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Gene Review

ESR1  -  estrogen receptor 1

Homo sapiens

Synonyms: ER, ER-alpha, ESR, ESRA, ESTRR, ...
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Disease relevance of ESR1

  • CONCLUSIONS: Our findings suggest that the genetic polymorphism in ESR1 may play a role in mediating susceptibility to HCC in Chinese hepatitis B virus carriers [1].
  • We examined whether the ESR1 polymorphisms were related to HCC risk among chronic hepatitis B virus carriers [1].
  • We observed three common haplotypes in ESR1 that were associated with a decreased risk for breast cancer [odds ratio (OR), approximately O.4; 95% confidence interval (CI), 0.2-0.8; P < 0.01] [2].
  • When examining the effects of two polymorphisms on prostate cancer risk, homozygosity for the ESR1 XbaI restriction site together with a longer AR was more frequent among controls (32%) than cases (18%; age- and BMI-adjusted OR, 0.39; 95% CI, 0.19-0.78) [3].
  • To explore this finding further, we analyzed ESR1 for this mutation in a series of breast tissues ranging from typical hyperplasia to invasive cancer [4].
  • Cross-talk among ER-alpha, Snail, and the TGF-beta pathway appears to control critical phenotypic properties of breast cancer cells [5].
  • Results suggest that intron 1 and intron 2 of the ESR1 gene may contain functionally important regions related to type 2 diabetes or ESRD risk [6].
  • We also found ESR1 amplification in benign and precancerous breast diseases, suggesting that ESR1 amplification may be a common mechanism in proliferative breast disease and a very early genetic alteration in a large subset of breast cancers [7].

Psychiatry related information on ESR1


High impact information on ESR1

  • Just as transgenic mice were produced in which estrogen receptors had been inactivated and we thought that we were about to understand the role of estrogen receptors in physiology and pathology, it was found that there was not one but two distinct and functional estrogen receptors, now called ER alpha and ER beta [13].
  • This decade also saw the description of a male patient who had no functional ER alpha and whose continued bone growth clearly revealed an important function of estrogen in men [13].
  • The development of selective estrogen receptor modulators has provided a new approach to the prevention of osteoporosis and other major diseases of menopause and has implications for the therapeutic use of other steroid hormones, including androgens [14].
  • New insights into estrogen receptor structure and function, recent discoveries about the development and activity of osteoclasts, and lessons learned from human and animal genetic mutations have all contributed to increased understanding of the skeletal effects of estrogen, both in males and females [14].
  • Cellular levels of REGgamma expression affect estrogen-receptor target-gene expression and cell growth as a result of its ability to promote degradation of the SRC-3 protein [15].

Chemical compound and disease context of ESR1


Biological context of ESR1

  • The ESR1 genotype dependent fracture risk is largely independent of BMD and bone area [21].
  • We analysed three polymorphic sites in the 5' region of the ESR1 gene; a (TA)(n)-repeat in the promoter region, and molecular haplotypes of the PvuII and XbaI RFLPs in intron 1, and inferred long-range haplotypes (LRH) thereof [21].
  • We conclude that ESR1 polymorphism in the 5' (promoter) region is associated with vertebral fracture risk, lumbar spine BMD and vertebral bone area in postmenopausal women, but not in men [21].
  • This study investigates the influence of genetic variation of the estrogen receptor alpha (ESR1) gene locus on several bone parameters in 2042 individuals of The Rotterdam Study, a prospective population-based cohort study of elderly subjects [21].
  • A cohort of 170 female, Caucasian AN sufferers and 152 female controls were typed for dinucleotide repeat polymorphisms in both ESR1 and ESR2 and two further SNPs at each locus [8].

Anatomical context of ESR1

  • These data suggest that GATA3 is involved in growth control and the maintenance of the differentiated state in epithelial cells, and that GATA3 variants may contribute to tumorigenesis in ESR1-positive breast tumors [22].
  • CONTEXT: Sequence variants in the estrogen receptor alpha gene (ESR1) may alter the atheroprotective effects of estrogens, and be associated with the severity of coronary artery disease (CAD) [23].
  • Using combined bisulfite restriction analysis, it was established that, in volunteers from whom biopsies were available, the levels of methylation at two CpG sites within ESR1 assayed using fecal DNA were significantly correlated with methylation in DNA from colorectal mucosa [24].
  • Other significant predictors were ESR1 Ivs1-397T/C genotype (2.2% at the spine); LRP5 2220C/T genotype (1.3% at the spine, 1.6% at the trochanter); LRP5 266A/G genotype (1.1% at Ward's triangle); age at menarche (1.3% at trochanter) and age (2.0% at Ward's triangle) [25].
  • The importance of oestrogen receptor-alpha (gene ESR1 ) and Her-2/ neu ( ERBB2 ) as classifiers for cell lines and tumours is underlined [26].

Associations of ESR1 with chemical compounds

  • The negative correlations observed between isoflavones and estradiol in women as a whole became no longer significant when we excluded women with ESR1 PvuII CC genotype, indicating that the correlations observed were due mainly to this group of women [27].
  • Finally, significant interactions were observed between the ESR1 PvuII-XbaI+ haplotype and the APOA1+83 variant allele regarding both HDL (p=0.042) and LDL (p=0.031) cholesterol responses [28].
  • Adjusting for age and body mass index, urinary daidzein, genistein, glycitein, and serum daidzein and glycitein were negatively correlated with plasma estradiol (R = -0.199 to -0.277, P <0.03), with particularly strong associations found in the 18 women with CC genotype for ESR1 PvuII polymorphism (R = -0.597 to -0.834, P < 0.03) [27].
  • The luminal epithelial tumor cluster, on the other hand, highly expressed ESR1, GATA binding protein 3 and N-acetyl transferase [29].
  • RESULTS: The ESR1 genotype persisted as the only significant predictor of adenosine stimulated coronary flow (P = 0.035) after adjustment for other coronary risk factors [30].
  • We also show that although it does not act directly on the steady-state level of ER alpha, XCT790 potentiates the ICI182,780-induced ER alpha degradation [31].
  • No current evidence that the investigated SNPs are functional is present, thus, we suggest that the association between T2D and ESR1 variants may be because of other unidentified ESR1 polymorphisms that regulate glucose homeostasis [32].
  • In primary cultures, there was an increase in association of the coactivators with estrogen receptor alpha following estrogen treatment but dissociation was evident with tamoxifen [33].

Physical interactions of ESR1


Enzymatic interactions of ESR1

  • Estrogen receptor protein interaction with phosphatidylinositol 3-kinase leads to activation of phosphorylated Akt and extracellular signal-regulated kinase 1/2 in the same population of cortical neurons: a unified mechanism of estrogen action [39].
  • These results demonstrate that the hER is phosphorylated on serine 167 by casein kinase II in a hormone-dependent manner [40].
  • Together, these results strongly suggest a direct role for the cyclin A/cdk2 complex in phosphorylating ER and regulating its transcriptional activity [41].
  • A significant correlation was also seen between estrogen receptor alpha specifically phosphorylated at Ser(118) and progesterone receptor levels (Spearman r = 0.236, P = 0.0118, n = 113) [42].
  • The highest pS2 protein level observed in ER-negative unfavorable subgroups (15 ng/mg) was considered as the cut-off value which defined estrogen-regulated expression of pS2 protein [43].

Co-localisations of ESR1


Regulatory relationships of ESR1


Other interactions of ESR1


Analytical, diagnostic and therapeutic context of ESR1


  1. Estrogen receptor alpha polymorphisms associated with susceptibility to hepatocellular carcinoma in hepatitis B virus carriers. Zhai, Y., Zhou, G., Deng, G., Xie, W., Dong, X., Zhang, X., Yu, L., Yang, H., Yuan, X., Zhang, H., Zhi, L., Yao, Z., Shen, Y., Qiang, B., He, F. Gastroenterology (2006) [Pubmed]
  2. Estrogen receptor genotypes and haplotypes associated with breast cancer risk. Gold, B., Kalush, F., Bergeron, J., Scott, K., Mitra, N., Wilson, K., Ellis, N., Huang, H., Chen, M., Lippert, R., Halldorsson, B.V., Woodworth, B., White, T., Clark, A.G., Parl, F.F., Broder, S., Dean, M., Offit, K. Cancer Res. (2004) [Pubmed]
  3. Allelic variants of aromatase and the androgen and estrogen receptors: toward a multigenic model of prostate cancer risk. Modugno, F., Weissfeld, J.L., Trump, D.L., Zmuda, J.M., Shea, P., Cauley, J.A., Ferrell, R.E. Clin. Cancer Res. (2001) [Pubmed]
  4. Estrogen receptor alpha (ESR1) mutant A908G is not a common feature in benign and malignant proliferations of the breast. Tebbit, C.L., Bentley, R.C., Olson, J.A., Marks, J.R. Genes Chromosomes Cancer (2004) [Pubmed]
  5. The transcription factor snail mediates epithelial to mesenchymal transitions by repression of estrogen receptor-alpha. Dhasarathy, A., Kajita, M., Wade, P.A. Mol. Endocrinol. (2007) [Pubmed]
  6. Investigation of the estrogen receptor-alpha gene with type 2 diabetes and/or nephropathy in African-American and European-American populations. Gallagher, C.J., Keene, K.L., Mychaleckyj, J.C., Langefeld, C.D., Hirschhorn, J.N., Henderson, B.E., Gordon, C.J., Freedman, B.I., Rich, S.S., Bowden, D.W., Sale, M.M. Diabetes (2007) [Pubmed]
  7. Estrogen receptor alpha (ESR1) gene amplification is frequent in breast cancer. Holst, F., Stahl, P.R., Ruiz, C., Hellwinkel, O., Jehan, Z., Wendland, M., Lebeau, A., Terracciano, L., Al-Kuraya, K., Jänicke, F., Sauter, G., Simon, R. Nat. Genet. (2007) [Pubmed]
  8. Variation in the ESR1 and ESR2 genes and genetic susceptibility to anorexia nervosa. Eastwood, H., Brown, K.M., Markovic, D., Pieri, L.F. Mol. Psychiatry (2002) [Pubmed]
  9. Estrogen receptor 1 gene (ESR1) variants in panic disorder. Sand, P.G., Schlurmann, K., Luckhaus, C., Götz, M., Stöber, G., Lesch, K.P., Riederer, P., Franke, P., Maier, W., Nöthen, M.M., Propping, P., Fritze, J., Deckert, J. Am. J. Med. Genet. (2002) [Pubmed]
  10. Lack of association between an estrogen receptor 1 gene polymorphism and Parkinson's disease with dementia. Mattila, K.M., Rinne, J.O., Röyttä, M., Laippala, P., Lehtimäki, T. Acta neurologica Scandinavica. (2002) [Pubmed]
  11. Reduced glucocorticoid and estrogen receptor alpha messenger ribonucleic acid levels in the amygdala of patients with major mental illness. Perlman, W.R., Webster, M.J., Kleinman, J.E., Weickert, C.S. Biol. Psychiatry (2004) [Pubmed]
  12. Association of estrogen receptor alpha (ESR1) PvuII and XbaI polymorphisms with sporadic Alzheimer's disease and their effect on apolipoprotein E concentrations. Corbo, R.M., Gambina, G., Ruggeri, M., Scacchi, R. Dementia and geriatric cognitive disorders. (2006) [Pubmed]
  13. Mechanisms of estrogen action. Nilsson, S., Mäkelä, S., Treuter, E., Tujague, M., Thomsen, J., Andersson, G., Enmark, E., Pettersson, K., Warner, M., Gustafsson, J.A. Physiol. Rev. (2001) [Pubmed]
  14. Sex steroids and bone. Compston, J.E. Physiol. Rev. (2001) [Pubmed]
  15. The SRC-3/AIB1 coactivator is degraded in a ubiquitin- and ATP-independent manner by the REGgamma proteasome. Li, X., Lonard, D.M., Jung, S.Y., Malovannaya, A., Feng, Q., Qin, J., Tsai, S.Y., Tsai, M.J., O'Malley, B.W. Cell (2006) [Pubmed]
  16. Estrogen and progesterone receptor gene polymorphisms and sporadic breast cancer risk: a Spanish case-control study. Fernández, L.P., Milne, R.L., Barroso, E., Cuadros, M., Arias, J.I., Ruibal, A., Benítez, J., Ribas, G. Int. J. Cancer (2006) [Pubmed]
  17. Age-dependent methylation of ESR1 gene in prostate cancer. Li, L.C., Shiina, H., Deguchi, M., Zhao, H., Okino, S.T., Kane, C.J., Carroll, P.R., Igawa, M., Dahiya, R. Biochem. Biophys. Res. Commun. (2004) [Pubmed]
  18. Multilocus analyses of estrogen-related genes reveal involvement of the ESR1 gene in male infertility and the polygenic nature of the pathology. Galan, J.J., Buch, B., Cruz, N., Segura, A., Moron, F.J., Bassas, L., Martinez-Pineiro, L., Real, L.M., Ruiz, A. Fertil. Steril. (2005) [Pubmed]
  19. p27(Kip1) induces quiescence and growth factor insensitivity in tamoxifen-treated breast cancer cells. Carroll, J.S., Lynch, D.K., Swarbrick, A., Renoir, J.M., Sarcevic, B., Daly, R.J., Musgrove, E.A., Sutherland, R.L. Cancer Res. (2003) [Pubmed]
  20. Raloxifene, a selective estrogen receptor modulator, induces apoptosis in androgen-responsive human prostate cancer cell line LNCaP through an androgen-independent pathway. Kim, I.Y., Seong, d.o. .H., Kim, B.C., Lee, D.K., Remaley, A.T., Leach, F., Morton, R.A., Kim, S.J. Cancer Res. (2002) [Pubmed]
  21. Association of 5' estrogen receptor alpha gene polymorphisms with bone mineral density, vertebral bone area and fracture risk. van Meurs, J.B., Schuit, S.C., Weel, A.E., van der Klift, M., Bergink, A.P., Arp, P.P., Colin, E.M., Fang, Y., Hofman, A., van Duijn, C.M., van Leeuwen, J.P., Pols, H.A., Uitterlinden, A.G. Hum. Mol. Genet. (2003) [Pubmed]
  22. Mutation of GATA3 in human breast tumors. Usary, J., Llaca, V., Karaca, G., Presswala, S., Karaca, M., He, X., Langerød, A., Kåresen, R., Oh, D.S., Dressler, L.G., Lønning, P.E., Strausberg, R.L., Chanock, S., Børresen-Dale, A.L., Perou, C.M. Oncogene (2004) [Pubmed]
  23. Estrogen receptor alpha gene polymorphisms are associated with the angiographic extent of coronary artery disease. Rokach, A., Pollak, A., Rosen, L., Friedlander, Y., Blumenfeld, A., Reznik, L., Dresner-Pollak, R. J. Clin. Endocrinol. Metab. (2005) [Pubmed]
  24. Use of DNA from human stools to detect aberrant CpG island methylation of genes implicated in colorectal cancer. Belshaw, N.J., Elliott, G.O., Williams, E.A., Bradburn, D.M., Mills, S.J., Mathers, J.C., Johnson, I.T. Cancer Epidemiol. Biomarkers Prev. (2004) [Pubmed]
  25. Genetic and environmental determinants of bone mineral density in Chinese women. Lau, H.H., Ng, M.Y., Ho, A.Y., Luk, K.D., Kung, A.W. Bone (2005) [Pubmed]
  26. Relevance of breast cancer cell lines as models for breast tumours: an update. Lacroix, M., Leclercq, G. Breast Cancer Res. Treat. (2004) [Pubmed]
  27. Phytoestrogen exposure correlation with plasma estradiol in postmenopausal women in European Prospective Investigation of Cancer and Nutrition-Norfolk may involve diet-gene interactions. Low, Y.L., Taylor, J.I., Grace, P.B., Dowsett, M., Scollen, S., Dunning, A.M., Mulligan, A.A., Welch, A.A., Luben, R.N., Khaw, K.T., Day, N.E., Wareham, N.J., Bingham, S.A. Cancer Epidemiol. Biomarkers Prev. (2005) [Pubmed]
  28. Gender-specific effects of estrogen receptor alpha gene haplotype on high-density lipoprotein cholesterol response to atorvastatin: interaction with apolipoprotein AI gene polymorphism. Kajinami, K., Brousseau, M.E., Lamon-Fava, S., Ordovas, J.M., Schaefer, E.J. Atherosclerosis (2005) [Pubmed]
  29. Effects of anastrozole on the intratumoral gene expression in locally advanced breast cancer. Kristensen, V.N., Sørlie, T., Geisler, J., Yoshimura, N., Linegjaerde, O.C., Glad, I., Frigessi, A., Harada, N., Lønning, P.E., Børresen-Dale, A.L. J. Steroid Biochem. Mol. Biol. (2005) [Pubmed]
  30. Oestrogen receptor gene variation is a determinant of coronary reactivity in healthy young men. Lehtimäki, T., Laaksonen, R., Mattila, K.M., Janatuinen, T., Vesalainen, R., Nuutila, P., Laakso, J., Jaakkola, O., Koivula, T., Knuuti, J. Eur. J. Clin. Invest. (2002) [Pubmed]
  31. Potentiation of ICI182,780 (Fulvestrant)-induced estrogen receptor-alpha degradation by the estrogen receptor-related receptor-alpha inverse agonist XCT790. Lanvin, O., Bianco, S., Kersual, N., Chalbos, D., Vanacker, J.M. J. Biol. Chem. (2007) [Pubmed]
  32. Estrogen receptor alpha gene variants associate with type 2 diabetes and fasting plasma glucose. Dahlman, I., Vaxillaire, M., Nilsson, M., Lecoeur, C., Gu, H.F., Cavalcanti-Proença, C., Efendic, S., Ostenson, C.G., Brismar, K., Charpentier, G., Gustafsson, J.A., Froguel, P., Dahlman-Wright, K., Steffensen, K.R. Pharmacogenet. Genomics (2008) [Pubmed]
  33. Coassociation of estrogen receptor and p160 proteins predicts resistance to endocrine treatment; SRC-1 is an independent predictor of breast cancer recurrence. Redmond, A.M., Bane, F.T., Stafford, A.T., McIlroy, M., Dillon, M.F., Crotty, T.B., Hill, A.D., Young, L.S. Clin. Cancer Res. (2009) [Pubmed]
  34. Human TAFII30 is present in a distinct TFIID complex and is required for transcriptional activation by the estrogen receptor. Jacq, X., Brou, C., Lutz, Y., Davidson, I., Chambon, P., Tora, L. Cell (1994) [Pubmed]
  35. Rapid estrogen-induced phosphorylation of the SRC-3 coactivator occurs in an extranuclear complex containing estrogen receptor. Zheng, F.F., Wu, R.C., Smith, C.L., O'Malley, B.W. Mol. Cell. Biol. (2005) [Pubmed]
  36. Epidermal growth factor binding by breast tumor biopsies and relationship to estrogen receptor and progestin receptor levels. Fitzpatrick, S.L., Brightwell, J., Wittliff, J.L., Barrows, G.H., Schultz, G.S. Cancer Res. (1984) [Pubmed]
  37. p300 Modulates the BRCA1 inhibition of estrogen receptor activity. Fan, S., Ma, Y.X., Wang, C., Yuan, R.Q., Meng, Q., Wang, J.A., Erdos, M., Goldberg, I.D., Webb, P., Kushner, P.J., Pestell, R.G., Rosen, E.M. Cancer Res. (2002) [Pubmed]
  38. Gamma synuclein, a novel heat-shock protein-associated chaperone, stimulates ligand-dependent estrogen receptor alpha signaling and mammary tumorigenesis. Jiang, Y., Liu, Y.E., Goldberg, I.D., Shi, Y.E. Cancer Res. (2004) [Pubmed]
  39. Estrogen receptor protein interaction with phosphatidylinositol 3-kinase leads to activation of phosphorylated Akt and extracellular signal-regulated kinase 1/2 in the same population of cortical neurons: a unified mechanism of estrogen action. Mannella, P., Brinton, R.D. J. Neurosci. (2006) [Pubmed]
  40. Serine 167 is the major estradiol-induced phosphorylation site on the human estrogen receptor. Arnold, S.F., Obourn, J.D., Jaffe, H., Notides, A.C. Mol. Endocrinol. (1994) [Pubmed]
  41. Regulation of estrogen receptor transcriptional enhancement by the cyclin A/Cdk2 complex. Trowbridge, J.M., Rogatsky, I., Garabedian, M.J. Proc. Natl. Acad. Sci. U.S.A. (1997) [Pubmed]
  42. Phospho-serine-118 estrogen receptor-alpha expression is associated with better disease outcome in women treated with tamoxifen. Murphy, L.C., Niu, Y., Snell, L., Watson, P. Clin. Cancer Res. (2004) [Pubmed]
  43. PS2 protein in breast carcinomas: cut-off value of estrogen-regulated expression. Nikolić-Vukosavljević, D., Grujić-Adanja, G., Janković, R., Nesković-Konstantinović, Z., Branković-Magić, M. Neoplasma (2001) [Pubmed]
  44. Expression of Pit-1 and estrogen receptor messenger RNA in prolactin-producing pituitary adenomas. Sanno, N., Teramoto, A., Matsuno, A., Takekoshi, S., Itoh, J., Osamura, R.Y. Mod. Pathol. (1996) [Pubmed]
  45. Ligand-independent recruitment of steroid receptor coactivators to estrogen receptor by cyclin D1. Zwijsen, R.M., Buckle, R.S., Hijmans, E.M., Loomans, C.J., Bernards, R. Genes Dev. (1998) [Pubmed]
  46. Correlation of insulin-like growth factor-binding protein-3 messenger RNA with protein expression in primary breast cancer tissues: detection of higher levels in tumors with poor prognostic features. Rocha, R.L., Hilsenbeck, S.G., Jackson, J.G., Lee, A.V., Figueroa, J.A., Yee, D. J. Natl. Cancer Inst. (1996) [Pubmed]
  47. Epidermal growth factor-induced nuclear factor kappa B activation: A major pathway of cell-cycle progression in estrogen-receptor negative breast cancer cells. Biswas, D.K., Cruz, A.P., Gansberger, E., Pardee, A.B. Proc. Natl. Acad. Sci. U.S.A. (2000) [Pubmed]
  48. Plasma membrane localization and function of the estrogen receptor alpha variant (ER46) in human endothelial cells. Li, L., Haynes, M.P., Bender, J.R. Proc. Natl. Acad. Sci. U.S.A. (2003) [Pubmed]
  49. Steroid hormone receptors compete for factors that mediate their enhancer function. Meyer, M.E., Gronemeyer, H., Turcotte, B., Bocquel, M.T., Tasset, D., Chambon, P. Cell (1989) [Pubmed]
  50. Activation of the estrogen receptor through phosphorylation by mitogen-activated protein kinase. Kato, S., Endoh, H., Masuhiro, Y., Kitamoto, T., Uchiyama, S., Sasaki, H., Masushige, S., Gotoh, Y., Nishida, E., Kawashima, H., Metzger, D., Chambon, P. Science (1995) [Pubmed]
  51. Nuclear receptor function requires a TFTC-type histone acetyl transferase complex. Yanagisawa, J., Kitagawa, H., Yanagida, M., Wada, O., Ogawa, S., Nakagomi, M., Oishi, H., Yamamoto, Y., Nagasawa, H., McMahon, S.B., Cole, M.D., Tora, L., Takahashi, N., Kato, S. Mol. Cell (2002) [Pubmed]
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