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PubMed2006

Testing of variants of the MTHFR and ESR1 genes in 1798 Finnish individuals fails to confirm the association with migraine with aura.

Among the few independently replicated genetic associations in migraine are polymorphisms in the methylenetetrahydrofolate reductase (MTHFR) and oestrogen receptor (ESR1) genes. We studied the contribution of these genes to migraine susceptibility by genotyping six MTHFR and 26 ESR1 polymorphisms in 898 unrelated migraine with aura (MA) patients and in 900 unrelated healthy controls. There were no differences in the genotype distributions of the previously migraine-associated SNPs C677T (MTHFR) and G2014A (ESR1) between cases and controls (P-values 0.83 and 0.55, respectively). Thus, we were not able to replicate the previous findings, although our study had considerable power. However, five of the ESR1 SNPs (rs6557170, rs2347867, rs6557171, rs4870062 and rs1801132) that were in strong linkage disequilibrium were nominally associated with MA (uncorrected P-values 0.007-0.034). These results did not, however, remain significant after taking multiple testing into account. Thus it seems unlikely that the studied genes are involved in migraine susceptibility, at least in this sample.

Estrogen Receptor alpha↗
PubMed2026

Activating mutations in ESR1 contribute to an immunosuppressive breast tumor microenvironment by dampening cytokine secretion.

Patients with estrogen receptor+ (ER+, ESR1+) breast cancer are most at risk of relapse, where activating mutations in ESR1 promote metastasis and therapeutic resistance. These patients are also disadvantaged in responding to immunotherapies, the mechanisms of which remain to be elucidated. Here, we engineered a transgenic mouse model carrying either Y541S or D542G mutation in ESR1, mirroring the 2 most common mutations seen in patients. ESR1mut tumors do not differ in the total number of immune cells yet display downregulation in immune pathways and decreased immune-modulatory cytokines, including IL-17a and IL-1β. T cells and macrophages have lower IFN-γ and antigen presentation, respectively. Mechanistically, ESR1mut negatively regulates immune modulator expression and upregulates Stat5 to dampen cytokine expression. In concordance, validation on ESR1mut patient tumors shows decreased IL-17a and IL-1β. Collectively, our findings reveal that ESR1 mutations contribute to an immunosuppressive tumor microenvironment by dampening cytokine secretion and immune cell activity.

Animals↗
PubMed2004

Estrogen receptor alpha (ESR1) mutant A908G is not a common feature in benign and malignant proliferations of the breast.

Alterations in estrogen responsive pathways are thought to contribute to benign and malignant breast disease. It has been reported previously that more than a third of typical epithelial hyperplasia lesions harbor the missense mutation A908G in the estrogen receptor alpha (ESR1) gene. This substitution of an arginine for a lysine at codon 303 was reported to confer mitogenic hypersensitivity to estrogen. To explore this finding further, we analyzed ESR1 for this mutation in a series of breast tissues ranging from typical hyperplasia to invasive cancer. In contrast to previous studies, no evidence for this mutation was found in 36 invasive cancers, 11 in situ carcinomas, 14 epithelial hyperplasias with atypia, 11 epithelial hyperplasias without atypia, and 11 breast cancer cell lines. These results indicate that ESR1 mutant A908G does not occur with significant frequency in either benign or malignant proliferations of breast epithelia.

Base Sequence↗
PubMed2006

COL1A1, ESR1, VDR and TGFB1 polymorphisms and haplotypes in relation to BMD in Spanish postmenopausal women.

INTRODUCTION AND HYPOTHESIS: Genetic studies of osteoporosis have focused on analysing single polymorphisms in individual genes - with inconclusive results. An alternative approach may involve haplotypes and gene-gene interactions. The aim of the study was to test the association between the COL1A1, ESR1, VDR and TGFB1 polymorphisms or haplotypes and bone mineral density (BMD) in Spanish postmenopausal women. METHODS: Sixteen polymorphisms were analysed in 719 postmenopausal women. ANOVA, ANCOVA and Xi2 tests were used to perform the statistical analysis. RESULTS: COL1A1 -1997G > T (p=0.04) and TGFB1 Leu10Pro (p=0.02) were found to be associated with adjusted lumbar spine (LS) BMD. Interactions were observed between: the COL1A1 -1997 G/T and Sp1 polymorphisms (p < 0.01 for LS BMD) and the COL1A1 -1663 indelT and VDR ApaI polymorphisms (p < 0.01 for femoral neck (FN) BMD). The COL1A1 GDs and ESR1 LPX haplotypes were associated with FN BMD (p=0.03 and p=0.03). CONCLUSIONS: Polymorphisms at COL1A1 and TGFB1 and haplotypes at COL1A1 and ESR1 were found to be associated with BMD in a cohort of postmenopausal Spanish women. Moreover, COL1A1 polymorphisms showed significant interactions among them and with the VDR 3' polymorphisms.

Bone Density↗
PubMed2006

ESR1, AR, body size, and breast cancer risk in Hispanic and non-Hispanic white women living in the Southwestern United States.

Estrogen and androgen are thought to influence breast cancer risk. The actions of estrogens and androgens are mediated through the respective receptors. In this study we examine the association of the Xb1 polymorphism of estrogen receptor alpha (ESR1) and the CAG repeat of the androgen receptor (AR) gene with risk of breast cancer in women living in the Southwestern United States. Cases (N = 1169 non-Hispanic white (NHW) and 576 Hispanic) with first primary breast cancer were matched to controls (N = 1330 NHW and 725 Hispanic) by location (Arizona, Colorado, New Mexico, or Utah) and 5-year age group. Detailed weight history was obtained along with other diet and lifestyle information. Neither the ESR1 nor the AR polymorphisms evaluated were associated independently with breast cancer risk in either Hispanic or NHW women. However, among Hispanic women taking hormone replacement therapy (HRT), there was a 40% reduced risk of breast cancer among women with an X allele (95% CI 0.39, 0.94). Also Hispanic women with the xx genotype had a significant reduced risk of breast cancer in the presence of weight gain prior to age 50 if post-menopausal or prior to diagnosis if pre-menopausal (P interaction 0.02 and <0.01 respectively). These results suggest differences in risk factors for NHW and Hispanic women. However, they provide only minor support for the role of the AR and ESR1 gene in the etiology of breast cancer.

Adult↗
PubMed2006

Association of migraine and ESR1 G325C polymorphism.

Migraine is a genetically complex disorder in which sexual hormones influence the phenotype. ESR1 G594A polymorphism has been associated with migraine in Australians. We performed a case-control study with G594A and G325C polymorphisms to determine whether ESR1 is associated with migraine in our population. An association between G594A and migraine could not be demonstrated here. By contrast, we observed that the C325 allele conferred a 1.6 (95% confidence interval=1.1-2.4) higher risk for suffering from migraine in women than the G allele. Women carrying the C352C genotype were over 3 times more likely to suffer from migraine than those carrying the G325G genotype. Therefore, we conclude that ESR1 G325C polymorphism is associated with migraine in our population.

Adult↗
PubMed2006

Comparison of genetic models for analysing the effects of a PvuII polymorphism in the oestrogen receptor 1 (ESR1) gene on prolificacy in an Iberian x Meishan pig population.

The effect of a previously reported PvuII polymorphism in oestrogen receptor 1 (ESR1) was analysed in an F(2) population of Iberian x Meishan pigs. We tested three hypotheses: (1) that a causal mutation was fixed in the parental populations, (2) that a causal mutation existed that was in complete linkage disequilibrium with the alleles of the PvuII polymorphism and (3) that a causal mutation existed in linkage disequilibrium within each parental population. The third model was the most plausible based on the available data. ESR1 alleles displayed different patterns of linkage disequilibrium with the causal mutation in each of the parental populations and the PvuII polymorphism was clearly not the causal mutation. As a consequence, the use of the ESR1 mutation for selection must be evaluated for a particular pig population before it is applied.

Alleles↗
PubMed2005

The Notch targets Esr1 and Esr10 are differentially regulated in Xenopus neural precursors.

The HES family of bHLH repressors plays a key role in regulating the differentiation of neural precursors in the vertebrate embryo. Members of the HES gene family are expressed in neural precursors as targets of the Notch signaling pathway, but how this occurs in the context of neurogenesis is not known. Here, we address this issue by identifying enhancers driving Notch-dependent gene expression of two Hes5-like genes expressed in Xenopus called Esr1 and Esr10. Using frog transgenesis, we identify enhancer elements driving expression of Esr1 and Esr10 in neural precursors or in response to ectopic expression of the proneural protein, Xngnr1. Using deletion and mutation analysis, we define motifs required for enhancer activity of both genes, namely Notch-responsive elements and, in the case of Esr10, E-box motifs. We find that Esr1 and Esr10 are differentially regulated both in terms of Notch input and its interaction with heterologous factors. These studies reveal inputs required for proneural expression of genes encoding bHLH repressors in the developing vertebrate nervous system.

Animals↗
PubMed2006

Temperature effects on sex determination and ontogenetic gene expression of the aromatases cyp19a and cyp19b, and the estrogen receptors esr1 and esr2 in atlantic halibut (Hippoglossus hippoglossus).

The aromatase (CYP19) and estrogen receptor (ESR) play important roles in the molecular mechanism of sex determination and differentiation of lower vertebrates. Several studies have proven these mechanisms to be temperature sensitive, which can influence the direction of phenotypic gender development. A temperature study was conducted to examine the effect of temperature on the sex differentiation in farmed Atlantic halibut. Sexually undifferentiated larvae were exposed to 7 degrees C, 10 degrees C, or 13 degrees C during gonadal differentiation. Temperature effects on the transcription rate of the aromatase genes cyp19a (ovary type) and cyp19b (brain type) and the ESR genes esr1 and esr2 were examined by quantitative real-time PCR. With increasing temperatures, both cyp19a mRNA levels and the female incidence showed a decreasing trend, thus strongly indicating a relation between the expression of cyp19a and morphological ovary differentiation. In contrast to cyp19a, the levels of cyp19b, esr1, and esr2 mRNA strongly increased in all temperature groups throughout the study period, and did not show obvious temperature-related expression patterns. The present data provide evidence that posthatching temperature exposure significantly affects the expression of cyp19a mRNA during the developmental period and that high temperature possibly influences genetic sex determination in Atlantic halibut. Though, the female incidence never exceeded 50%, suggesting that only the homogametic (XX) female is thermolabile. So whereas temperature treatment is not likely suitable for direct feminization in halibut, the possibility for high-temperature production of XX neomales for broodstock to obtain all-female offspring by crossing with XX females is suggested.

Animals↗
PubMed1999

Potential role of the estrogen receptor gene (ESR1) in anxiety.

In addition to neurotransmitters, hormones, acting through the blood stream, also play a role in behavior. To test the potential contribution of genetic variations in hormone receptors we have examined the association between the alleles of the dinucleotide repeat of the estrogen receptor 1 gene (ESR1) and the nine subscores and total score of the SCL-90 in a group of 179 adult males treated for substance abuse. Based on our prior hypothesis that the length of repeat polymorphisms may play a direct role in gene regulation, the alleles were divided into two groups, short (S) and long (L). ANOVA of the SS, LS, and LL genotypes showed a significant association at alpha </=0.05 for three of the SCL-90 scores: anxiety, phobic anxiety, and total symptoms. Of these the anxiety score remained significant at a Bonferroni corrected alpha of </=0.005. By regression analysis, the ESR1 gene accounted for 7% of the variance of the anxiety score (P </= 0.0004). These results are consistent with a role of the ESR1gene in human behavior. Since estrogen levels are much higher in women than men, this could account for the increased frequency of anxiety in women.

Adult↗
PubMed2004

About GATA3, HNF3A, and XBP1, three genes co-expressed with the oestrogen receptor-alpha gene (ESR1) in breast cancer.

In breast tumours and breast cancer cell (BCC) lines, microarray analyses have revealed that a series of genes are expressed in close association with the oestrogen receptor-alpha (ER-alpha) gene, ESR1. Three of them, GATA3, HNF3A (also known as FOXA1), and XBP1 encode transcription factors. Here, we present these factors and we discuss their potential involvement in the ER-alpha-mediated actions in BCC. We notably show the relations that exist, or that might exist, between these factors and the oestrogen-inducible trefoil factor TFF1.

Base Sequence↗
PubMed2006

Molecular cloning of estrogen receptor alpha (ERalpha; ESR1) of the Japanese giant salamander, Andrias japonicus.

Estrogens are essential for normal reproductive activity in females and males and for ovarian differentiation during a critical developmental stage in many vertebrates. To understand the molecular mechanisms of estrogen action and to evaluate estrogen receptor ligand interactions in the Japanese giant salamander (Andrias japonicus), we isolated cDNA encoding the estrogen receptor (ER) from the liver. A full-length Japanese giant salamander ER cDNA (jgsER) was obtained using 5' and 3' rapid amplification cDNA ends (RACE). The deduced amino acid sequence of the jgsER showed high identity to the Xenopus ERalpha (ESR1) (77.7%). We have applied both the conventional ERE-luciferase reporter assay system and the GAL4-transactivation system to characterize this receptor. In two different transient transfection assay systems using mammalian cells, the jgsER protein displayed estrogen-dependent activation of transcription. The GAL4-transactivation system showed about 10-fold greater activity of the estrogen receptor by hormone when compared to the conventional ERE-luciferase reporter assay system. Tissue distribution of ERalpha mRNA was examined and kidney, ovary and liver exhibited expression. This is the first isolation of an estrogen receptor from a salamander and also is the first functional cDNA obtained from the Japanese giant salamander, an endangered species considered a special natural monument of Japan.

Amino Acid Sequence↗
PubMed2006

Phytoestrogen exposure, polymorphisms in COMT, CYP19, ESR1, and SHBG genes, and their associations with prostate cancer risk.

Prospective phytoestrogen exposure was assessed using both biomarkers and estimates of intake in 89 British men recruited into the Norfolk arm of the European Prospective Investigation into Cancer and Nutrition study, men who subsequently developed prostate cancer. Results were compared with those from 178 healthy men matched by age and date of recruitment. Levels of seven phytoestrogens (daidzein, genistein, glycitein, O-desmethylangolensin, equol, enterodiol, and enterolactone) were measured in spot urine and serum samples. Five single-nucleotide polymorphisms in COMT, CYP19, ESR1, and SHBG genes were genotyped. Urinary levels of all phytoestrogens correlated strongly with serum levels. Correlation coefficients ranged from 0.63 (glycitein) to 0.88 (daidzein) (P < 0.001). Urinary and serum levels correlated significantly with isoflavone intake assessed from food diaries (R = 0.15-0.20; P < 0.05) but not with that from a food-frequency questionnaire. Odds ratios for phytoestrogen exposure, as assessed using the four methods, were not significantly associated with prostate cancer risk (P = 0.15-0.94). Men with the CC genotype for the ESRI PvuII polymorphism had significantly higher risk for prostate cancer compared with men with the TT genotype [adjusted odds ratio = 4.65 (1.60-13.49); P = 0.005]. Our results utilizing a combined prospective exposure provide no evidence that phytoestrogens alter prostate cancer risk in British men, whereas the C allele for the PvuII polymorphism may be associated with increased risk.

Aged↗
PubMed2025

Deciphering estrogen receptor alpha-driven transcription in human endometrial stromal cells via transcriptome, cistrome, and integration with chromatin landscape.

OBJECTIVE: To investigate estrogen receptor gene 1 (ESR1) and estrogen-driven transcription in human endometrial stromal cells. DESIGN: RNA sequencing (RNA-seq) and Cleavage Under Targets and Release Using Nuclease (Cut&Run) were performed on telomerase-immortalized human endometrial stromal cells with Clustered Regularly Interspaced Short Palindromic Repeats-mediated ESR1 activation. Hi-C-based chromatin architecture analysis (H3K27ac HiChIP) was conducted in primary endometrial stromal cells. SUBJECTS: Biopsies from two healthy, reproductive-aged volunteers with regular menstrual cycles and no history of gynecological malignancies. EXPOSURE: The ESR1-activated and control endometrial stromal cells were treated with estradiol (E2) or vehicle. Primary endometrial stromal cells were treated with vehicle or a decidualization cocktail. MAIN OUTCOME MEASURES: Differential gene expression analysis (RNA-seq) identified ligand-independent and -dependent ESR1 activity. Cut&Run profiled ESR1 genomic binding in ESR1-activated cells. H3K27ac HiChIP mapped hormone-induced changes in chromatin looping in primary cells. RESULTS: Among seven tested guide RNAs (gRNA), the ESR1-3 gRNA induced robust ESR1 activation and restored E2 responsiveness. Bulk RNA-seq revealed both ligand-dependent and -independent ESR1 transcriptional programs regulating inflammation, proliferation, and cancer-related pathways. Notably, 72% of differentially expressed genes overlapped with genes active in human endometrial tissue during the proliferative estrogen-dominant phase, supporting their physiological relevance. The Cut&Run-seq identified genome-wide ESR1 binding sites, with most binding sites located at distal regulatory elements. Integration of Cut&Run data with H3K27ac HiChIP chromatin loops linked distal ESR1 binding sites to gene promoters, including genes involved in decidualization (e.g., FOXO1) and endometrial cancer (e.g., ERRFI1, NRIP1, and EPAS1). Functional assays showed that ESR1 promotes cell viability and, in the presence of E2, enhances migration. CONCLUSION: The CRISPR-mediated ESR1 activation restores estrogen responsiveness in endometrial stromal cells. Combined transcriptomic, cistromic, and chromatin architecture analyses reveal ESR1's role in regulating decidualization and inflammation-related gene networks, with relevance to endometrial pathologies including endometrial cancer. This model serves as a powerful tool to study estrogen signaling in endometrial stromal cell biology and related pathologies.

Humans↗