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ESR1

Official Full Name
estrogen receptor 1
Organism
Homo sapiens
GeneID
2099
Background
This gene encodes an estrogen receptor and ligand-activated transcription factor. The canonical protein contains an N-terminal ligand-independent transactivation domain, a central DNA binding domain, a hinge domain, and a C-terminal ligand-dependent transactivation domain. The protein localizes to the nucleus where it may form either a homodimer or a heterodimer with estrogen receptor 2. The protein encoded by this gene regulates the transcription of many estrogen-inducible genes that play a role in growth, metabolism, sexual development, gestation, and other reproductive functions and is expressed in many non-reproductive tissues. The receptor encoded by this gene plays a key role in breast cancer, endometrial cancer, and osteoporosis. This gene is reported to have dozens of transcript variants due to the use of alternate promoters and alternative splicing, however, the full-length nature of many of these variants remain uncertain. [provided by RefSeq, Jul 2020]
Synonyms
ER; ESR; Era; ESRA; ESTRR; NR3A1;
Bio Chemical Class
Nuclear hormone receptor
Protein Sequence
MTMTLHTKASGMALLHQIQGNELEPLNRPQLKIPLERPLGEVYLDSSKPAVYNYPEGAAYEFNAAAAANAQVYGQTGLPYGPGSEAAAFGSNGLGGFPPLNSVSPSPLMLLHPPPQLSPFLQPHGQQVPYYLENEPSGYTVREAGPPAFYRPNSDNRRQGGRERLASTNDKGSMAMESAKETRYCAVCNDYASGYHYGVWSCEGCKAFFKRSIQGHNDYMCPATNQCTIDKNRRKSCQACRLRKCYEVGMMKGGIRKDRRGGRMLKHKRQRDDGEGRGEVGSAGDMRAANLWPSPLMIKRSKKNSLALSLTADQMVSALLDAEPPILYSEYDPTRPFSEASMMGLLTNLADRELVHMINWAKRVPGFVDLTLHDQVHLLECAWLEILMIGLVWRSMEHPGKLLFAPNLLLDRNQGKCVEGMVEIFDMLLATSSRFRMMNLQGEEFVCLKSIILLNSGVYTFLSSTLKSLEEKDHIHRVLDKITDTLIHLMAKAGLTLQQQHQRLAQLLLILSHIRHMSNKGMEHLYSMKCKNVVPLYDLLLEMLDAHRLHAPTSRGGASVEETDQSHLATAGSTSSHSLQKYYITGEAEGFPATV
Open
Disease
Acne vulgaris, Acquired prion disease, Adrenal cancer, Alzheimer disease, Atrophy, Brain cancer, Breast cancer, Breast in situ carcinoma, Contraceptive management, Diabetes mellitus, Dissociative neurological symptom disorder, Dyspareunia, Endometriosis, Eye disorder, Female genital tract noninflammatory disorder, Female infertility, Female pelvic pain, Hyper-lipoproteinaemia, Irregularities, Joint pain, Leukaemia, Low bone mass disorder, Male infertility, Menopausal disorder, Menstrual cycle bleeding disorder, Metastatic tumour, Multiple sclerosis, Pain, Parkinsonism, Pituitary gland disorder, Prostate cancer, Sexual dysfunction, Skeletal anomaly, Solid tumour/cancer, Thrombocytopenia, Trematode disease, Vaginitis, Virus infection
Approved Drug
37 +
Clinical Trial Drug
37 +
Discontinued Drug
21 +

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Detailed Information

Particularly in controlling the effects of estrogen on different tissues, the ESR1 gene—also known as estrogen Receptor 1—is vital in human biology. It codes for the ligand-activated transcription factor involved in development, metabolism, reproduction, and other essential processes—the estrogen receptor alpha (ERα). Many physiological and pathological settings highlight the relevance of ESR1, particularly in endometrial cancer, osteoporosis, and breast cancer. The ESR1 gene's structure, function, and clinical relevance—especially about cancer and treatment resistance—will be discussed in this article.

Structure and Function of ESR1

Comprising eight exons and seven introns, the ESR1 gene is found on chromosome 6q25.1 and codes for a protein with a molecular weight of around 66 kDa and 595 amino acids. ERα's protein structure consists of multiple domains, each with specific purposes. Whereas the C-terminal area comprises a ligand-dependent activation function (AF-2), the N-terminal domain is ligand-independent and in charge of transactivation. A DNA-binding domain (DBD) and a hinge region vital for receptor dimerization and DNA engagement abound in the center.

ERα's main function is to modulate the effects of estrogen by binding to estrogen response elements (ERE) on DNA, therefore inducing a cascade of transcriptional activity controlling the expression of different estrogen-responsive genes. Among the many activities these genes are engaged in include sexual development, reproduction, cell proliferation, and differentiation. Interacting with estrogen receptor beta (ERβ), the receptor may either be a homodimer or heterodimer, hence mediating its varied actions. To control gene expression free from ERE binding, it also interacts with other transcription factors including AP-1, Sp1, and c-Jun.

Though it is also present in non-reproductive tissues such as the liver, brain, and bones, ERα is mostly expressed in reproductive organs including the uterus, mammary glands, and ovaries. Its great frequency emphasizes its part in many physiological mechanisms.

Figure 1 explains the mechanisms by which the ER influences gene expression and how resistance to aromatase inhibitors can occur through various pathways, including direct transcriptional activation and crosstalk with other growth factor receptors.Figure 1. ER pathway and mechanisms of resistance. (Reinert T, et al., 2018)

ESR1 Mutations and Endocrine Therapy Resistance

Although ESR1 mutations are mostly responsible for resistance, other factors also cause endocrine treatment failure. These encompass:

ERα's and growth factor signaling pathways' cross-talk: Independently of ERα, activation of the PI3K/AKT/mTOR and MAPK pathways may induce cell proliferation and survival, hence generating resistance. Sometimes mutations in genes like PIK3CA, which codes the catalytic subunit of PI3K, cause these pathways to be triggered.

Changes in ERα co-activator's expression or activity may also affect the response to endocrine treatment using co-regulating proteins. For instance, tamoxifen resistance has been related to overexpression of the co-activator SRC-3.

Sometimes cancer cells may completely avoid ERα by activating other signaling channels that drive tumor development. These channels include the HER2 and FGFR signaling cascades, which may become hyperactivated and resist treatments aiming at ERα.

Mechanisms of Resistance Beyond ESR1 Mutations

While ESR1 mutations are a major driver of resistance, other mechanisms contribute to endocrine therapy failure. These include:

  • Cross-talk between ERα and growth factor signaling pathways: Activation of the PI3K/AKT/mTOR and MAPK pathways can promote cell proliferation and survival independently of ERα, leading to resistance. In some cases, the activation of these pathways is driven by mutations in genes such as PIK3CA, which encodes the catalytic subunit of PI3K.
  • Alterations in co-regulatory proteins: Changes in the expression or function of ERα co-activators and co-repressors can also modulate the response to endocrine therapy. For example, overexpression of the co-activator SRC-3 has been linked to tamoxifen resistance.
  • ERα-independent mechanisms: In some cases, cancer cells can bypass ERα entirely by activating alternative signaling pathways that drive tumor growth. These pathways include the HER2 and FGFR signaling cascades, which can become hyperactivated and confer resistance to therapies targeting ERα.

Clinical Implications and Future Directions

The clinical treatment of ER-positive breast cancer has been changed by the discovery of ESR1 mutations and their function in endocrine therapy resistance. Currently being included in clinical practice, genetic testing for ESR1 mutations enables more individualized treatment plans. Therapies aiming at the mutant receptor, like oral SERDs or combination treatments targeting both ERα and the PI3K/AKT pathway, could help patients with ESR1 mutations.

Apart from these advances in therapy, knowledge of the whole spectrum of ESR1 splice variants and their possible influence on cancer growth and treatment resistance is attracting more and more attention. Multiple transcript variants produced by alternative splicing of ESR1 may include shortened receptors devoid of functional domains and show changed transcriptional activity. An area of continuous inquiry is the therapeutic relevance of these variations.

At last, the value of combining endocrine therapy with other focused treatments—such as mTOR inhibitors, PI3K inhibitors, and CDK4/6 inhibitors—is under growing appreciation. Targeting many mechanisms engaged in cancer cell growth and survival, these combination approaches seek to overcome resistance.

References:

  1. Grinshpun A, Chen V, Sandusky ZM, et al. ESR1 activating mutations: From structure to clinical application. Biochim Biophys Acta Rev Cancer. 2023;1878(1):188830.
  2. Jeselsohn R, Buchwalter G, De Angelis C, et al. ESR1 mutations—a mechanism for acquired endocrine resistance in breast cancer. Nat Rev Clin Oncol. 2015;12(10):573-583.
  3. Alataki A, Dowsett M. Human epidermal growth factor receptor-2 and endocrine resistance in hormone-dependent breast cancer. Endocr Relat Cancer. 2022;29(8):R105-R122.
  4. Reinert T, Gonçalves R, Bines J. Implications of ESR1 Mutations in Hormone Receptor-Positive Breast Cancer. Curr Treat Options Oncol. 2018;19(5):24. Published 2018 Apr 17.
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