 vs 88.2 cm...

‣ The Arabidopsis KH-Domain RNA-Binding Protein ESR1 Functions in Components of Jasmonate Signalling, Unlinking Growth Restraint and Resistance to Stress

Thatcher, Louise F.; Kamphuis, Lars G.; Hane, James K.; Oñate-Sánchez, Luis; Singh, Karam B.
Fonte: Public Library of Science Publicador: Public Library of Science
Tipo: Artigo de Revista Científica
Publicado em 18/05/2015 Português
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Glutathione S-transferases (GSTs) play important roles in the protection of cells against toxins and oxidative damage where one Arabidopsis member, GSTF8, has become a commonly used marker gene for early stress and defense responses. A GSTF8 promoter fragment fused to the luciferase reporter gene was used in a forward genetic screen for Arabidopsis mutants with up-regulated GSTF8 promoter activity. This identified the esr1-1 (enhanced stress response 1) mutant which also conferred increased resistance to the fungal pathogen Fusarium oxysporum. Through positional cloning, the ESR1 gene was found to encode a KH-domain containing RNA-binding protein (At5g53060). Whole transcriptome sequencing of esr1-1 identified altered expression of genes involved in responses to biotic and abiotic stimuli, hormone signaling pathways and developmental processes. In particular was an overall significant enrichment for jasmonic acid (JA) mediated processes in the esr1-1 down-regulated dataset. A subset of these genes were tested for MeJA inducibility and we found the expression of some but not all were reduced in esr1-1. The esr1-1 mutant was not impaired in other aspects of JA-signalling such as JA- sensitivity or development, suggesting ESR1 functions in specific components of the JA-signaling pathway. Examination of salicylic acid (SA) regulated marker genes in esr1-1 showed no increase in basal or SA induced expression suggesting repression of JA-regulated genes is not due to antagonistic SA-JA crosstalk. These results define new roles for KH-domain containing proteins with ESR1 unlinking JA-mediated growth and defense responses.

‣ ESR1 gene promoter region methylation in free circulating DNA and its correlation with estrogen receptor protein expression in tumor tissue in breast cancer patients

Mart??nez-Gal??n, Joaquina; Torres-Torres, Blanca; N????ez, Mar??a Isabel; L??pez-Pe??alver, Jes??s; Moral ??vila, Rosario del; Ruiz de Almod??var, Mariano; Menj??n, Salom??n; Concha, ??ngel; Chamorro, Clara; R??os-Arrabal, Sandra; Delgado, Juan Ram??n
Fonte: Biomed Central Publicador: Biomed Central
Tipo: Artigo de Revista Científica
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[Background] Tumor expression of estrogen receptor (ER) is an important marker of prognosis, and is predictive of response to endocrine therapy in breast cancer. Several studies have observed that epigenetic events, such methylation of cytosines and deacetylation of histones, are involved in the complex mechanisms that regulate promoter transcription. However, the exact interplay of these factors in transcription activity is not well understood. In this study, we explored the relationship between ER expression status in tumor tissue samples and the methylation of the 5??? CpG promoter region of the estrogen receptor gene (ESR1) isolated from free circulating DNA (fcDNA) in plasma samples from breast cancer patients. [Methods] Patients (n???=???110) with non-metastatic breast cancer had analyses performed of ER expression (luminal phenotype in tumor tissue, by immunohistochemistry method), and the ESR1-DNA methylation status (fcDNA in plasma, by quantitative methylation specific PCR technique). [Results] Our results showed a significant association between presence of methylated ESR1 in patients with breast cancer and ER negative status in the tumor tissue (p???=???0.0179). There was a trend towards a higher probability of ESR1-methylation in those phenotypes with poor prognosis i.e. 80% of triple negative patients...

‣ ESR1 Is Co-Expressed with Closely Adjacent Uncharacterised Genes Spanning a Breast Cancer Susceptibility Locus at 6q25.1

Dunbier, Anita K.; Anderson, Helen; Ghazoui, Zara; Lopez-Knowles, Elena; Pancholi, Sunil; Ribas, Ricardo; Drury, Suzanne; Sidhu, Kally; Leary, Alexandra; Martin, Lesley-Ann; Dowsett, Mitch
Fonte: Public Library of Science Publicador: Public Library of Science
Tipo: Artigo de Revista Científica
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Approximately 80% of human breast carcinomas present as oestrogen receptor α-positive (ER+ve) disease, and ER status is a critical factor in treatment decision-making. Recently, single nucleotide polymorphisms (SNPs) in the region immediately upstream of the ER gene (ESR1) on 6q25.1 have been associated with breast cancer risk. Our investigation of factors associated with the level of expression of ESR1 in ER+ve tumours has revealed unexpected associations between genes in this region and ESR1 expression that are important to consider in studies of the genetic causes of breast cancer risk. RNA from tumour biopsies taken from 104 postmenopausal women before and after 2 weeks treatment with an aromatase (oestrogen synthase) inhibitor was analyzed on Illumina 48K microarrays. Multiple-testing corrected Spearman correlation revealed that three previously uncharacterized open reading frames (ORFs) located immediately upstream of ESR1, C6ORF96, C6ORF97, and C6ORF211 were highly correlated with ESR1 (Rs = 0.67, 0.64, and 0.55 respectively, FDR<1×10−7). Publicly available datasets confirmed this relationship in other groups of ER+ve tumours. DNA copy number changes did not account for the correlations. The correlations were maintained in cultured cells. An ERα antagonist did not affect the ORFs' expression or their correlation with ESR1...

‣ Comprehensive genetic assessment of the ESR1 locus identifies a risk region for endometrial cancer

O'Mara, Tracy A.; Glubb, Dylan M.; Painter, Jodie N.; Cheng, Timothy; Dennis, Joe; Australian National Endometrial Cancer Study Group (ANECS); Attia, John; Holliday, Elizabeth G.; McEvoy, Mark; Scott, Rodney J.; Ashton, Katie; Proietto, Tony; Otton, Geoff
Fonte: Society for Endocrinology Publicador: Society for Endocrinology
Tipo: Article; published version
Português
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This is the final version of the article. It first appeared from the Society for Endocrinology via http://dx.doi.org/10.1530/ERC-15-0319; Excessive exposure to estrogen is a well-established risk factor for endometrial cancer (EC), particularly for cancers of endometrioid histology. The physiological function of estrogen is primarily mediated by estrogen receptor alpha, encoded by ESR1. Consequently, several studies have investigated whether variation at the ESR1 locus is associated with risk of EC, with conflicting results. We performed comprehensive fine-mapping analyses of 3633 genotyped and imputed single nucleotide polymorphisms (SNPs) in 6607 EC cases and 37 925 controls. There was evidence of an EC risk signal located at a potential alternative promoter of the ESR1 gene (lead SNP rs79575945, P=1.86?10?5), which was stronger for cancers of endometrioid subtype (P=3.76?10?6). Bioinformatic analysis suggests that this risk signal is in a functionally important region targeting ESR1, and eQTL analysis found that rs79575945 was associated with expression of SYNE1, a neighbouring gene. In summary, we have identified a single EC risk signal located at ESR1, at study-wide significance. Given SNPs located at this locus have been associated with risk for breast cancer...