Estrogen receptor alpha explained

Estrogen receptor alpha (ERα), also known as NR3A1 (nuclear receptor subfamily 3, group A, member 1), is one of two main types of estrogen receptor, a nuclear receptor (mainly found as a chromatin-binding protein^[1]) that is activated by the sex hormone estrogen. In humans, ERα is encoded by the gene ESR1 (EStrogen Receptor 1).^{[2] [3] [4]}

Structure

The estrogen receptor (ER) is a ligand-activated transcription factor composed of several domains important for hormone binding, DNA binding, and activation of transcription.^[5] Alternative splicing results in several ESR1 mRNA transcripts, which differ primarily in their 5-prime untranslated regions. The translated receptors show less variability.^{[6] [7]}

Ligands

Agonists

Non-selective

• Endogenous estrogens (e.g., estradiol, estrone, estriol, estetrol)
• Natural estrogens (e.g., conjugated equine estrogens)
• Synthetic estrogens (e.g., ethinylestradiol, diethylstilbestrol)

Selective

Agonists of ERα selective over ERβ include:

• Propylpyrazoletriol (PPT)
• 16α-LE₂ (Cpd1471)
• 16α-IE₂
• ERA-63 (ORG-37663)
• SKF-82,958 – also a D₁-like receptor full agonist
• (R,R)-Tetrahydrochrysene ((R,R)-THC) – actually not selective over ERβ, but rather an antagonist instead of an agonist of ERβ

Mixed

• Phytoestrogens (e.g., coumestrol, daidzein, genistein, miroestrol)
• Selective estrogen receptor modulators (e.g., tamoxifen, clomifene, raloxifene)

Antagonists

Non-selective

• Antiestrogens (e.g., fulvestrant, ICI-164384, ethamoxytriphetol)

Selective

Antagonists of ERα selective over ERβ include:

• Methylpiperidinopyrazole (MPP)

Affinities

Tissue distribution and function

ERα plays a role in the physiological development and function of a variety of organ systems to varying degrees, including the reproductive, central nervous, skeletal, and cardiovascular systems.^[8] Accordingly, ERα is widely expressed throughout the body, including the uterus and ovary, male reproductive organs, mammary gland, bone, heart, hypothalamus, pituitary gland, liver, lung, kidney, spleen, and adipose tissue.^{[9] [10]} The development and function of these tissues is disrupted in animal models lacking active ERα genes, such as the ERα knockout mouse (ERKO), providing a preliminary understanding of ERα function at specific target organs.^[11]

Uterus and ovary

ERα is essential in the maturation of the female reproductive phenotype. In the absence of ERα, the ERKO mouse develops an adult uterus, indicating that ERα may not mediate the initial growth of the uterus. However, ERα plays a role in the completion of this development, and the subsequent function of the tissue. Activation of ERα is known to trigger cell proliferation in the uterus. The uterus of female ERKO mice is hypoplastic, suggesting that ERα mediates mitosis and differentiation in the uterus in response to estrogen stimulation.

Similarly, prepubertal female ERKO mice develop ovaries that are nearly indistinguishable from those of their wildtype counterparts. However, as the ERKO mice mature they progressively present an abnormal ovarian phenotype in both physiology and function. Specifically, female ERKO mice develop enlarged ovaries containing hemorrhagic follicular cysts, which also lack the corpus luteum, and therefore do not ovulate. This adult ovarian phenotype suggests that in the absence of ERα, estrogen is no longer able to perform negative feedback on the hypothalamus, resulting in chronically elevated LH levels and constant ovarian stimulation. These results identify a pivotal role for ERα in the hypothalamus, in addition to its role in the estrogen-driven maturation through theca and interstitial cells of the ovary.

Male reproductive organs

ERα is similarly essential in the maturation and maintenance of the male reproductive phenotype, as male ERKO mice are infertile and present undersized testes. The integrity of testicular structures of ERKO mice, such as the seminiferous tubules of the testes and the seminiferous epithelium, declines over time. Furthermore, the reproductive performance of male ERKO mice is hindered by abnormalities in sexual physiology and behavior, such as impaired spermatogenesis and loss of intromission and ejaculatory responses.

Mammary gland

Estrogen stimulation of ERα is known to stimulate cell proliferation in breast tissue. ERα is thought to be responsible for pubertal development of the adult phenotype, through mediation of mammary gland response to estrogens. This role is consistent with the abnormalities of female ERKO mice: the epithelial ducts of female ERKO mice fail to grow beyond their pre-pubertal length, and lactational structures do not develop. As a result, the functions of the mammary gland—including both lactation and release of prolactin—are greatly impaired in ERKO mice.

Bone

Though its expression in bone is moderate, ERα is known to be responsible for maintenance of bone integrity. It is hypothesized that estrogen stimulation of ERα may trigger the release of growth factors, such as epidermal growth factor or insulin-like growth factor-1, which in turn regulate bone development and maintenance. Accordingly, male and female ERKO mice exhibit decreased bone length and size.

Brain

Estrogen signaling through ERα appears to be responsible for various aspects of central nervous development, such as synaptogenesis and synaptic remodeling. In the brain, ERα is found in hypothalamus, and preoptic area, and arcuate nucleus, all three of which have been linked to reproductive behavior, and the masculinization of the mouse brain appears to take place through ERα function. Furthermore, studies in models of psychopathology and neurodegenerative disease states suggest that estrogen receptors mediate the neuroprotective role of estrogen in the brain. Finally, ERα appears to mediate positive feedback effects of estrogen on the brain's secretion of GnRH and LH, by way increasing expression of kisspeptin in neurons of the arcuate nucleus and anteroventral periventricular nucleus.^{[12] [13]} Although classical studies have suggested that negative feedback effects of estrogen also operate through ERα, female mice lacking ERα in kisspeptin-expressing neurons continue to demonstrate a degree of negative feedback response.^[14]

Clinical significance

Estrogen insensitivity syndrome is a very rare condition characterized by a defective ERα that is insensitive to estrogens.^{[15] [16] [17] [18]} The clinical presentation of a female was observed to include absence of breast development and other female secondary sexual characteristics at puberty, hypoplastic uterus, primary amenorrhea, enlarged multicystic ovaries and associated lower abdominal pain, mild hyperandrogenism (manifested as cystic acne), and delayed bone maturation as well as an increased rate of bone turnover. The clinical presentation in a male was reported to include lack of epiphyseal closure, tall stature, osteoporosis, and poor sperm viability. Both individuals were completely insensitive to exogenous estrogen treatment, even with high doses.

Genetic polymorphisms in the gene encoding the ERα have been associated with breast cancer in women, gynecomastia in men^{[19] [20]} and dysmenorrhea.^[21]

In patients with breast cancer, mutations in the gene encoding ERα (ESR1) have been associated with resistance to endocrine therapy, especially aromatase inhibitors.^[22]

Coactivators

Coactivators of ER-α include:

• SRC-1^{[23] [24]}
• AIB1 – amplified in breast 1^[25]
• PELP-1 – Proline-, glutamic acid-, leucine-rich protein 1^[26]

Interactions

Estrogen receptor alpha has been shown to interact with:

• AKAP13^[27]
• AHR^{[28] [29]}
• BRCA1^{[30] [31] [32]}
• CAV1^[33]
• CCNC
• CDC25B^[34]
• CEBPB^{[35] [36]}
• COBRA1^[37]
• COUP-TFI^[38]
• CREBBP^{[39] [40]}
• CRSP3
• Cyclin D1^[41]
• DNTTIP2^[42]
• EP300^{[39] [43]}
• ESR2^{[44] [45]}
• FOXO1^[46]
• GREB1^[47]
• GTF2H1^[48]
• HSPA1A^[49]
• HSPA8^[49]
• HSP90AA1^{[50] [51]}
• ISL1^[52]
• JARID1A^[53]
• MVP^[54]
• MED1
• MED12
• MED14^[55]
• MED16^[55]
• MED24^[55]
• MED6^[55]
• MGMT
• MNAT1^[56]
• MTA1^{[57] [58]}
• NCOA6^{[59] [60]}
• NCOA1^{[55] [40] [61] [62]}
• NCOA2^{[63] [64] [65]}
• NCOA3^{[66] [67]}
• NRIP1^{[68] [69] [70]}
• PDLIM1^[71]
• POU4F1
• POU4F2^[72]
• PRDM2^[73]
• PRMT2^[74]
• RBM39^[75]
• RNF12^[71]
• SAFB^{[76] [77]}
• SAFB2^[78]
• SHC1^[79]
• SHP^{[80] [81]}
• SMARCA4^{[61] [82]}
• SMARCE1^[83]
• Src^{[84] [85] [86] [87]}
• TR2^[88]
• TR4^[89]
• TDG^[90]
• TRIM24^{[69] [91]} and
• XBP1.^[92]

Further reading

• McDonnell DP, Norris JD . Connections and regulation of the human estrogen receptor . Science . 296 . 5573 . 1642–1644 . May 2002 . 12040178 . 10.1126/science.1071884 . 30428909 . 2002Sci...296.1642M .
• Simoncini T, Fornari L, Mannella P, Varone G, Caruso A, Liao JK, Genazzani AR . Novel non-transcriptional mechanisms for estrogen receptor signaling in the cardiovascular system. Interaction of estrogen receptor alpha with phosphatidylinositol 3-OH kinase . Steroids . 67 . 12 . 935–939 . November 2002 . 12398989 . 10.1016/S0039-128X(02)00040-5 . 42656927 .
• Lannigan DA . Estrogen receptor phosphorylation . Steroids . 68 . 1 . 1–9 . January 2003 . 12475718 . 10.1016/S0039-128X(02)00110-1 . 23163361 .
• Herrington DM . Role of estrogen receptor-alpha in pharmacogenetics of estrogen action . Current Opinion in Lipidology . 14 . 2 . 145–150 . April 2003 . 12642782 . 10.1097/00041433-200304000-00005 . 74820004 .
• Tanaka Y, Sasaki M, Kaneuchi M, Fujimoto S, Dahiya R . Estrogen receptor alpha polymorphisms and renal cell carcinoma--a possible risk . Molecular and Cellular Endocrinology . 202 . 1–2 . 109–116 . April 2003 . 12770739 . 10.1016/S0303-7207(03)00071-6 . 34059244 .
• Ali S, Coombes RC . Estrogen receptor alpha in human breast cancer: occurrence and significance . Journal of Mammary Gland Biology and Neoplasia . 5 . 3 . 271–281 . July 2000 . 14973389 . 10.1023/A:1009594727358 . 23500213 .
• Olsson H . Estrogen receptor content in malignant breast tumors in men--a review . Journal of Mammary Gland Biology and Neoplasia . 5 . 3 . 283–287 . July 2000 . 14973390 . 10.1023/A:1009546811429 . 7342455 .
• Surmacz E, Bartucci M . Role of estrogen receptor alpha in modulating IGF-I receptor signaling and function in breast cancer . Journal of Experimental & Clinical Cancer Research . 23 . 3 . 385–394 . September 2004 . 15595626 .
• Evinger AJ, Levin ER . Requirements for estrogen receptor alpha membrane localization and function . Steroids . 70 . 5–7 . 361–363 . 2005 . 15862818 . 10.1016/j.steroids.2005.02.015 . 54297122 .
• Wang CL, Tang XY, Chen WQ, Su YX, Zhang CX, Chen YM . Association of estrogen receptor alpha gene polymorphisms with bone mineral density in Chinese women: a meta-analysis . Osteoporosis International . 18 . 3 . 295–305 . March 2007 . 17089081 . 10.1007/s00198-006-0239-2 . 11168531 .
• Keaveney M, Klug J, Gannon F . Sequence analysis of the 5' flanking region of the human estrogen receptor gene . DNA Sequence . 2 . 6 . 347–358 . 1992 . 1476547 . 10.3109/10425179209020816 .
• Piva R, Gambari R, Zorzato F, Kumar L, del Senno L . Analysis of upstream sequences of the human estrogen receptor gene . Biochemical and Biophysical Research Communications . 183 . 3 . 996–1002 . March 1992 . 1567414 . 10.1016/S0006-291X(05)80289-X .
• Reese JC, Katzenellenbogen BS . Characterization of a temperature-sensitive mutation in the hormone binding domain of the human estrogen receptor. Studies in cell extracts and intact cells and their implications for hormone-dependent transcriptional activation . The Journal of Biological Chemistry . 267 . 14 . 9868–9873 . May 1992 . 1577818 . 10.1016/S0021-9258(19)50174-0 . free .
• Dotzlaw H, Alkhalaf M, Murphy LC . Characterization of estrogen receptor variant mRNAs from human breast cancers . Molecular Endocrinology . 6 . 5 . 773–785 . May 1992 . 10.1210/mend.6.5.1603086 . 1603086 . 25208340 . free .
• Keaveney M, Klug J, Dawson MT, Nestor PV, Neilan JG, Forde RC, Gannon F . Evidence for a previously unidentified upstream exon in the human oestrogen receptor gene . Journal of Molecular Endocrinology . 6 . 1 . 111–115 . February 1991 . 2015052 . 10.1677/jme.0.0060111 .
• Reese JC, Katzenellenbogen BS . Mutagenesis of cysteines in the hormone binding domain of the human estrogen receptor. Alterations in binding and transcriptional activation by covalently and reversibly attaching ligands . The Journal of Biological Chemistry . 266 . 17 . 10880–10887 . June 1991 . 2040605 . 10.1016/S0021-9258(18)99101-5 . free .
• Schwabe JW, Neuhaus D, Rhodes D . Solution structure of the DNA-binding domain of the oestrogen receptor . Nature . 348 . 6300 . 458–461 . November 1990 . 2247153 . 10.1038/348458a0 . 1990Natur.348..458S . 4349385 .
• Tora L, Mullick A, Metzger D, Ponglikitmongkol M, Park I, Chambon P . The cloned human oestrogen receptor contains a mutation which alters its hormone binding properties . The EMBO Journal . 8 . 7 . 1981–1986 . July 1989 . 2792078 . 401066 . 10.1002/j.1460-2075.1989.tb03604.x .
• Ponglikitmongkol M, Green S, Chambon P . Genomic organization of the human oestrogen receptor gene . The EMBO Journal . 7 . 11 . 3385–3388 . November 1988 . 3145193 . 454836 . 10.1002/j.1460-2075.1988.tb03211.x .
• Greene GL, Gilna P, Waterfield M, Baker A, Hort Y, Shine J . Sequence and expression of human estrogen receptor complementary DNA . Science . 231 . 4742 . 1150–1154 . March 1986 . 3753802 . 10.1126/science.3753802 . 1986Sci...231.1150G .

Notes and References

1. Dhamad AE, Zhou Z, Zhou J, Du Y . Systematic Proteomic Identification of the Heat Shock Proteins (Hsp) that Interact with Estrogen Receptor Alpha (ERα) and Biochemical Characterization of the ERα-Hsp70 Interaction . PLOS ONE . 11 . 8 . e0160312 . 2016-08-02 . 27483141 . 4970746 . 10.1371/journal.pone.0160312 . 2016PLoSO..1160312D . Picard D . free .
2. Web site: Entrez Gene: ESR1 estrogen receptor 1.
3. Walter P, Green S, Greene G, Krust A, Bornert JM, Jeltsch JM, Staub A, Jensen E, Scrace G, Waterfield M . Cloning of the human estrogen receptor cDNA . Proceedings of the National Academy of Sciences of the United States of America . 82 . 23 . 7889–7893 . December 1985 . 3865204 . 390875 . 10.1073/pnas.82.23.7889 . free . 1985PNAS...82.7889W .
4. Greene GL, Gilna P, Waterfield M, Baker A, Hort Y, Shine J . Sequence and expression of human estrogen receptor complementary DNA . Science . 231 . 4742 . 1150–1154 . March 1986 . 3753802 . 10.1126/science.3753802 . 1986Sci...231.1150G .
5. Dahlman-Wright K, Cavailles V, Fuqua SA, Jordan VC, Katzenellenbogen JA, Korach KS, Maggi A, Muramatsu M, Parker MG, Gustafsson JA . International Union of Pharmacology. LXIV. Estrogen receptors . Pharmacological Reviews . 58 . 4 . 773–781 . December 2006 . 17132854 . 10.1124/pr.58.4.8 . 45996586 .
6. Web site: Entrez Gene: DBI diazepam binding inhibitor (GABA receptor modulator, acyl-Coenzyme A binding protein).
7. Kos M, Reid G, Denger S, Gannon F . Minireview: genomic organization of the human ERalpha gene promoter region . Molecular Endocrinology . 15 . 12 . 2057–2063 . December 2001 . 10.1210/mend.15.12.0731 . 11731608 . free .
8. Bondesson M, Hao R, Lin CY, Williams C, Gustafsson JÅ . Estrogen receptor signaling during vertebrate development . Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms . 1849 . 2 . 142–151 . February 2015 . 24954179 . 4269570 . 10.1016/j.bbagrm.2014.06.005 .
9. Curtis Hewitt S, Couse JF, Korach KS . Estrogen receptor transcription and transactivation: Estrogen receptor knockout mice: what their phenotypes reveal about mechanisms of estrogen action . Breast Cancer Research . 2 . 5 . 345–352 . 2000 . 11250727 . 138656 . 10.1186/bcr79 . free .
10. Paterni I, Granchi C, Katzenellenbogen JA, Minutolo F . Estrogen receptors alpha (ERα) and beta (ERβ): subtype-selective ligands and clinical potential . Steroids . 90 . 13–29 . November 2014 . 24971815 . 4192010 . 10.1016/j.steroids.2014.06.012 .
11. Lee HR, Kim TH, Choi KC . Functions and physiological roles of two types of estrogen receptors, ERα and ERβ, identified by estrogen receptor knockout mouse . Laboratory Animal Research . 28 . 2 . 71–76 . June 2012 . 22787479 . 3389841 . 10.5625/lar.2012.28.2.71 .
12. Clarkson J . Effects of estradiol on kisspeptin neurons during puberty . Frontiers in Neuroendocrinology . 34 . 2 . 120–131 . April 2013 . 23500175 . 10.1016/j.yfrne.2013.02.002 . 26118271 .
13. Moenter SM, Chu Z, Christian CA . Neurobiological mechanisms underlying oestradiol negative and positive feedback regulation of gonadotrophin-releasing hormone neurones . Journal of Neuroendocrinology . 21 . 4 . 327–333 . March 2009 . 19207821 . 2738426 . 10.1111/j.1365-2826.2009.01826.x .
14. Plant TM . 60 YEARS OF NEUROENDOCRINOLOGY: The hypothalamo-pituitary-gonadal axis . The Journal of Endocrinology . 226 . 2 . T41–T54 . August 2015 . 25901041 . 4498991 . 10.1530/JOE-15-0113 .
15. Book: Jameson JL, De Groot LJ . Endocrinology: Adult and Pediatric . February 2015 . Elsevier Health Sciences . 978-0-323-32195-2 . 238– .
16. Korach KS, Couse JF, Curtis SW, Washburn TF, Lindzey J, Kimbro KS, Eddy EM, Migliaccio S, Snedeker SM, Lubahn DB, Schomberg DW, Smith EP . Estrogen receptor gene disruption: molecular characterization and experimental and clinical phenotypes . Recent Progress in Hormone Research . 51 . 159–86; discussion 186–8 . 1996 . 8701078 .
17. Smith EP, Boyd J, Frank GR, Takahashi H, Cohen RM, Specker B, Williams TC, Lubahn DB, Korach KS . Estrogen resistance caused by a mutation in the estrogen-receptor gene in a man . The New England Journal of Medicine . 331 . 16 . 1056–1061 . October 1994 . 8090165 . 10.1056/NEJM199410203311604 . free .
18. Quaynor SD, Stradtman EW, Kim HG, Shen Y, Chorich LP, Schreihofer DA, Layman LC . Delayed puberty and estrogen resistance in a woman with estrogen receptor α variant . The New England Journal of Medicine . 369 . 2 . 164–171 . July 2013 . 23841731 . 3823379 . 10.1056/NEJMoa1303611 .
19. Jahandoost S, Farhanghian P, Abbasi S . The Effects of Sex Protein Receptors and Sex Steroid Hormone Gene Polymorphisms on Breast Cancer Risk . Journal of the National Medical Association . 109 . 2 . 126–138 . 2017 . 28599754 . 10.1016/j.jnma.2017.02.003 .
20. Eren E, Edgunlu T, Korkmaz HA, Cakir ED, Demir K, Cetin ES, Celik SK . Genetic variants of estrogen beta and leptin receptors may cause gynecomastia in adolescent . Gene . 541 . 2 . 101–106 . May 2014 . 24625355 . 10.1016/j.gene.2014.03.013 .
21. Woo HY, Kim KH, Lim SW . Estrogen receptor 1, glutathione S-transferase P1, glutathione S-transferase M1, and glutathione S-transferase T1 genes with dysmenorrhea in Korean female adolescents . The Korean Journal of Laboratory Medicine . 30 . 1 . 76–83 . February 2010 . 20197727 . 10.3343/kjlm.2010.30.1.76 . free .
22. Henry NL, Somerfield MR, Dayao Z, Elias A, Kalinsky K, McShane LM, Moy B, Park BH, Shanahan KM, Sharma P, Shatsky R, Stringer-Reasor E, Telli M, Turner NC, DeMichele A . Biomarkers for Systemic Therapy in Metastatic Breast Cancer: ASCO Guideline Update . Journal of Clinical Oncology . 40 . 27 . 3205–3221 . September 2022 . 35759724 . 10.1200/JCO.22.01063 . free .
23. Shang Y, Brown M . Molecular determinants for the tissue specificity of SERMs . Science . 295 . 5564 . 2465–2468 . March 2002 . 11923541 . 10.1126/science.1068537 . 30634073 . 2002Sci...295.2465S .
24. Smith CL, O'Malley BW . Coregulator function: a key to understanding tissue specificity of selective receptor modulators . Endocrine Reviews . 25 . 1 . 45–71 . February 2004 . 14769827 . 10.1210/er.2003-0023 . free .
25. Anzick SL, Kononen J, Walker RL, Azorsa DO, Tanner MM, Guan XY, Sauter G, Kallioniemi OP, Trent JM, Meltzer PS . AIB1, a steroid receptor coactivator amplified in breast and ovarian cancer . Science . 277 . 5328 . 965–968 . August 1997 . 9252329 . 10.1126/science.277.5328.965 .
26. Vadlamudi RK, Wang RA, Mazumdar A, Kim Y, Shin J, Sahin A, Kumar R . Molecular cloning and characterization of PELP1, a novel human coregulator of estrogen receptor alpha . The Journal of Biological Chemistry . 276 . 41 . 38272–38279 . October 2001 . 11481323 . 10.1074/jbc.M103783200 . free .
27. Rubino D, Driggers P, Arbit D, Kemp L, Miller B, Coso O, Pagliai K, Gray K, Gutkind S, Segars J . Characterization of Brx, a novel Dbl family member that modulates estrogen receptor action . Oncogene . 16 . 19 . 2513–2526 . May 1998 . 9627117 . 10.1038/sj.onc.1201783 . 20906586 .
28. Wormke M, Stoner M, Saville B, Walker K, Abdelrahim M, Burghardt R, Safe S . The aryl hydrocarbon receptor mediates degradation of estrogen receptor alpha through activation of proteasomes . Molecular and Cellular Biology . 23 . 6 . 1843–1855 . March 2003 . 12612060 . 149455 . 10.1128/MCB.23.6.1843-1855.2003 .
29. Klinge CM, Kaur K, Swanson HI . The aryl hydrocarbon receptor interacts with estrogen receptor alpha and orphan receptors COUP-TFI and ERRalpha1 . Archives of Biochemistry and Biophysics . 373 . 1 . 163–174 . January 2000 . 10620335 . 10.1006/abbi.1999.1552 .
30. Zheng L, Annab LA, Afshari CA, Lee WH, Boyer TG . BRCA1 mediates ligand-independent transcriptional repression of the estrogen receptor . Proceedings of the National Academy of Sciences of the United States of America . 98 . 17 . 9587–9592 . August 2001 . 11493692 . 55496 . 10.1073/pnas.171174298 . free . 2001PNAS...98.9587Z .
31. Fan S, Ma YX, Wang C, Yuan RQ, Meng Q, Wang JA, Erdos M, Goldberg ID, Webb P, Kushner PJ, Pestell RG, Rosen EM . Role of direct interaction in BRCA1 inhibition of estrogen receptor activity . Oncogene . 20 . 1 . 77–87 . January 2001 . 11244506 . 10.1038/sj.onc.1204073 . 24657209 .
32. Kawai H, Li H, Chun P, Avraham S, Avraham HK . Direct interaction between BRCA1 and the estrogen receptor regulates vascular endothelial growth factor (VEGF) transcription and secretion in breast cancer cells . Oncogene . 21 . 50 . 7730–7739 . October 2002 . 12400015 . 10.1038/sj.onc.1205971 . 32740995 .
33. Schlegel A, Wang C, Pestell RG, Lisanti MP . Ligand-independent activation of oestrogen receptor alpha by caveolin-1 . The Biochemical Journal . 359 . Pt 1 . 203–210 . October 2001 . 11563984 . 1222136 . 10.1042/0264-6021:3590203 .
34. Ma ZQ, Liu Z, Ngan ES, Tsai SY . Cdc25B functions as a novel coactivator for the steroid receptors . Molecular and Cellular Biology . 21 . 23 . 8056–8067 . December 2001 . 11689696 . 99972 . 10.1128/MCB.21.23.8056-8067.2001 .
35. Boruk M, Savory JG, Haché RJ . AF-2-dependent potentiation of CCAAT enhancer binding protein beta-mediated transcriptional activation by glucocorticoid receptor . Molecular Endocrinology . 12 . 11 . 1749–1763 . November 1998 . 9817600 . 10.1210/mend.12.11.0191 .
36. Stein B, Yang MX . Repression of the interleukin-6 promoter by estrogen receptor is mediated by NF-kappa B and C/EBP beta . Molecular and Cellular Biology . 15 . 9 . 4971–4979 . September 1995 . 7651415 . 230744 . 10.1128/MCB.15.9.4971 .
37. Aiyar SE, Sun JL, Blair AL, Moskaluk CA, Lu YZ, Ye QN, Yamaguchi Y, Mukherjee A, Ren DM, Handa H, Li R . Attenuation of estrogen receptor alpha-mediated transcription through estrogen-stimulated recruitment of a negative elongation factor . Genes & Development . 18 . 17 . 2134–2146 . September 2004 . 15342491 . 515291 . 10.1101/gad.1214104 .
38. Métivier R, Gay FA, Hübner MR, Flouriot G, Salbert G, Gannon F, Kah O, Pakdel F . Formation of an hER alpha-COUP-TFI complex enhances hER alpha AF-1 through Ser118 phosphorylation by MAPK . The EMBO Journal . 21 . 13 . 3443–3453 . July 2002 . 12093745 . 126093 . 10.1093/emboj/cdf344 .
39. Fan S, Ma YX, Wang C, Yuan RQ, Meng Q, Wang JA, Erdos M, Goldberg ID, Webb P, Kushner PJ, Pestell RG, Rosen EM . p300 Modulates the BRCA1 inhibition of estrogen receptor activity . Cancer Research . 62 . 1 . 141–151 . January 2002 . 11782371 .
40. Sheppard HM, Harries JC, Hussain S, Bevan C, Heery DM . Analysis of the steroid receptor coactivator 1 (SRC1)-CREB binding protein interaction interface and its importance for the function of SRC1 . Molecular and Cellular Biology . 21 . 1 . 39–50 . January 2001 . 11113179 . 86566 . 10.1128/MCB.21.1.39-50.2001 .
41. Zwijsen RM, Wientjens E, Klompmaker R, van der Sman J, Bernards R, Michalides RJ . CDK-independent activation of estrogen receptor by cyclin D1 . Cell . 88 . 3 . 405–415 . February 1997 . 9039267 . 10.1016/S0092-8674(00)81879-6 . free . 16492666 . 1874/21074 .
42. Bu H, Kashireddy P, Chang J, Zhu YT, Zhang Z, Zheng W, Rao SM, Zhu YJ . ERBP, a novel estrogen receptor binding protein enhancing the activity of estrogen receptor . Biochemical and Biophysical Research Communications . 317 . 1 . 54–59 . April 2004 . 15047147 . 10.1016/j.bbrc.2004.02.179 .
43. Fajas L, Egler V, Reiter R, Hansen J, Kristiansen K, Debril MB, Miard S, Auwerx J . The retinoblastoma-histone deacetylase 3 complex inhibits PPARgamma and adipocyte differentiation . Developmental Cell . 3 . 6 . 903–910 . December 2002 . 12479814 . 10.1016/S1534-5807(02)00360-X . free .
44. Ogawa S, Inoue S, Watanabe T, Hiroi H, Orimo A, Hosoi T, Ouchi Y, Muramatsu M . The complete primary structure of human estrogen receptor beta (hER beta) and its heterodimerization with ER alpha in vivo and in vitro . Biochemical and Biophysical Research Communications . 243 . 1 . 122–126 . February 1998 . 9473491 . 10.1006/bbrc.1997.7893 .
45. Poelzl G, Kasai Y, Mochizuki N, Shaul PW, Brown M, Mendelsohn ME . Specific association of estrogen receptor beta with the cell cycle spindle assembly checkpoint protein, MAD2 . Proceedings of the National Academy of Sciences of the United States of America . 97 . 6 . 2836–2839 . March 2000 . 10706629 . 16016 . 10.1073/pnas.050580997 . free . 2000PNAS...97.2836P .
46. Schuur ER, Loktev AV, Sharma M, Sun Z, Roth RA, Weigel RJ . Ligand-dependent interaction of estrogen receptor-alpha with members of the forkhead transcription factor family . The Journal of Biological Chemistry . 276 . 36 . 33554–33560 . September 2001 . 11435445 . 10.1074/jbc.M105555200 . free. 11652289 .
47. Deschênes J, Bourdeau V, White JH, Mader S . Regulation of GREB1 transcription by estrogen receptor alpha through a multipartite enhancer spread over 20 kb of upstream flanking sequences . The Journal of Biological Chemistry . 282 . 24 . 17335–17339 . June 2007 . 17463000 . 10.1074/jbc.C700030200 . 24262059 . free .
48. Chen D, Riedl T, Washbrook E, Pace PE, Coombes RC, Egly JM, Ali S . Activation of estrogen receptor alpha by S118 phosphorylation involves a ligand-dependent interaction with TFIIH and participation of CDK7 . Molecular Cell . 6 . 1 . 127–137 . July 2000 . 10949034 . 10.1016/S1097-2765(00)00014-9 .
49. Dhamad AE, Zhou Z, Zhou J, Du Y . Systematic Proteomic Identification of the Heat Shock Proteins (Hsp) that Interact with Estrogen Receptor Alpha (ERα) and Biochemical Characterization of the ERα-Hsp70 Interaction . PLOS ONE . 11 . 8 . e0160312 . 2016 . 27483141 . 4970746 . 10.1371/journal.pone.0160312 . 2016PLoSO..1160312D . free .
50. Nair SC, Toran EJ, Rimerman RA, Hjermstad S, Smithgall TE, Smith DF . A pathway of multi-chaperone interactions common to diverse regulatory proteins: estrogen receptor, Fes tyrosine kinase, heat shock transcription factor Hsf1, and the aryl hydrocarbon receptor . Cell Stress & Chaperones . 1 . 4 . 237–250 . December 1996 . 10.1379/1466-1268(1996)001<0237:APOMCI>2.3.CO;2 . 2024-03-29 . 9222609 . 376461 .
51. Lee MO, Kim EO, Kwon HJ, Kim YM, Kang HJ, Kang H, Lee JE . Radicicol represses the transcriptional function of the estrogen receptor by suppressing the stabilization of the receptor by heat shock protein 90 . Molecular and Cellular Endocrinology . 188 . 1–2 . 47–54 . February 2002 . 11911945 . 10.1016/S0303-7207(01)00753-5 . 37933406 .
52. Gay F, Anglade I, Gong Z, Salbert G . The LIM/homeodomain protein islet-1 modulates estrogen receptor functions . Molecular Endocrinology . 14 . 10 . 1627–1648 . October 2000 . 11043578 . 10.1210/mend.14.10.0538 . free .
53. Chan SW, Hong W . Retinoblastoma-binding protein 2 (Rbp2) potentiates nuclear hormone receptor-mediated transcription . The Journal of Biological Chemistry . 276 . 30 . 28402–28412 . July 2001 . 11358960 . 10.1074/jbc.M100313200 . 22993127 . free .
54. Abbondanza C, Rossi V, Roscigno A, Gallo L, Belsito A, Piluso G, Medici N, Nigro V, Molinari AM, Moncharmont B, Puca GA . Interaction of vault particles with estrogen receptor in the MCF-7 breast cancer cell . The Journal of Cell Biology . 141 . 6 . 1301–1310 . June 1998 . 9628887 . 2132791 . 10.1083/jcb.141.6.1301 .
55. Kang YK, Guermah M, Yuan CX, Roeder RG . The TRAP/Mediator coactivator complex interacts directly with estrogen receptors alpha and beta through the TRAP220 subunit and directly enhances estrogen receptor function in vitro . Proceedings of the National Academy of Sciences of the United States of America . 99 . 5 . 2642–2647 . March 2002 . 11867769 . 122401 . 10.1073/pnas.261715899 . free . 2002PNAS...99.2642K .
56. Talukder AH, Mishra SK, Mandal M, Balasenthil S, Mehta S, Sahin AA, Barnes CJ, Kumar R . MTA1 interacts with MAT1, a cyclin-dependent kinase-activating kinase complex ring finger factor, and regulates estrogen receptor transactivation functions . The Journal of Biological Chemistry . 278 . 13 . 11676–11685 . March 2003 . 12527756 . 10.1074/jbc.M209570200 . 25527041 . free .
57. Kumar R, Wang RA, Mazumdar A, Talukder AH, Mandal M, Yang Z, Bagheri-Yarmand R, Sahin A, Hortobagyi G, Adam L, Barnes CJ, Vadlamudi RK . A naturally occurring MTA1 variant sequesters oestrogen receptor-alpha in the cytoplasm . Nature . 418 . 6898 . 654–657 . August 2002 . 12167865 . 10.1038/nature00889 . 4355677 . 2002Natur.418..654K .
58. Mazumdar A, Wang RA, Mishra SK, Adam L, Bagheri-Yarmand R, Mandal M, Vadlamudi RK, Kumar R . Transcriptional repression of oestrogen receptor by metastasis-associated protein 1 corepressor . Nature Cell Biology . 3 . 1 . 30–37 . January 2001 . 11146623 . 10.1038/35050532 . 23477845 .
59. Lee SK, Anzick SL, Choi JE, Bubendorf L, Guan XY, Jung YK, Kallioniemi OP, Kononen J, Trent JM, Azorsa D, Jhun BH, Cheong JH, Lee YC, Meltzer PS, Lee JW . A nuclear factor, ASC-2, as a cancer-amplified transcriptional coactivator essential for ligand-dependent transactivation by nuclear receptors in vivo . The Journal of Biological Chemistry . 274 . 48 . 34283–34293 . November 1999 . 10567404 . 10.1074/jbc.274.48.34283 . 36982011 . free .
60. Ko L, Cardona GR, Iwasaki T, Bramlett KS, Burris TP, Chin WW . Ser-884 adjacent to the LXXLL motif of coactivator TRBP defines selectivity for ERs and TRs . Molecular Endocrinology . 16 . 1 . 128–140 . January 2002 . 11773444 . 10.1210/mend.16.1.0755 . free .
61. DiRenzo J, Shang Y, Phelan M, Sif S, Myers M, Kingston R, Brown M . BRG-1 is recruited to estrogen-responsive promoters and cooperates with factors involved in histone acetylation . Molecular and Cellular Biology . 20 . 20 . 7541–7549 . October 2000 . 11003650 . 86306 . 10.1128/MCB.20.20.7541-7549.2000 .
62. Kalkhoven E, Valentine JE, Heery DM, Parker MG . Isoforms of steroid receptor co-activator 1 differ in their ability to potentiate transcription by the oestrogen receptor . The EMBO Journal . 17 . 1 . 232–243 . January 1998 . 9427757 . 1170374 . 10.1093/emboj/17.1.232 .
63. Wärnmark A, Treuter E, Gustafsson JA, Hubbard RE, Brzozowski AM, Pike AC . Interaction of transcriptional intermediary factor 2 nuclear receptor box peptides with the coactivator binding site of estrogen receptor alpha . The Journal of Biological Chemistry . 277 . 24 . 21862–21868 . June 2002 . 11937504 . 10.1074/jbc.M200764200 . 45251979 . free .
64. He B, Wilson EM . Electrostatic modulation in steroid receptor recruitment of LXXLL and FXXLF motifs . Molecular and Cellular Biology . 23 . 6 . 2135–2150 . March 2003 . 12612084 . 149467 . 10.1128/MCB.23.6.2135-2150.2003 .
65. Fenne IS, Hoang T, Hauglid M, Sagen JV, Lien EA, Mellgren G . Recruitment of coactivator glucocorticoid receptor interacting protein 1 to an estrogen receptor transcription complex is regulated by the 3',5'-cyclic adenosine 5'-monophosphate-dependent protein kinase . Endocrinology . 149 . 9 . 4336–4345 . September 2008 . 18499756 . 10.1210/en.2008-0037 . free .
66. Wong CW, Komm B, Cheskis BJ . Structure-function evaluation of ER alpha and beta interplay with SRC family coactivators. ER selective ligands . Biochemistry . 40 . 23 . 6756–6765 . June 2001 . 11389589 . 10.1021/bi010379h .
67. Tikkanen MK, Carter DJ, Harris AM, Le HM, Azorsa DO, Meltzer PS, Murdoch FE . Endogenously expressed estrogen receptor and coactivator AIB1 interact in MCF-7 human breast cancer cells . Proceedings of the National Academy of Sciences of the United States of America . 97 . 23 . 12536–12540 . November 2000 . 11050174 . 18799 . 10.1073/pnas.220427297 . free . 2000PNAS...9712536T .
68. Cavaillès V, Dauvois S, L'Horset F, Lopez G, Hoare S, Kushner PJ, Parker MG . Nuclear factor RIP140 modulates transcriptional activation by the estrogen receptor . The EMBO Journal . 14 . 15 . 3741–3751 . August 1995 . 7641693 . 394449 . 10.1002/j.1460-2075.1995.tb00044.x .
69. Thénot S, Henriquet C, Rochefort H, Cavaillès V . Differential interaction of nuclear receptors with the putative human transcriptional coactivator hTIF1 . The Journal of Biological Chemistry . 272 . 18 . 12062–12068 . May 1997 . 9115274 . 10.1074/jbc.272.18.12062 . 32098587 . free .
70. L'Horset F, Dauvois S, Heery DM, Cavaillès V, Parker MG . RIP-140 interacts with multiple nuclear receptors by means of two distinct sites . Molecular and Cellular Biology . 16 . 11 . 6029–6036 . November 1996 . 8887632 . 231605 . 10.1128/MCB.16.11.6029 .
71. Johnsen SA, Güngör C, Prenzel T, Riethdorf S, Riethdorf L, Taniguchi-Ishigaki N, Rau T, Tursun B, Furlow JD, Sauter G, Scheffner M, Pantel K, Gannon F, Bach I . Regulation of estrogen-dependent transcription by the LIM cofactors CLIM and RLIM in breast cancer . Cancer Research . 69 . 1 . 128–136 . January 2009 . 19117995 . 2713826 . 10.1158/0008-5472.CAN-08-1630 .
72. Budhram-Mahadeo V, Parker M, Latchman DS . POU transcription factors Brn-3a and Brn-3b interact with the estrogen receptor and differentially regulate transcriptional activity via an estrogen response element . Molecular and Cellular Biology . 18 . 2 . 1029–1041 . February 1998 . 9448000 . 108815 . 10.1128/mcb.18.2.1029 .
73. Abbondanza C, Medici N, Nigro V, Rossi V, Gallo L, Piluso G, Belsito A, Roscigno A, Bontempo P, Puca AA, Molinari AM, Moncharmont B, Puca GA . The retinoblastoma-interacting zinc-finger protein RIZ is a downstream effector of estrogen action . Proceedings of the National Academy of Sciences of the United States of America . 97 . 7 . 3130–3135 . March 2000 . 10706618 . 16204 . 10.1073/pnas.050015697 . free .
74. Qi C, Chang J, Zhu Y, Yeldandi AV, Rao SM, Zhu YJ . Identification of protein arginine methyltransferase 2 as a coactivator for estrogen receptor alpha . The Journal of Biological Chemistry . 277 . 32 . 28624–28630 . August 2002 . 12039952 . 10.1074/jbc.M201053200 . 25844266 . free .
75. Jung DJ, Na SY, Na DS, Lee JW . Molecular cloning and characterization of CAPER, a novel coactivator of activating protein-1 and estrogen receptors . The Journal of Biological Chemistry . 277 . 2 . 1229–1234 . January 2002 . 11704680 . 10.1074/jbc.M110417200 . 39443808 . free .
76. Townson SM, Kang K, Lee AV, Oesterreich S . Structure-function analysis of the estrogen receptor alpha corepressor scaffold attachment factor-B1: identification of a potent transcriptional repression domain . The Journal of Biological Chemistry . 279 . 25 . 26074–26081 . June 2004 . 15066997 . 10.1074/jbc.M313726200 . free .
77. Oesterreich S, Zhang Q, Hopp T, Fuqua SA, Michaelis M, Zhao HH, Davie JR, Osborne CK, Lee AV . Tamoxifen-bound estrogen receptor (ER) strongly interacts with the nuclear matrix protein HET/SAF-B, a novel inhibitor of ER-mediated transactivation . Molecular Endocrinology . 14 . 3 . 369–381 . March 2000 . 10707955 . 10.1210/mend.14.3.0432 . free .
78. Townson SM, Dobrzycka KM, Lee AV, Air M, Deng W, Kang K, Jiang S, Kioka N, Michaelis K, Oesterreich S . SAFB2, a new scaffold attachment factor homolog and estrogen receptor corepressor . The Journal of Biological Chemistry . 278 . 22 . 20059–20068 . May 2003 . 12660241 . 10.1074/jbc.M212988200 . 36827119 . free .
79. Song RX, McPherson RA, Adam L, Bao Y, Shupnik M, Kumar R, Santen RJ . Linkage of rapid estrogen action to MAPK activation by ERalpha-Shc association and Shc pathway activation . Molecular Endocrinology . 16 . 1 . 116–127 . January 2002 . 10.1210/mend.16.1.0748 . 11773443 . free .
80. Seol W, Hanstein B, Brown M, Moore DD . Inhibition of estrogen receptor action by the orphan receptor SHP (short heterodimer partner) . Molecular Endocrinology . 12 . 10 . 1551–1557 . October 1998 . 9773978 . 10.1210/mend.12.10.0184 . free .
81. Klinge CM, Jernigan SC, Risinger KE . The agonist activity of tamoxifen is inhibited by the short heterodimer partner orphan nuclear receptor in human endometrial cancer cells . Endocrinology . 143 . 3 . 853–867 . March 2002 . 11861507 . 10.1210/endo.143.3.8676 . free .
82. Ichinose H, Garnier JM, Chambon P, Losson R . Ligand-dependent interaction between the estrogen receptor and the human homologues of SWI2/SNF2 . Gene . 188 . 1 . 95–100 . March 1997 . 9099865 . 10.1016/S0378-1119(96)00785-8 .
83. Belandia B, Orford RL, Hurst HC, Parker MG . Targeting of SWI/SNF chromatin remodelling complexes to estrogen-responsive genes . The EMBO Journal . 21 . 15 . 4094–4103 . August 2002 . 12145209 . 126156 . 10.1093/emboj/cdf412 .
84. Teo AK, Oh HK, Ali RB, Li BF . The modified human DNA repair enzyme O(6)-methylguanine-DNA methyltransferase is a negative regulator of estrogen receptor-mediated transcription upon alkylation DNA damage . Molecular and Cellular Biology . 21 . 20 . 7105–7114 . October 2001 . 11564893 . 99886 . 10.1128/MCB.21.20.7105-7114.2001 .
85. Migliaccio A, Castoria G, Di Domenico M, de Falco A, Bilancio A, Lombardi M, Barone MV, Ametrano D, Zannini MS, Abbondanza C, Auricchio F . Steroid-induced androgen receptor-oestradiol receptor beta-Src complex triggers prostate cancer cell proliferation . The EMBO Journal . 19 . 20 . 5406–5417 . October 2000 . 11032808 . 314017 . 10.1093/emboj/19.20.5406 .
86. Kim HJ, Yi JY, Sung HS, Moore DD, Jhun BH, Lee YC, Lee JW . Activating signal cointegrator 1, a novel transcription coactivator of nuclear receptors, and its cytosolic localization under conditions of serum deprivation . Molecular and Cellular Biology . 19 . 9 . 6323–6332 . September 1999 . 10454579 . 84603 . 10.1128/mcb.19.9.6323 .
87. Slentz-Kesler K, Moore JT, Lombard M, Zhang J, Hollingsworth R, Weiner MP . Identification of the human Mnk2 gene (MKNK2) through protein interaction with estrogen receptor beta . Genomics . 69 . 1 . 63–71 . October 2000 . 11013076 . 10.1006/geno.2000.6299 .
88. Hu YC, Shyr CR, Che W, Mu XM, Kim E, Chang C . Suppression of estrogen receptor-mediated transcription and cell growth by interaction with TR2 orphan receptor . The Journal of Biological Chemistry . 277 . 37 . 33571–33579 . September 2002 . 12093804 . 10.1074/jbc.M203531200 . 21803067 . free .
89. Shyr CR, Hu YC, Kim E, Chang C . Modulation of estrogen receptor-mediated transactivation by orphan receptor TR4 in MCF-7 cells . The Journal of Biological Chemistry . 277 . 17 . 14622–14628 . April 2002 . 11844790 . 10.1074/jbc.M110051200 . 9875107 . free.
90. Chen D, Lucey MJ, Phoenix F, Lopez-Garcia J, Hart SM, Losson R, Buluwela L, Coombes RC, Chambon P, Schär P, Ali S . T:G mismatch-specific thymine-DNA glycosylase potentiates transcription of estrogen-regulated genes through direct interaction with estrogen receptor alpha . The Journal of Biological Chemistry . 278 . 40 . 38586–38592 . October 2003 . 12874288 . 10.1074/jbc.M304286200 . 41922647 . free .
91. Thénot S, Bonnet S, Boulahtouf A, Margeat E, Royer CA, Borgna JL, Cavaillès V . Effect of ligand and DNA binding on the interaction between human transcription intermediary factor 1alpha and estrogen receptors . Molecular Endocrinology . 13 . 12 . 2137–2150 . December 1999 . 10.1210/mend.13.12.0387 . 10598587 . 23486519 . free .
92. Ding L, Yan J, Zhu J, Zhong H, Lu Q, Wang Z, Huang C, Ye Q . Ligand-independent activation of estrogen receptor alpha by XBP-1 . Nucleic Acids Research . 31 . 18 . 5266–5274 . September 2003 . 12954762 . 203316 . 10.1093/nar/gkg731 .