Estrogen receptor test

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The estrogen receptor test (ERT) is a laboratory test to determine whether cancer cells have estrogen receptors. This information can guide treatment of the cancer. [1]

Contents

The test uses immunohistochemical techniques on the estrogen receptor (ER). Immunohistochemistry (IHC) methods involve selective identification of antigen proteins by exploiting antigen–antibody relationships.

History

Historically, the ligand binding assay was used to determine ER activity. This method was limited because large quantities of fresh tissue were needed for each assay. IHC can be performed on fixed tissue and needle biopsies, [2] and is more accurate in assessing ER status of a tumor. [3]

Today, ER analysis is one of many routinely performed immunohistochemical assays performed to classify hormone receptor status of breast cancers to provide insight into cancer prognosis and management.

Estrogen receptor types

There are two main types of estrogen receptor (ER): estrogen receptor alpha (ERα), and estrogen receptor beta (ER-β), also known as NR3A2. Both are nuclear receptors activated by the sex hormone estrogen. Estrogen signaling can be selectively stimulated or inhibited, dependent on the equilibrium of these two receptor types in target organs. [4] These two ER types are encoded by different genes located on separate chromosomes and have different functions. ERα is encoded by the ESR1 (Estrogen Receptor 1) gene, is mostly active in the mammary gland and uterus, and aids in the regulation of skeletal homeostasis and metabolism. [5] ER-β plays a prominent role in the central nervous and immune systems. [5]

Immunohistochemical assessment

The ERT immunohistochemical assessment is a semi-quantitative method used to predict the likelihood of successful treatment of breast cancer with anti-estrogen therapy. ER-positive breast carcinomas are likely to respond to endocrine treatments. Therefore, monitoring ER activity can be essential in understanding disease progression and guiding treatment.

Various target antibodies may be used in the IHC assessment of the ER. Typically, the antibody used is the anti-Estrogen Receptor (ER) (SP1) Rabbit Monoclonal Antibody. Employing SP1 allows detection of estrogen receptor (ER) antigens in sections of the fixed tissue samples. In conjunction with light microscopy, approximate ER activity can be estimated using the level of staining of the cell's components. The anti-ER (SP1) antibody targets the ER alpha protein (ERα) located in the nucleus of ER-positive cells. [6] The anti-ER (SP1) antibody's response is a useful indication of the progression, management, and prediction of therapy outcome of breast cancer. These antibodies are commercially available from three commonly used auto strain vendors: Dako, Leica, and Ventana. In a study by Kornaga et al., all behaved similarly in the semi-quantitative analysis of breast cancer biopsy samples. [6]

In a study in 2002, six breast carcinoma cases were received, characterized, and analyzed through the ERT IHC assessment. The level of known ER activity was classified (negative, low, medium, and high) and selected for observation. After embedment in a paraffin block, the samples were stained using a hematoxylin and eosin staining (H & E staining) system. The IHC analysis was performed on the same day using anti-ER monoclonal antibodies. There was a consistently strong correlation between the IHC results and the known ER activity. [7]

Estrogen receptor test and breast cancer

Observation of estrogen receptor activity provides insight into growth and proliferation of breast cancer. The complex biochemical reactions of estrogen receptors are necessary for the mediation of cellular interactions in response to various cell-altering factors, including ligands, cofactors, and other simulative complexes. [8]

Monitoring tumor development with the estrogen receptor test

Tumor Growth Tumor Growth.png
Tumor Growth

The estrogen receptor is a regulator of cellular functions, including cell growth and proliferation, and can serve as a means of inter-cellular differentiation. [8] Monitoring the activity of the ER via the ERT is necessary as it plays an essential role in normal breast development and function, as well as in cancerous situations. Accurate measurements of the ER activities are critical in the initial classification and monitoring of progression in breast cancers. The ER can serve as an indicative biomarker as it is a potential predictor for the clinical responses of a patient to certain treatments. Patients with breast cancer that is ER-positive at presentation are most likely to respond to cancer treatments through endocrine therapy. [9]

Estrogen receptor test in mammary epithelial cancer

Estrogen receptors are over-expressed in approximately 70% of diagnosed breast cancers. Growing exposure of the mammary epithelium to estrogen is related to the risk of breast cancer as the binding of estrogen to the HER2 receptor in mammary cells causes a rise in the division and cell synthesis. This ultimately leads to a higher risk of replication errors, and the disruption of the normal cellular processes results in mistakes in apoptosis, cellular proliferation, or DNA repair. [10]

The ERT has been suggested as a predictor for the level of success of the use of endocrine therapy in cancer treatment. Many of the endocrine therapies for breast cancer treatments involve the use of selective estrogen receptor modulators (SERMs). SERMs, such as tamoxifen, are ER antagonists in breast tissue. Estrogen receptor tests are used in determining the sensitivity of breast cancer lesions to tamoxifen. Patients with ER-positive tumors are likely to respond well to these endocrine therapies.

Related Research Articles

<span class="mw-page-title-main">Immunohistochemistry</span> Common application of immunostaining

Immunohistochemistry (IHC) is a form of immunostaining. It involves the process of selectively identifying antigens (proteins) in cells and tissue, by exploiting the principle of antibodies binding specifically to antigens in biological tissues. Albert Hewett Coons, Ernest Berliner, Norman Jones and Hugh J Creech was the first to develop immunofluorescence in 1941. This led to the later development of immunohistochemistry.

<span class="mw-page-title-main">Selective estrogen receptor modulator</span> Drugs acting on the estrogen receptor

Selective estrogen receptor modulators (SERMs), also known as estrogen receptor agonist/antagonists (ERAAs), are a class of drugs that act on the estrogen receptor (ER). A characteristic that distinguishes these substances from pure ER agonists and antagonists is that their action is different in various tissues, thereby granting the possibility to selectively inhibit or stimulate estrogen-like action in various tissues.

<span class="mw-page-title-main">Tamoxifen</span> Medication

Tamoxifen, sold under the brand name Nolvadex among others, is a selective estrogen receptor modulator used to prevent breast cancer in women and men. It is also being studied for other types of cancer. It has been used for Albright syndrome. Tamoxifen is typically taken daily by mouth for five years for breast cancer.

<span class="mw-page-title-main">Estrogen receptor</span> Proteins activated by the hormone estrogen

Estrogen receptors (ERs) are a group of proteins found inside cells. They are receptors that are activated by the hormone estrogen (17β-estradiol). Two classes of ER exist: nuclear estrogen receptors, which are members of the nuclear receptor family of intracellular receptors, and membrane estrogen receptors (mERs), which are mostly G protein-coupled receptors. This article refers to the former (ER).

<span class="mw-page-title-main">HER2</span> Mammalian protein found in humans

Receptor tyrosine-protein kinase erbB-2 is a protein that normally resides in the membranes of cells and is encoded by the ERBB2 gene. ERBB is abbreviated from erythroblastic oncogene B, a gene originally isolated from the avian genome. The human protein is also frequently referred to as HER2 or CD340.

<span class="mw-page-title-main">Toremifene</span> Chemical compound

Toremifene, sold under the brand name Fareston among others, is a medication which is used in the treatment of advanced breast cancer in postmenopausal women. It is taken by mouth.

<span class="mw-page-title-main">Estrogen receptor alpha</span> Protein-coding gene in the species Homo sapiens

Estrogen receptor alpha (ERα), also known as NR3A1, is one of two main types of estrogen receptor, a nuclear receptor that is activated by the sex hormone estrogen. In humans, ERα is encoded by the gene ESR1.

<span class="mw-page-title-main">Estrogen receptor beta</span> Protein-coding gene in the species Homo sapiens

Estrogen receptor beta (ERβ) also known as NR3A2 is one of two main types of estrogen receptor—a nuclear receptor which is activated by the sex hormone estrogen. In humans ERβ is encoded by the ESR2 gene.

<span class="mw-page-title-main">Afimoxifene</span> Chemical compound

Afimoxifene, also known as 4-hydroxytamoxifen (4-OHT) and by its tentative brand name TamoGel, is a selective estrogen receptor modulator (SERM) of the triphenylethylene group and an active metabolite of tamoxifen. The drug is under development under the tentative brand name TamoGel as a topical gel for the treatment of hyperplasia of the breast. It has completed a phase II clinical trial for cyclical mastalgia, but further studies are required before afimoxifene can be approved for this indication and marketed.

Breast cancer classification divides breast cancer into categories according to different schemes criteria and serving a different purpose. The major categories are the histopathological type, the grade of the tumor, the stage of the tumor, and the expression of proteins and genes. As knowledge of cancer cell biology develops these classifications are updated.

<span class="mw-page-title-main">Trioxifene</span> Chemical compound

Trioxifene, or as the salt trioxifene mesylate (USAN), is a selective estrogen receptor modulator (SERM) with competitive binding activity against estradiol for the ERα and antagonistic activity against ERα-mediated gene expression, that was under preclinical and clinical development by Eli Lilly and Company for breast cancer and prostate cancer, but was abandoned. Its affinity for the rat estrogen receptor was reported to be 20% relative to estradiol.

<span class="mw-page-title-main">Elacestrant</span> Chemical compound

Elacestrant, sold under the brand name Orserdu, is an anticancer medication which is used in the treatment of breast cancer. It is taken by mouth.

Estrogen deprivation therapy, also known as endocrine therapy, is a form of hormone therapy that is used in the treatment of breast cancer. Modalities include antiestrogens or estrogen blockers such as selective estrogen receptor modulators (SERMs) like tamoxifen, selective estrogen receptor degraders like fulvestrant, and aromatase inhibitors like anastrozole and ovariectomy.

E-SCREEN is a cell proliferation assay based on the enhanced proliferation of human breast cancer cells (MCF-7) in the presence of estrogen active substances. The E-SCREEN test is a tool to easily and rapidly assess estrogenic activity of suspected xenoestrogens. This bioassay measures estrogen-induced increase of the number of human breast cancer cell, which is biologically equivalent to the increase of mitotic activity in tissues of the genital tract. It was originally developed by Soto et al. and was included in the first version of the OECD Conceptual Framework for Testing and Assessment of Endocrine Disrupters published in 2012. However, due to failed validation, it was not included in the updated version of the framework published in 2018.

<span class="mw-page-title-main">Endoxifen</span> Chemical compound

Endoxifen, also known as 4-hydroxy-N-desmethyltamoxifen, is a nonsteroidal selective estrogen receptor modulator (SERM) of the triphenylethylene group as well as a protein kinase C (PKC) inhibitor. It is under development for the treatment of estrogen receptor-positive breast cancer and for the treatment of mania in bipolar disorder. It is taken by mouth.

Tesmilifene, also known as N,N-diethyl-2-(4-phenylmethyl)ethanamine (DPPE), is a small-molecule antineoplastic drug and chemopotentiator that was under development by YM BioSciences for the treatment of breast cancer in the 2000s but was never marketed. It reached phase III clinical trials for advanced/metastatic breast cancer before development was discontinued.

<span class="mw-page-title-main">D-15414</span> Chemical compound

D-15414 is a nonsteroidal weak estrogen of the 2-phenylindole group which was never marketed. It is the major metabolite of the selective estrogen receptor modulator (SERM) zindoxifene (D-16726). D-15414 has high affinity for the estrogen receptor (ER) and inhibits the growth of ER-positive MCF-7 breast cancer cells in vitro. However, contradictorily, subsequent research found that the drug produced fully estrogenic effects in vitro similarly to but less actively than estradiol, with no antiestrogenic activity observed. The reason for the discrepancy between the findings is unclear, though may be due to methodology. The unexpected estrogenic activity of D-15414 may be responsible for the failure of zindoxifene in clinical trials as a treatment for breast cancer.

Benita S. Katzenellenbogen née Schulman is an American physiologist and cell biologist at the University of Illinois at Urbana-Champaign. She has studied cancer, endocrinology, and women's health, focusing on nuclear receptors. She also dedicated efforts to focusing on improving the effectiveness of endocrine therapies in breast cancer.

<span class="mw-page-title-main">ERX-11</span> Chemical compound

ERX-11, also known as ERα coregulator-binding modulator-11, is a novel antiestrogen and experimental hormonal antineoplastic agent which is being researched for the potential treatment of estrogen receptor-positive breast cancer. It is not a competitive antagonist of the estrogen receptor (ER) like conventional antiestrogens such as tamoxifen or fulvestrant; instead of binding to the ligand-binding site of the ER, ERX-11 interacts with a different part of the ERα and blocks protein–protein interactions of the ERα with coregulators that are necessary for the receptor to act and regulate gene expression. It was designed to bind to the coregulator binding region of the ERα and inhibit the ERα/coactivator interaction, although its precise binding site and mode of action have yet to be fully elucidated and understood. Nonetheless, it is clear that ERX-11 binds within the AF-2 domain of the ERα.

Endocrine therapy is a common treatment for estrogen receptor positive breast cancer. However, resistance to this therapy can develop, leading to relapse and progression of disease. This highlights the need for new strategies to combat this resistance.

References

  1. ↑ "NCI Dictionary of Cancer Terms: estrogen receptor test". National Cancer Institute. National Institutes of Health. Retrieved 25 August 2023.
  2. ↑ Alberts, S.R.; Ingle, J.N.; Roche, P.R.; Cha, S.S.; Wold, L.E.; Farr Jr, G.H.; Krook, J.E.; Wieand, H.S. (1996-08-15). "Comparison of estrogen receptor determinations by a biochemical ligand-binding assay and immunohistochemical staining with monoclonal antibody ER1D5 in females with lymph node positive breast carcinoma entered on two prospective clinical trials". Cancer. 78 (4): 764–772. doi:10.1002/(SICI)1097-0142(19960815)78:4<764::AID-CNCR12>3.0.CO;2-T. PMID   8756370.
  3. ↑ Harvey, J.M.; Clark, G.M.; Osborne, C.K.; Allred, D.C. (May 1999). "Estrogen receptor status by immunohistochemistry is superior to the ligand-binding assay for predicting response to adjuvant endocrine therapy in breast cancer". J Clin Oncol. 17 (5): 1474–1481. doi:10.1200/JCO.1999.17.5.1474. PMID   10334533.
  4. ↑ Lee, Hye-Rim; Kim, Tae-Hee; Choi, Kyung-Chul (2012). "Functions and physiological roles of two types of estrogen receptors, ERα and ERβ, identified by estrogen receptor knockout mouse". Laboratory Animal Research. 28 (2): 71–6. doi:10.5625/lar.2012.28.2.71. PMC   3389841 . PMID   22787479.
  5. 1 2 Paterni, Ilaria; Granchi, Carlotta; Katzenellenbogen, John A.; Minutolo, Filippo (November 2014). "Estrogen receptors alpha (ERα) and beta (ERβ): Subtype-selective ligands and clinical potential". Steroids. 90: 13–29. doi:10.1016/j.steroids.2014.06.012. PMC   4192010 . PMID   24971815.
  6. 1 2 Kornaga EN, Klimowicz AC, Guggisberg N, Ogilvie T, Morris DG, Webster M, Magliocco AM (August 2016). "A systematic comparison of three commercial estrogen receptor assays in a single clinical outcome breast cancer cohort". Mod. Pathol. 29 (8): 799–809. doi: 10.1038/modpathol.2016.74 . PMID   27125355.
  7. ↑ von Wasielewski R, Mengel M, Wiese B, Rüdiger T, Müller-Hermelink HK, Kreipe H (November 2002). "Tissue array technology for testing interlaboratory and interobserver reproducibility of immunohistochemical estrogen receptor analysis in a large multicenter trial". Am. J. Clin. Pathol. 118 (5): 675–82. doi: 10.1309/URLK-6AVK-331U-0V5P . PMID   12428786.
  8. 1 2 Diaz LK, Sneige N (January 2005). "Estrogen receptor analysis for breast cancer: current issues and keys to increasing testing accuracy". Adv Anat Pathol. 12 (1): 10–9. doi:10.1097/00125480-200501000-00003. PMID   15614160. S2CID   39527926.
  9. ↑ Lledge, R. M. E.; Reen, S. G.; Ugh, R. P.; Llred, D. C. A.; Lark, G. M. C.; Ill, J. H.; Avdin, P. R.; Artino, S. M.; Sborne, C. K. O. (2000). "Estrogen Receptor ( Er ) And Progesterone Receptor ( Pgr ), By Ligand-Binding Assay Compared With Er, Pgr And Ps2, By Immuno-Histochemistry In Predicting Response To Tamoxifen In Metastatic Breast Cancer : A Southwest Oncology Group Study". Int. J. Cancer (Pred. Oncol.). 89 (2): 111–117. doi:10.1002/(sici)1097-0215(20000320)89:2<111::aid-ijc2>3.0.co;2-w. PMID   10754487. S2CID   21778716.
  10. ↑ Deroo, B. J.; Korach, K. S. (1 March 2006). "Estrogen receptors and human disease". Journal of Clinical Investigation. 116 (3): 561–570. doi:10.1172/JCI27987. PMC   2373424 . PMID   16511588.
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