Receptors
Hormone receptors play a key role in regulating the growth and differentiation of breast epithelium and hormone receptor status is a prognostic indicator in invasive carcinoma. The expression of hormone receptors as determined by immunohistochemical stains indicates that the cells retain the ability to be manipulated by exogenous hormone therapy.
Estrogen receptors (ER) and progesterone receptors (PR) are uniformly expressed in normal breast tissue, ductal hyperplasia of the usual type, and ADH. In DCIS, there is less uniform expression, particularly in the higher-grade lesions. The overall expression of estrogen receptors in DCIS is about 75%.8 In current practice in the United States, estrogen receptor is reported for cases of DCIS. Although HER2/neu is not assessed currently in cases of DCIS, it is known to be overexpressed in high-grade DCIS.
Patients with DCIS have a relative risk of 8 to 11 for developing invasive breast carcinoma—more so in the ipsilateral breast.8
Receptors
ETH receptors identified in D. melanogaster are G-protein-coupled receptors.29,30 A single gene (CG5911) containing 5 exons encodes two ETH receptor subtypes through alternative splicing of two 3′ exons to generate CG5911a and CG5911b. Phylogenetic analysis shows that CG5911 is most closely related to vertebrate thyrotropin releasing hormone and neuromedin receptors, as well as to Drosophila receptors for PBAN-like pyrokinin receptors.
ETH receptors are coupled to Gαq, which mobilizes calcium from intracellular stores via the phosphoinositide turnover pathway. Pharmacological profiles of ETH receptors were determined by heterologous expression in mammalian CHO cells using aequorin as an intracellular calcium reporter. ETH receptors in Drosophila show high sensitivity and selectivity to fly and moth ETHs. Remarkably, CG5911b shows a considerably higher sensitivity to ETH1 and ETH2 as compared with CG5911a. Both DrmETH1 and DrmETH2 activate CG5911b with EC50 values of approximately 1 nM. By contrast, ETH1 and ETH2 activate CG5911a with EC50 values of approximately 400 nM and approximately 4 µM, respectively.11 Thus, although CG5911b is more sensitive to the cognate ETH ligands than CG5911a, the latter is more discriminating between ETH1 and ETH2.
ETH receptors were subsequently sequenced and pharmacologically characterized in the moth, M. sexta.9 As in Drosophila, two receptor subtypes (ETHR-A, ETHR-B) are produced through alternative splicing of 3′ exons. Both receptor subtypes are specific for ETH peptides; PETH and ETH show EC50 values for ETHR-A of 33 and 17 nM. For ETHR-B, PETH and ETH show EC50 values of 10 and 30 nM, respectively. Thus, unlike their Drosophila orthologs, Manduca ETH receptors have similar sensitivity to ETH ligands.
ETH receptors have been cloned and expressed in the yellow fever mosquito, A. aegypti.3 As previously reported for Drosophila and Manduca, Aedes receptors occur as two subtypes (AeaETHR-A and AeaETHR-B) by alternative splicing of 3′ exons. Pharmacological profiling of the mosquito receptors revealed that, like the Manduca receptors, both receptor subtypes have comparable sensitivities to ETH ligands.
Expression of ETH receptors in Manduca and Aedes coincides with the surge of ecdysteroids that initiates molting. This association supports previous evidence for a causal relationship between ecdysteroid elevation and onset of sensitivity of the CNS to ETH in Manduca.35
ETHR-A receptors are expressed in discrete sets of central neurons in moths and flies. The majority of these are "peptidergic ensembles" that release peptides involved in scheduling of successive steps of the ecdysis behavioral sequence (see below). For example, subsets of ETH receptor neurons in Drosophila release FMRFamide, kinin, or eclosion hormone. Other ensembles co-release myoinhibitory peptides (MIPs), CCAP, and bursicon. In Manduca, one ensemble co-releases kinin and CRF-like diuretic hormone, whereas another releases CCAP, MIPs, sNPF and MIPs, or calcitonin-like DH31 and MIPs.
ETH receptors have been found widely in the Insecta using in silico screening17 (see the chapter in the Peptide Biosynthesis/Processing section of the book). This approach also has led to their discovery in representative species from the Crustacea (Daphnia) and Arachnida (Ixodes). Interestingly, ETH receptor subtypes in Ixodes are predicted to arise through the expression of two distinct genes. This differs from all other species examined, where subtype diversity occurs through alternative splicing of pre-RNAs.
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Hormone Receptor and Human Epidermal Growth Factor Receptor 2 Co-expressing Tumors
Debora de Melo Gagliato MD, ... Javier Cortes MD, PhD, in Her2-Positive Breast Cancer, 2019
Introduction
Hormone receptor (HR) and human epidermal growth factor receptor 2 (HER2) are important drivers of breast cancer (BC) biology. Amplification or overexpression of HER2 is found in approximately 15%–20% of human BCs. Of note, approximately half of tumors that harbor HER2 amplification also display HR positivity.1,2 On the basis of genomic profiling, HER2+ tumors are highly heterogeneous. Different intrinsic molecular subtypes, including luminal A and B, can be found among HR+ and HER2+ BC patients, enabling delineation of distinct treatment strategies for each specific subtype.
Both estrogen receptor (ER) and HER2 signaling pathways might interact through a bidirectional cross talk. In this interaction, ER can be activated regardless of direct estrogen interaction with ER α and β, over a variety of kinases, including mitogen-activated protein kinases and protein kinase B (Akt), resulting in phosphorylation of specific sites of the ER.3 In this process, ligand-independent ER activation is achieved, leading to the transcription of genes that may promote proliferation, cell survival, and resistance to treatment.3–5
Observation of in vitro cell line experiments and analysis of published trial data suggest that HER2 expression might confer resistance and poor response to antiestrogen therapies.5,6 As an example, a small retrospective analysis of a neoadjuvant (NAT) trial suggested that women with HER2+ tumors (by fluorescence in situ hybridization [FISH]), who received NAT letrozole, experienced significantly less Ki-67 suppression compared with the FISH-negative cohort.7
The paradigm of "intrinsic" endocrine resistance, combined with the doctrine of treating all HER2+ BC patients equally, has lead to a plethora of clinical trials in which the combination of HER2 therapy with chemotherapy was the mainstay of treatment in different disease scenarios, regardless of ER status and biologic characterization. Indeed, many large phase III randomized clinical trials demonstrated that patients with HR-positive disease derived as much benefit as those with HR-negative disease from the addition of trastuzumab to chemotherapy.8,9 Therefore, there is no evidence that the efficacy of trastuzumab is different according to the HR status of the primary tumor, and the benefit of trastuzumab is also noted in overall survival in both subgroups of ER status.9–11
Although the majority of clinical trials in HER2+ explored HER2-targeting strategies in combination with cytotoxic agents, strategies focused on the combination of ER and other targeted therapies in combination with anti-HER2 therapies are being increasingly explored. This strategy might have the potential to spare patients from short- and long-term toxicities from cytotoxic agents.12–15
In term of prognosis, compared with patients with HR-negative tumors, patients with co-expressing HR and HER2 tumors seem to have better disease-free survival (DFS) and overall survival. This finding appeared to be independent of therapy received and of classical anatomic pathologic characteristics.16,17 Despite overexpression of the HER2 oncogene, HR status is still a determinant of disease outcome, with many trials demonstrating more recurrences and deaths in women with HER2+ HR-negative disease and also differences in time patterns of disease recurrence.9,18
Taking into account our current knowledge of tumor biology, the approach of considering all HER2+ BCs as a uniform disease group, with no distinction based on ER status, should change. This chapter will discuss different treatment strategies and provide a detailed characterization of the group of HR+/HER2+ tumors.
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Delayed Puberty and Hypogonadism, Male
Dennis M. Styne, in Encyclopedia of Endocrine Diseases, 2004
LHRH Receptor Mutations
LHRH receptor mutations are reported in familial and sporadic patients and lead to various degrees of hypogonadotropic hypogonadism with normosmia. In the autosomal-recessive form, there are heterozygous or homozygous mutations in the LHRH receptor. The patients may present with severe features of isolated hypogonadotropic hypogonadism, sexual infantilism, ranging to delayed puberty, or relatively mild hypogonadism and infertility. The clinical variants include the fertile eunuch variant. In all types of congenital gonadotropin deficiency, male patients are likely to manifest micropenis due to a lack of fetal gonadotropin stimulation of fetal testes during the last half of gestation. Micropenis may also occur in boys with congenital growth hormone deficiency.
No mutations of the LHRH genes have been reported.
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Endocrinology and Behavior: Methods
K.L. Ayres, in Encyclopedia of Animal Behavior, 2010
Hormone Receptors
Hormone receptors are proteins that bind hormones. Once bound, the hormone/receptor complex initiates a cascade of cellular effects resulting in some modification of physiology and/or behavior. Hormones usually require receptor binding to mediate a cellular response. Receptor binding and the associated cellular cascades amplify the hormone signal allowing hormones to act at very low concentrations, sometimes as low as parts per trillion! Scientists who study hormone receptors are interested in the cells and tissues that possess the receptors (i.e., the ovary, the testis, the stomach lining, specific parts of the brain, etc.). The location of the receptor shows where the hormone should be biologically active.
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Overcoming Endocrine Resistance in Breast Cancer
Paola Ferrari, Andrea Nicolini, in Oncogenomics, 2019
Introduction
Hormone receptor (HR)-positive breast cancer represents approximately 75%–80% of breast tumors; it is predominantly estrogen receptor-positive (ER+) and, to a lesser extent, progesterone receptor-positive (PR+) (Anderson, Chatterjee, Ershler, & Brawley, 2002; Cancer Genome Atlas Network et al., 2012; Huang et al., 2005). HR expression is an important prognostic indicator in breast cancer and a determinant of systemic treatment selection (Mestres et al., 2017). Endocrine therapy is the mainstay in HR+ breast cancer treatment (Cardoso, Costa, & Norton, 2014; Gradishar et al., 2016). In first-line setting, response rates to antiestrogenic agents range from 20% to 40%, with a median duration of response of 14 months. In second-line treatment, the response rates are less than 10%, with a median progression-free survival (PFS) of approximately 4 months (Augereau et al., 2017). Unfortunately, not all patients respond to first-line endocrine therapy due to intrinsic resistance, whereas others may initially respond but eventually progress because of secondary acquired resistance (Osborne & Schiff, 2011). In an attempt to delay the raising of resistance or even reverse it, many agents targeting several cell processes have been combined with endocrine treatment. Advanced/metastatic breast cancer (MBC) is the main clinical model in which these combinations are being tested.
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Handbook of Immunohistochemistry and in situ Hybridization of Human Carcinomas, Volume 3
Thomas Rüdiger, Hans Konrad Müller-Hermelink, in Handbook of Immunohistochemistry and in Situ Hybridization of Human Carcinomas, 2005
Estrogen and Progesterone Receptors
Hormone receptor detection in breast carcinoma is a prerequisite for antihormone (tamoxifen) treatment: 50–60% of estrogen receptor positive but only 5% of negative breast carcinomas respond to a hormone treatment. Being originally based on enzyme immunoassays, the gold standard for hormone receptors has transmutated to IHC, which is more sensitive, specific, and economical (Zafrani et al., 2000). As a morphology-based method IHC allows distinguishing between reactivity originating from the tumor itself and activity originating from reactive tissues.
Despite very good results in unicentric studies, hormone receptor expression is still not measured reproducibly: In a U.K. NEQUAS (National External Quality Assessment Scheme) study including 200 laboratories in 26 countries, reproducible results over a 2-year period could only be achieved in 24 of 66 laboratories. Of the laboratories, 80% could demonstrate receptor positivity in medium- and high-expressing tumors, but only 37% revealed it in low-expressing tumors (Rhodes et al., 2000c). The latter low-expressing tumors are problematic in all studies (Mengel et al., 2002; von Wasielewski et al., 2002). Compared to these tumors sent to the laboratories externally, their pass rate on in-house tumors was 81–97% (Rhodes et al., 2000c). However, there was a significant positive correlation between performance in both external and in-house tumors of the study. Underachievement was usually the result of overall staining sensitivity but neither of scoring nor the assay system used. The variability between laboratories increased if the participants used their own threshold values. Because there was also a significant correlation between the assay sensitivity and the reported frequency of receptor positivity (Rhodes et al., 2000a), as a minimum requirement of quality control the latter should be noted in every institution and steps should be taken if it is too low (Table 6).
Table 6. Frequency of positive results for hormone receptors in breast carcinoma in larger studies (Rhodes et al., 2000a; Zafrani et al., 2000)
Estrogen receptorProgesterone receptor%++55+–20–+3––22+59–78+52–71
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Hormones and Breast Cancer
Sebastián Giulianelli, ... Claudia Lanari, in Vitamins & Hormones, 2013
Abstract
Hormone receptors represent the earliest biomarkers used in breast cancer not only as prognosis markers but, in addition, to decide treatment. However, mostly estrogen receptors have been used as therapeutic targets. There is compelling evidence indicating that progesterone receptors (PRs) play a hierarchical role in breast cancer growth and that they might be potentially used to improve the success of endocrine treatments. The two PR isoforms, PR-A and PR-B, play differential roles in regulating gene expression. Tumors overexpressing one or other PR isoform may respond different to endocrine treatment. In this chapter, we highlight the evidence regarding progestins as promoters or inhibitors of cell proliferation in order to understand the dual role of PR in regulating tumor growth, underscoring thus the need of biomarkers to identify which patients may benefit with an antiprogestin/progestin treatment.
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Adjuvant Endocrine Therapy
Karen Lisa Smith, Vered Stearns, in The Breast (Fifth Edition), 2018
Determining the Duration of Therapy: Biomarkers for Late Recurrence
Hormone receptor–positive breast cancer can recur many years after diagnosis.5,87,88 As noted earlier, extended adjuvant endocrine therapy reduces the risk of recurrence; however, such treatment may involve extended treatment-associated toxicities.8,36,52,53 Ideally, a tool to identify individuals who are disease free after 5 years of adjuvant therapy, face high risk for late recurrence, and can benefit from extended adjuvant therapy would guide patient selection for extended therapy. To date, several tools have been developed that can identify individuals at risk for late relapse. For example, the breast cancer index (BCI) assay, a gene expression–based signature, identifies patients with hormone receptor–positive node-negative early-stage breast cancer at risk for both early (within 5 years) and late recurrence (>5 years).89,90 Similarly, one of the implications of the PAM50 risk of recurrence (ROR) score, based on a 46-gene subset of the PAM50 genes plus tumor size, and of the EndoPredict gene expression signature is that both may identify patients at risk for late recurrence.91,92 Recent data also suggest that higher ER mRNA expression on the Oncotype Dx test may be a prognostic factor to identify women at increased risk of late recurrence.93 However, although prognostic, there are only limited data currently supporting the use of these biomarkers for predicting benefit of extended adjuvant endocrine therapy. Furthermore, given the ongoing risk of late recurrence and the carryover effect of adjuvant endocrine therapy, data regarding risks of recurrence beyond 10 years are required to better identify those at risk for late recurrence and those who may benefit from extended therapy.
Methods in Enzymology
Volume 150, 1987, Pages 615-627
C5a receptor☆
Author links open overlay panelR.HueyT.E.Hugli
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Publisher Summary
This chapter focuses on the characterization of a membrane component specific for binding the ligand C5a and describes methods used to identify the neutrophil C5a receptor. A membrane component has been identified on the neutrophil surface having a binding specificity for the chemotactic factor C5a. The C5a receptor on human neutrophils (polymorphonuclear leukocytes) is directly involved in mediating chemotactic responses of these cells, as well as inducing changes in cellular aggregation, in intracellular oxygen metabolism and Ca2+ mobilization, and an up-regulated expression of phagocytic receptors. Activation events in the neutrophil mediated by the C5a ligand are common mechanisms of the host response system. The criterion for specificity of C5a binding to a neutrophil receptor was supported by the fact that neither human C3a nor C4a, close chemical analogs of the ligand C5a, bind or compete with C5a for the putative receptor. These studies lead to the more recent identification and characterization of a cellular receptor specific for C5a on the human neutrophil.