Estrogen Receptor

The estrogen receptor (ER) has two isoforms (ERalpha and ERbeta) that bind estrogen as their ligand.

From: Human Biochemistry , 2018

Aldosterone's Mechanism of Action

Rene Baudrand , ... Jose R. Romero , in Textbook of Nephro-Endocrinology (Second Edition), 2018

4.3 G Protein-Coupled Estrogen Receptor

GPER was first described as an estradiol receptor that mediated its rapid effects via MAPK, PI3K, and EGFR activation. GPER is expressed in numerous cells/tissues including cardiomyocytes, VSMCs, endothelium, lung, and liver. 18,118–121 GPER has also been reported to mediate aldosterone's rapid cellular effects on ERK signaling in VSMCs, ECs, and more recently in the cardiomyocyte cell line, H9C2. 122,123 However, the mechanisms for aldosterone's rapid effects via GPER are not clear. Potential pathways have been recently reviewed and described in detail by Feldman and Limbird. 124 To this end, there is evidence that aldosterone activates GPER at physiological levels. However, binding of aldosterone to GPER has not been clearly established. 125,126 Others have proposed a direct interaction of GPER and MR 126 and cross talk via second messengers and/or modification of striatin 127 as an alternative mechanism of action. Of importance, in vivo cardiovascular effects for GPER activation have been reported. G1 agonists specifically activate GPER leading to vasodilation of mouse carotid vessels: an event that was absent in vessels from GPER knockout mice. 128 Vasodilation by GPER activation has also reported vessels from mRen2.Lewis rats. 129 GPER activation lowers BP acutely. 128 However, GPER ablation leads to increase in mean BP in female mice. 130 However, more studies are needed to clarify these signaling mechanisms and the role of biological sex, aldosterone, and GPER in cardiovascular diseases.

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Immunocytology

Mamatha Chivukula , David J. Dabbs , in Diagnostic Immunohistochemistry (Third Edition), 2011

Estrogen Receptor

Estrogen receptor antibodies have been suggested as a tool to identify metastatic breast carcinoma in effusions from patients without solid tissue metastases. Although reactive mesothelial cells are ER negative, ER is not a sensitive or specific marker by itself. Gynecological carcinomas (vulva, vagina, cervix, endometrium, ovary, and fallopian tube) are often positive for ER in a patchy fashion. A positive ER result can be useful in indicating a breast or gynecological origin, but one must exercise caution when the differential diagnosis includes pulmonary adenocarcinoma, a subset of these tumors may be associated with significant nuclear expression with both 6F11 and 1D5 ER clones ( Fig. 21.8). 71,72

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Estrogen Receptor-β Structure and Function

Karin Dahlman-Wright , ... Jan-Åke Gustafsson , in Encyclopedia of Hormones, 2003

II.A.2 ER-βins

ER-βins, also called ER-β2, contains an extra 54 bp insertion in the reading frame, causing an 18-amino-acid insertion in the LBD between exons 5 and 6 (Fig. 3) . This insertion occurs through alternative splicing. ER-βins shows severely impaired ligand binding and transcriptional activation. However, ER-βins binds to an estrogen-response element (ERE) and can heterodimerize with ER-β variants and ER-α. ER-βins acts as a dominant negative regulator of ER-β and ER-α and causes a dose-dependent inhibition of ER-β and ER-α transcriptional activity. ER-βins has been described for mouse and rat.

Figure 3. ER-β isoforms. The ins domain found in the variant ER-βins in rodents is indicated in white. The CX domain found in the variant ER-βCX in humans is indicated in black.

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Cellular and Molecular Mechanisms of Hormone Actions on Behavior

S. Srinivasan , Z. Nawaz , in Hormones, Brain and Behavior (Second Edition), 2009

3.35.5 Conclusion

ER is a member of a superfamily of hormone-regulated transcription factors that stimulate gene expression in response to estrogens. The ability to switch ER functions from inactive to active state by simply adding ligand has illuminated several fundamental insights into eukaryotic transcriptional regulation. However, the answer to the important question of how this simple linear model eventually culminates in gene transcription lies with coregulator proteins. The ever-expanding number of coregulators and its associated enzymatic activities has created a dramatic impact in the understanding ER mechanism of action. Multiple post-translational modifications on ERs, its coregulators, and histones create a complex matrix of combinatorial codes dictating individual gene expression. The multifaceted mode of ER action has expanded the role of ER from a simple ligand-activated transcription factor to a diverse signaling molecule functioning from the membrane, cytoplasm, and nucleus ( Figure 5 ). The advancements in microarrays have generated genome-wide information regarding ER binding and have sketched an overall picture of ER transcriptome and its cis-acting regulatory elements. There is no doubt that research on ER molecular mechanism of action will continue to contribute more fascinating themes, which not only expands our understanding of ER action in biology, but also serves as a paradigm for eukaryotic gene transcription as a whole.

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Hormonal Treatment of Breast Cancer

Stéphanie Bécourt Marc Espié , in Encyclopedia of Endocrine Diseases (Second Edition), 2019

Hormonal Therapy: Principles (Fig. 2)

➢

ER targeting

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By competitive inhibition of ER: SERM (selective estrogen receptor modulator)

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By ER degradation: SERD (selective estrogen receptor downregulator)

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Decreasing circulating estrogen levels

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LH-RH agonists before menopause

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AIs in postmenopausal women

Fig. 2

Fig. 2. Principles of hormonal therapy.

 From Smith, I. E. and Dowsett, M. (2003). Case vignettes in metastatic breast cancer, partially adapted -Aromatase inhibitors in breast cancer. N Engl J Med. 348, 2431–2442.

ER Targeting

•

By competitive inhibition of ER: SERM

These drugs act as receptor binding competitors of estrogen and block their effects. They bind to the ligand-binding domain of the ER and cause a conformational change in this domain.

The most common is tamoxifen, a nonsteroidal antiestrogen used in treatment of breast cancer, and in prevention in some countries (like the United States) (Cole et al., 1971). It exerts a strong antagonist action at the mammary level and partial agonist on other tissues (endometrium, bones, vessels) (Weinberg et al., 2005).

•

By ER degradation: SERD

They are antiestrogens with no agonist activity, and more potent than SERMs.

The most common is fulvestrant, a steroidal antiestrogen. Fulvestrant has a 100-fold higher affinity than tamoxifen to the ER, with no agonist activity in the uterus (Howell et al., 2000).

It is routinely used at the metastatic stage in postmenopausal patients.

Decreasing Circulating Estrogen Levels

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AIs in postmenopausal women

AIs block the enzyme involved in estrogen biosynthesis (aromatase cytochrome P450), to stop the production of estrogens from androgens, which is the main pathway of estrogen production in postmenopausal women.

Third-generation AIs have been developed; nonsteroidal (anastrozole, letrozole) and steroidal (exemestane).

These drugs are active in postmenopausal women, or undergoing suppression of ovarian function.

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LH-RH agonists

LH stimulates the ovaries to produce estrogen. GnRH, such as LH-RH, downregulates its own production in the hypothalamus through a reversible reaction. Common examples include buserelin, goserelin, leuprorelin, and triptorelin.

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Hormone-Responsive Cancers

Myles Brown , ... Rinath Jeselsohn , in Yen and Jaffe's Reproductive Endocrinology (Eighth Edition), 2019

Estrogen Receptor

ER is a transcription factor and a member of the nuclear receptor super family. ER regulates the transcription of hundreds of genes and ultimately leads to cell division, and has an important role in mammary gland development and the cell proliferation growth that occurs during pregnancy. In ER positive (ER+) breast cancers, ER has a key role in tumorigenesis, leading to uncontrolled cell division, resulting in tumor initiation and progression. Endocrine treatments that target ER are the first class of targeted treatments in cancer and are the mainstay treatment in ER+ breast cancers.

ER is composed of several conserved functional domains. These include an N-terminal transcriptional activation function (AF-1) domain; within AF-1 is a DNA-binding domain (DBD) that includes a zinc-finger domain that is responsible for recognizing the estrogen responsive element (ERE) and a second zinc finger that stabilizes protein-DNA interactions. 63 The zinc finger domains likely have a role in tethering ER to noncanonical or imperfect ERE DNA motifs. ER has a hinge region between AF1 and the ligand binding domain (LBD), which forms the second activation domain (AF-2). The ER LBD structure is similar to those of the nuclear receptor superfamily and includes an α helical pocket, which is the site of estrogen binding as well as antagonists such as tamoxifen. After estrogen binds to ER, helices 3, 4, 5, and 12 form a groove to enable interaction with co-activators. The p160 co-activator family is the most well-characterized of ER co-activators and includes SRC1, GRIP1, and A1B1. 64 In breast cancers, AIB1 is amplified in about 10% of tumors and overexpressed in more than 50% of tumors. Studies in engineered mouse models demonstrated the oncogenic activity of AIB1, indicating a role in breast cancer development. 65-67 In addition, there are also co-repressors, such as NCOR1 and SMRT, which inhibit ER activity. ER chromatin binding is further regulated by chromatin accessibility, as many predicted EREs do not correspond to observable ER binding. The foxhead box protein A1 (FOXA1) is a pioneer factor and was found to be required for chromatin accessibility and ER binding. Furthermore, FOXA1 dictates the distribution of ER binding in a cell-dependent manner. 68,69 In addition, there is also evidence of ligand independent activation of ER by receptor tyrosine kinases (RTKs), such as EGFR and HER2, which leads to distinct ER recruitment that is enriched in sites that co-localize with AP1 binding. 70

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Molecular and Cellular Changes in the Cancer Cell

S. Radhi , in Progress in Molecular Biology and Translational Science, 2016

Abstract

Estrogen receptors (ERs) are expressed in 75% of breast cancers. ERs and their estrogen ligands play a key role in the development and progression of breast cancer. ERs have a genomic activity involving direct modulation of expression of genes vital to cell growth and survival by their classic nuclear receptors. The nongenomic activity is mediated by membrane receptor tyrosine kinases that activate signaling pathways resulting in activation of ER pathway modulators.

Endocrine therapies inhibit the growth promoting activity of estrogen. ERs-positive breast cancers can exhibit de novo or acquired endocrine resistance. The mechanisms of endocrine therapy resistance are complex include deregulation of ER pathway, growth factor receptor signaling, cell cycle machinery, and tumor microenvironment.

In this chapter, we will review the literature on the biology of ERs, the postulated mechanisms of endocrine therapy resistance, and their clinical implications.

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Molecular Pathology of Breast Cancer

David G. Hicks , in Cell and Tissue Based Molecular Pathology, 2009

HER2

The next major advance in the evolving role of prognostic and predictive markers in the diagnosis and therapeutic decision making for breast cancer came with the discovery of the importance of the HER2 receptor tyrosine kinase in the biology and the clinical course of disease in breast cancer. Normal cells have one copy of the HER2 gene on each chromosome 17 (CHR17), and when this gene is expressed in normal breast epithelial cells, it is translated into a 185-kDa transmembrane growth factor receptor with cytoplasmic tyrosine kinase activity, which transmits signals regulating cell growth and survival. In approximately 15% to 25% of breast cancers, the HER2 gene is found to be amplified 2-fold to greater than 20-fold in each tumor cell nucleus relative to CHR17, and this amplification drives gene expression, generating up to 100 times the normal number of HER2 receptor proteins at the cell surface.

ESTROGEN AND PROGESTERONE RECEPTORS—FACT SHEET

Estrogen is the main hormone that controls breast cancer proliferation, interacting with breast epithelial cells through ER.

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Two isoforms of ER are known, ER-α and ER-β. ER-α is the dominant mediator of estrogen signaling in breast cancer pathogenesis.

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ER-α expression has been shown to be a strong predictive factor for benefit from adjuvant hormonal therapy.

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Recent studies suggest that a shift in expression to ER-β receptors may occur in endocrine-resistant breast tumors.

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Validated methods for the assessment of ER in breast tissue include measurement of the ER content of the tumor using biochemical ligand-binding assays such as the dextran-coated charcoal assay, which has been replaced by immunohistochemistry (IHC) performed on formalin-fixed, paraffin-embedded tissues; the IHC correlates well with results from biochemical assays.

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An emerging method to assess ER is by quantitative reverse transcriptase–polymerase chain reaction (RT-PCR) to measure messenger RNA levels.

PR is a surrogate marker of ER activity in breast cancer.

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ER and PR are codependent variables, and PR is a weaker predictor of response to endocrine therapy than ER when both are included in multivariate analysis.

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An ER-positive, PR-negative breast cancer phenotype may represent a distinct subset of ER-positive breast cancer, with a more aggressive clinical course and increased resistance to antiendocrine therapy.

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The PR status of the tumor may reflect activated HER1/HER growth factor signaling in these tumors.

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Loss of PR in ER-positive tumors may represent a surrogate marker for increased growth factor signaling and tamoxifen resistance.

HER2, also known as ERBB2, is a member of a family of transmembrane growth factor receptors, all of which are involved in regulating normal cell proliferation and survival. Like HER2, other members of this receptor family have been implicated in cancer. Several high-affinity ligands bind to several of the HER family members, which leads to receptor dimerization, activation of the cytoplasmic tyrosine kinase, and initiation of downstream signaling. It is now believed that HER2 functions as the preferred dimerization partner for other HER members, leading to increased stability and prolonged activation of signal transduction. This, in turn, results in a proliferative drive, increased cell migration, and survival of those tumor cells that aberrantly overexpress this protein. Therefore, for those tumors with the HER2 molecular alteration, the overexpression of the receptor plays a direct pivotal role in mediating the tumor's biologic and clinical behavior. As a result, HER2-positive breast cancers tend to be more aggressive, resulting in a significantly shortened disease-free survival rate and overall survival rate regardless of other prognostic factors. Furthermore, HER2-positive breast cancer is significantly correlated with several unfavorable pathologic tumor characteristics, including larger tumor size, positive axillary nodes, higher nuclear grade, and higher proliferative index. In addition to the prognostic significance, retrospective studies have suggested that HER2 overexpression may have a predictive role for response to adjuvant chemotherapy and endocrine therapy.

The location of the HER2 protein on the surface of the tumor cell, along with its pivotal role in determining the clinical course of disease for these patients, makes this molecule an ideal target for therapy. Trastuzumab (Herceptin®, Genetech), a humanized antibody that combined the mouse recognition sequence of a monoclonal antibody with the framework of a human IgG1, was developed as a biologic targeted therapeutic against an extracellular epitope of the HER2 receptor. The Herceptin molecule has been shown to demonstrate a high specificity and affinity for the HER2 protein and in preclinical studies was shown to be most effective against tumor cells with HER2 overexpression. The therapeutic efficacy and tolerability of Herceptin therapy has been investigated in several clinical trials, and this drug has proved to be a remarkably effective therapeutic agent in both the metastatic and, more recently, the adjuvant setting, particularly in combination with cytotoxic chemotherapy. What is clear from these trials is that a positive HER2 status, as assessed by either IHC (Figure 27-2) for protein overexpression or fluorescence in situ hybridization (FISH) (Figures 27-3 through 27-6) for gene amplification, is predictive for a clinical response from Herceptin treatment, thus providing a rationale for testing all newly diagnosed breast cancer patients. In contrast, patients who test negative for HER2 have been shown to receive no additional benefit from the inclusion of Herceptin to their therapeutic regimen. Given the increasingly important role of this testing for patient selection and therapeutic decision making, the performance of HER2 assays on clinical samples has become a priority for laboratory quality control and pathologic standardization. As an alternative to FISH for genotyping breast cancer, bright-field in situ hybridization methodologies (CISH™ and SISH™) have been developed, which allow detection of gene copy status using conventional bright-field microscopy (Figures 27-7 through 27-12). Such assays allow direct light microscopic evaluation and better correlation with morphology, and their results have been shown to correlate well with FISH assays, as well as demonstrate the potential to predict clinical outcomes in breast cancer.

Unlike most tests performed by diagnostic surgical pathologists, the results of a HER2 assay does not serve as an adjunct to rendering a diagnosis but, rather, stands alone in determining which breast cancer patients are the most likely to benefit from Herceptin treatment. As such, this testing needs to be accurate, precise, and reproducible to help ensure that only the most appropriate patients will be selected for therapy. Given concerns about cost, potential side effects, and toxicities, it is critically important that Herceptin only be used in selected patients whose tumors have been evaluated by a validated HER2 assay. Data from clinical trials with Herceptin in both the adjuvant and the metastatic settings have demonstrated that the incidence of cardiac dysfunction was higher in patients who received Herceptin in addition to chemotherapy compared with those receiving chemotherapy alone. In the metastatic setting, the incidence and severity of cardiac dysfunction was particularly high in patients who received Herceptin concurrently with an anthracycline.

Among the most important lessons learned from our experience with HER2 testing is the need for standardization of all aspects of the handling of clinical biopsies or resection samples, which will require some form of testing for a predictive biomarker like HER2. This standardization includes all aspects of preanalytic tissue sample acquisition and handling, the type and duration of fixation, tissue processing, assay performance, interpretation, and reporting. Regardless of the laboratory methodology employed, specific guidelines and training to gain proficiency in HER2 testing are needed to ensure accuracy, specificity, and reproducibility of the test results. National guidelines (see fact sheets) recommend that HER2 overexpression or amplification be evaluated for every newly diagnosed breast cancer patient. Per these guidelines, both IHC and FISH (Boxes 27-1 and 27-2) are appropriate testing methodologies for clinical laboratories, provided that high concordance rates are established and appropriate quality control procedures are in place. As articulated by the guidelines developed by the American Society of Clinical Oncology and the College of American Pathologists (ASCO/CAP) (see fact sheets), a rigorous quality control program, experience, and proper training for accurate interpretation and proficiency testing is now mandatory for all laboratories engaged in HER2 testing. The goal should be to achieve a greater than 95% concordance between IHC negative/FISH negative (gene nonamplified) and IHC positive (3+)/FISH positive (gene amplified) within a given laboratory and across laboratories; this concordance should be established for each laboratory engaged in testing by rigorous test validation.

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Magnetic Resonance Imaging and Spectroscopy

H. Allouche-Arnon , ... R. Katz-Brull , in Comprehensive Biomedical Physics, 2014

3.19.2.5.1.3 ER status

ER status has been used in the clinical management of breast cancer as both a predictive factor for treatment and a prognostic factor for survival. Compared with ER-positive cancer, ER-negative cancer has a poorer clinical outcome and a shorter median survival (Chang et al., 2003; Sanna et al., 2007). ER-negative cancer was previously reported to be more aggressive, with bigger tumor size, and more prominent tumor infiltration showing nonmass type enhancements on MRI evaluation (Chen et al., 2008a). ER-negative tumors showed higher intratumoral microvessel density than did ER-positive tumors (Koukourakis et al., 2003). ER-negative breast carcinoma was also associated with increased choline kinase activity (Ramirez de Molina et al., 2002), which is likely to lead to high intracellular phosphocholine or higher choline signal on 1H-MRS. Baek et al. (2008b) investigated the effect of ER status on 1H-MRS choline signal presence and showed that the choline detection rate as well as the absolute choline concentration in the ER-negative group, although higher, was not significantly different from that of the ER-positive group. The lack of any significant finding was mainly attributed to the heterogeneity of the breast cancer tissue and to the difficulty in choline detection in diffuse enhancement-type cancers because of the intermingling of tumor cells with adipose tissues. In general, diffusive-enhancement-type cancer showed a much lower overall choline level than mass type cancer (Baek et al., 2008d), and this could also explain the lack of coherent findings. The authors concluded that in vivo quantitative 1H-MRS cannot provide useful information for characterizing ER status in breast carcinoma (Baek et al., 2008b).

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Biomarkers in Breast Cancer

Michael J. Duffy , ... John Crown , in Advances in Clinical Chemistry, 2015

3.1 Estrogen Receptor for Predicting Response to Endocrine Therapy

ER is predominantly a nuclear protein existing in two main forms, ERα and ERβ [41]. Although both forms of ER bind estradiol and the tamoxifen metabolite, endoxifen, they appear to mediate different biological activities. In particular, while ERα enhances breast cancer cell proliferation, ERβ has been reported to inhibit proliferation [41,42]. Currently, a validated clinical role has only been established for ERα which will be referred to as ER in this chapter. While the original ligand-binding ER assays are likely to have detected both ERα and ERβ, the current immunohistochemistry measurements detect only ERα.

Studies carried several decades ago showed that only approximately 30% of patients with metastatic breast cancer responded to the then available hormone therapy (oophorectomy, adrenalectomy, or high-dose steroids) [41]. However, if the ER protein was present in the primary tumor, 50–60% of patients benefited. In contrast, patients negative for ER were found to rarely respond to hormone treatment [41]. Although ER is still used to predict response to hormone therapy in advanced cancer, currently its main application is in identifying patients with early breast cancer that are sensitive to tamoxifen or an aromatase inhibitor. In this setting, the administration of adjuvant tamoxifen for approximately 5 years to patients with ER-positive invasive breast cancer was found to decrease recurrence rates by almost 50% and mortality by about 30% [43]. As in advanced disease, ER-negative patients failed to benefit from adjuvant tamoxifen.

More recently, administration of tamoxifen to ER-positive patients for 10 years was shown to be superior to treatment for 5 years [36,37]. Similarly, administration of an aromatase inhibitor to postmenopausal women for 5 years has been shown to be superior to treatment with tamoxifen for the same period of time [44–48]. For premenopausal ER-positive patients, a recent phase III study concluded that the addition of ovarian suppression to tamoxifen failed to provide a significant benefit in the overall study population. However, for patients who were deemed to be at sufficient risk for recurrence to receive adjuvant chemotherapy and who remained premenopausal, the combination of ovarian suppression and tamoxifen was found to enhance outcome [49].

Because of its critical importance in planning treatment, measurement of ER on all newly diagnoses patients with invasive breast cancer is now universally recommended [15–18] and indeed, mandatory. However, as the ER status may change between a primary tumor and a subsequently formed metastatic lesion [50], measurement should also be performed on the metastatic lesion, where feasible. Detailed guidelines for performing ER immunohistochemistry assays have been published [51].

An ongoing debate in reporting ER concentration relates to the cutoff point for defining positivity. According to the ASCO/College of American Pathologists (CAPs) guidelines, the presence of immunoreactive ER in ≥   1% of the tumor nuclei should be regarded as positive [51]. Some recent studies, however, have suggested that patients with ER staining in 1–10% of tumor nuclei behave more like ER-negative than ER-positive cancers [52,53]. Thus, Gloyeske et al. [52] showed that cancers with 1–10% positive nuclei exhibited specific morphological and biochemical features more frequently found in ER-negative than ER-positive tumors such as necrosis, inflammatory infiltrate, and absence of PRs. In another study, patients with tumors having 1–10% nuclei staining exhibited a significantly worse survival than did patients with >   10% nuclei staining, even when adjusted for tumor grade and tumor stage [53]. Indeed, survival rates were similar for patients with 1–10% nuclei staining and those totally negative for ER. These findings suggest that further research is necessary to establish the optimum cutoff point for ER in detecting endocrine-sensitive breast cancers.

PR is frequently measured alongside ER. Although the predictive potential of PR for response to adjuvant endocrine therapy is not clear [43], several different studies have shown that PR is independently prognostic in breast cancer, i.e., high levels are generally associated with a favorable outcome [54–58]. Because of its prognostic role, most published guidelines recommend simultaneous measurement of ER and PR [15–18]. Like ER, PR is also measured using immunohistochemistry [51]. However, as with ER, further work is necessary to establish the optimum cutoff point for PR [56].

It is important to state that ER and PR are not the only biomarkers used in guiding therapy in patients with breast cancer. Approximately, 7% of ER-positive patients are HER2 positive. These ER-positive and HER2-positive patients not only receive hormone therapy but are also candidates for anti-HER2 treatment, see below.

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