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Cancers
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Estrogen Receptor (ER) Signalling Pathway in Cancers
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Estrogen Receptor (ER) Signalling Pathway in Cancers

A special issue of Cancers (ISSN 2072-6694).

Deadline for manuscript submissions: closed (29 February 2020) | Viewed by 41597

Special Issue Editor

Dr. Simon Langdon

E-Mail Website
Guest Editor
Cancer Research UK Edinburgh Centre, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Crewe Road South, Edinburgh EH4 2XR, UK
Interests: ovarian cancer; cell signaling; experimental therapeutics
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear colleagues,

The importance of estrogen receptor signalling is well recognised in estrogen-dependent cancers, most notably in breast cancer. The two major estrogen receptor subtypes (ERα and ERβ) regulate different functions and actions. While the genomic role of these receptors has long been recognised to mediate transcription through DNA binding, there has also been increasing recognition of the nongenomic role of the cell membrane receptor GPER1 (GPR30). Cell signalling pathways that cross-talk with estrogen signalling are important in influencing the dominance of this pathway within cancer cells and will influence estrogen (and anti-estrogen) sensitivity. Further understanding of these interacting pathways is required to bypass resistance and to help develop therapeutic strategies for hormone-resistant cancers. 

This Special Issue welcomes original articles and reviews related to estrogen receptor signalling and also pathways that interact and cross-talk with estrogen signaling, giving rise to hormone resistance in cancer.

Dr. Simon Langdon
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • estrogen receptor
  • cell signaling
  • human cancers
  • pathway cross-talk
  • anti-estrogen

Published Papers (8 papers)

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Editorial

Jump to: Research, Review

3 pages, 145 KiB  
Editorial
Estrogen Receptor Signaling in Cancer
by Simon P. Langdon
Cancers 2020, 12(10), 2744; https://doi.org/10.3390/cancers12102744 - 24 Sep 2020
Cited by 11 | Viewed by 2020
Abstract
Estrogen receptor signaling plays Full article
(This article belongs to the Special Issue Estrogen Receptor (ER) Signalling Pathway in Cancers)

Research

Jump to: Editorial, Review

18 pages, 3227 KiB  
Article
The Histone Methyltransferase DOT1L Is a Functional Component of Estrogen Receptor Alpha Signaling in Ovarian Cancer Cells
by Annamaria Salvati, Valerio Gigantino, Giovanni Nassa, Giorgio Giurato, Elena Alexandrova, Francesca Rizzo, Roberta Tarallo and Alessandro Weisz
Cancers 2019, 11(11), 1720; https://doi.org/10.3390/cancers11111720 - 4 Nov 2019
Cited by 24 | Viewed by 3675
Abstract
Although a large fraction of high-grade serous epithelial ovarian cancers (OCs) expresses Estrogen Receptor alpha (ERα), anti-estrogen-based therapies are still not widely used against these tumors due to a lack of sufficient evidence. The histone methyltransferase Disruptor of telomeric silencing-1-like (DOT1L), which is [...] Read more.
Although a large fraction of high-grade serous epithelial ovarian cancers (OCs) expresses Estrogen Receptor alpha (ERα), anti-estrogen-based therapies are still not widely used against these tumors due to a lack of sufficient evidence. The histone methyltransferase Disruptor of telomeric silencing-1-like (DOT1L), which is a modulator of ERα transcriptional activity in breast cancer, controls chromatin functions involved in tumor initiation and progression and has been proposed as a prognostic OC biomarker. As molecular and clinico-pathological data from TCGA suggest a correlation between ERα and DOT1L expression and OC prognosis, the presence and significance of ERα/DOT1L association was investigated in chemotherapy-sensitive and chemotherapy-resistant ER+ OC cells. RNA sequencing before and after inhibition of these factors showed that their activity is implicated in OC cell proliferation and that they functionally cooperate with each other to control the transcription of genes involved in key cancer cell features, such as the cell cycle, epithelial-mesenchymal transition (EMT), drug metabolism, and cell-to-cell signaling, as well as expression of the ERα gene itself. Together with evidence from loss-of-function genetic screens showing that ERα and DOT1L behave as core fitness factors in OC cells, these results suggest that combined inhibition of their activity might be effective against ERα-expressing, chemotherapy-resistant ovarian tumors. Full article
(This article belongs to the Special Issue Estrogen Receptor (ER) Signalling Pathway in Cancers)
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18 pages, 1625 KiB  
Article
The Histone Demethylase Enzymes KDM3A and KDM4B Co-Operatively Regulate Chromatin Transactions of the Estrogen Receptor in Breast Cancer
by Dominic Jones, Laura Wilson, Huw Thomas, Luke Gaughan and Mark A. Wade
Cancers 2019, 11(8), 1122; https://doi.org/10.3390/cancers11081122 - 6 Aug 2019
Cited by 15 | Viewed by 5193
Abstract
Many estrogen receptor (ER)-positive breast cancers develop resistance to endocrine therapy but retain canonical receptor signalling in the presence of selective ER antagonists. Numerous co-regulatory proteins, including enzymes that modulate the chromatin environment, control the transcriptional activity of the ER. Targeting ER co-regulators [...] Read more.
Many estrogen receptor (ER)-positive breast cancers develop resistance to endocrine therapy but retain canonical receptor signalling in the presence of selective ER antagonists. Numerous co-regulatory proteins, including enzymes that modulate the chromatin environment, control the transcriptional activity of the ER. Targeting ER co-regulators has therefore been proposed as a novel therapeutic approach. By assessing DNA-binding dynamics in ER-positive breast cancer cells, we have identified that the histone H3 lysine 9 demethylase enzymes, KDM3A and KDM4B, co-operate to regulate ER activity via an auto-regulatory loop that facilitates the recruitment of each co-activating enzyme to chromatin. We also provide evidence that suggests that KDM3A primes chromatin for deposition of the ER pioneer factor FOXA1 and recruitment of the ER-transcriptional complex, all prior to ER recruitment, therefore establishing an important mechanism of chromatin regulation involving histone demethylases and pioneer factors, which controls ER functionality. Importantly, we show via global gene-expression analysis that a KDM3A/KDM4B/FOXA1 co-regulated gene signature is enriched for pro-proliferative and ER-target gene sets, suggesting that abrogation of this network could be an efficacious therapeutic strategy. Finally, we show that depletion of both KDM3A and KDM4B has a greater inhibitory effect on ER activity and cell growth than knockdown of each individual enzyme, suggesting that targeting both enzymes represents a potentially efficacious therapeutic option for ER-driven breast cancer. Full article
(This article belongs to the Special Issue Estrogen Receptor (ER) Signalling Pathway in Cancers)
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Review

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17 pages, 606 KiB  
Review
Estrogen Signaling and Its Potential as a Target for Therapy in Ovarian Cancer
by Simon P. Langdon, C. Simon Herrington, Robert L. Hollis and Charlie Gourley
Cancers 2020, 12(6), 1647; https://doi.org/10.3390/cancers12061647 - 22 Jun 2020
Cited by 57 | Viewed by 5512
Abstract
The estrogen receptor (ER) has functionality in selected ovarian cancer subtypes and represents a potential target for therapy. The majority (>80%) of high grade serous, low grade serous and endometrioid carcinomas and many granulosa cell tumors express ER-alpha (ERα), and these tumor types [...] Read more.
The estrogen receptor (ER) has functionality in selected ovarian cancer subtypes and represents a potential target for therapy. The majority (>80%) of high grade serous, low grade serous and endometrioid carcinomas and many granulosa cell tumors express ER-alpha (ERα), and these tumor types have demonstrated responses to endocrine therapy (tamoxifen and aromatase inhibitors) in multiple clinical studies. Biomarkers of responses to these drugs are actively being sought to help identify responsive cancers. Evidence for both pro-proliferative and pro-migratory roles for ERα has been obtained in model systems. ER-beta (ERβ) is generally considered to have a tumor suppressor role in ovarian cancer cells, being associated with the repression of cell growth and invasion. The differential expression of the specific ERβ isoforms may determine functionality within ovarian cancer cells. The more recently identified G protein-coupled receptor (GPER1; GPR30) has been shown to mediate both tumor-suppressive and tumor-promoting action in ovarian cancer cells, suggesting a more complex role. This review will summarize recent findings in this field. Full article
(This article belongs to the Special Issue Estrogen Receptor (ER) Signalling Pathway in Cancers)
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24 pages, 4708 KiB  
Review
Current Landscape of Breast Cancer Imaging and Potential Quantitative Imaging Markers of Response in ER-Positive Breast Cancers Treated with Neoadjuvant Therapy
by Ella F. Jones, Deep K. Hathi, Rita Freimanis, Rita A. Mukhtar, A. Jo Chien, Laura J. Esserman, Laura J. van’t Veer, Bonnie N. Joe and Nola M. Hylton
Cancers 2020, 12(6), 1511; https://doi.org/10.3390/cancers12061511 - 9 Jun 2020
Cited by 11 | Viewed by 8628
Abstract
In recent years, neoadjuvant treatment trials have shown that breast cancer subtypes identified on the basis of genomic and/or molecular signatures exhibit different response rates and recurrence outcomes, with the implication that subtype-specific treatment approaches are needed. Estrogen receptor-positive (ER+) breast cancers present [...] Read more.
In recent years, neoadjuvant treatment trials have shown that breast cancer subtypes identified on the basis of genomic and/or molecular signatures exhibit different response rates and recurrence outcomes, with the implication that subtype-specific treatment approaches are needed. Estrogen receptor-positive (ER+) breast cancers present a unique set of challenges for determining optimal neoadjuvant treatment approaches. There is increased recognition that not all ER+ breast cancers benefit from chemotherapy, and that there may be a subset of ER+ breast cancers that can be treated effectively using endocrine therapies alone. With this uncertainty, there is a need to improve the assessment and to optimize the treatment of ER+ breast cancers. While pathology-based markers offer a snapshot of tumor response to neoadjuvant therapy, non-invasive imaging of the ER disease in response to treatment would provide broader insights into tumor heterogeneity, ER biology, and the timing of surrogate endpoint measurements. In this review, we provide an overview of the current landscape of breast imaging in neoadjuvant studies and highlight the technological advances in each imaging modality. We then further examine some potential imaging markers for neoadjuvant treatment response in ER+ breast cancers. Full article
(This article belongs to the Special Issue Estrogen Receptor (ER) Signalling Pathway in Cancers)
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15 pages, 2806 KiB  
Review
Estrogen Receptors Alpha and Beta in Acute Myeloid Leukemia
by Alessia Roma and Paul A. Spagnuolo
Cancers 2020, 12(4), 907; https://doi.org/10.3390/cancers12040907 - 8 Apr 2020
Cited by 18 | Viewed by 4917
Abstract
Estrogen receptor (ER) signaling has been widely studied in a variety of solid tumors, where the differential expression of ERα and ERβ subtypes can impact prognosis. ER signaling has only recently emerged as a target of interest in acute myeloid leukemia (AML), an [...] Read more.
Estrogen receptor (ER) signaling has been widely studied in a variety of solid tumors, where the differential expression of ERα and ERβ subtypes can impact prognosis. ER signaling has only recently emerged as a target of interest in acute myeloid leukemia (AML), an aggressive hematological malignancy with sub-optimal therapeutic options and poor clinical outcomes. In a variety of tumors, ERα activation has proliferative effects, while ERβ targeting results in cell senescence or death. Aberrant ER expression and hypermethylation have been characterized in AML, making ER targeting in this disease of great interest. This review describes the expression patterns of ERα and ERβ in AML and discusses the differing signaling pathways associated with each of these receptors. Furthermore, we assess how these signaling pathways can be targeted by various selective estrogen receptor modulators to induce AML cell death. We also provide insight into ER targeting in AML and discuss pending questions that require further study. Full article
(This article belongs to the Special Issue Estrogen Receptor (ER) Signalling Pathway in Cancers)
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15 pages, 673 KiB  
Review
The Emerging Role of ESR1 Mutations in Luminal Breast Cancer as a Prognostic and Predictive Biomarker of Response to Endocrine Therapy
by Irene De Santo, Amelia McCartney, Ilenia Migliaccio, Angelo Di Leo and Luca Malorni
Cancers 2019, 11(12), 1894; https://doi.org/10.3390/cancers11121894 - 28 Nov 2019
Cited by 52 | Viewed by 4934
Abstract
Mutations in the hotspot ligand-binding domain of the estrogen receptor (ER) gene ESR1 have recently been recognized as mechanisms of endocrine resistance in endocrine receptor-positive metastatic breast cancer (MBC). Accumulating data suggest these mutations develop under the selective pressure of endocrine treatments, and [...] Read more.
Mutations in the hotspot ligand-binding domain of the estrogen receptor (ER) gene ESR1 have recently been recognized as mechanisms of endocrine resistance in endocrine receptor-positive metastatic breast cancer (MBC). Accumulating data suggest these mutations develop under the selective pressure of endocrine treatments, and are infrequent in untreated ER-positive breast cancers. In vitro studies show that these mutations confer ligand-independent activity, resistance to estrogen deprivation, and relative resistance to tamoxifen and fulvestrant. Post-hoc retrospective and prospective analyses of ESR1 mutations in patients with MBC have consistently found that these mutations are markers of poor prognosis and predict resistance to aromatase inhibitors (AIs). These results warrant further investigation and prospective validation in dedicated studies. Moreover, studies are ongoing to clarify the activity of novel drugs in the context of metastatic endocrine resistant luminal breast cancer harboring ESR1 mutations. In this review, we summarize the pre-clinical and clinical findings defining the characteristics of ESR1 mutant breast cancer, and highlight the potential clinical developments in this field. Full article
(This article belongs to the Special Issue Estrogen Receptor (ER) Signalling Pathway in Cancers)
17 pages, 1502 KiB  
Review
Estrogen Receptors in Epithelial-Mesenchymal Transition of Prostate Cancer
by Erika Di Zazzo, Giovanni Galasso, Pia Giovannelli, Marzia Di Donato, Antonio Bilancio, Bruno Perillo, Antonio A. Sinisi, Antimo Migliaccio and Gabriella Castoria
Cancers 2019, 11(10), 1418; https://doi.org/10.3390/cancers11101418 - 23 Sep 2019
Cited by 40 | Viewed by 5665
Abstract
Prostate cancer (PC) remains a widespread malignancy in men. Since the androgen/androgen receptor (AR) axis is associated with the pathogenesis of prostate cancer, suppression of AR-dependent signaling by androgen deprivation therapy (ADT) still represents the primary intervention for this disease. Despite the initial [...] Read more.
Prostate cancer (PC) remains a widespread malignancy in men. Since the androgen/androgen receptor (AR) axis is associated with the pathogenesis of prostate cancer, suppression of AR-dependent signaling by androgen deprivation therapy (ADT) still represents the primary intervention for this disease. Despite the initial response, prostate cancer frequently develops resistance to ADT and progresses. As such, the disease becomes metastatic and few therapeutic options are available at this stage. Although the majority of studies are focused on the role of AR signaling, compelling evidence has shown that estrogens and their receptors control prostate cancer initiation and progression through a still debated mechanism. Epithelial versus mesenchymal transition (EMT) is involved in metastatic spread as well as drug-resistance of human cancers, and many studies on the role of this process in prostate cancer progression have been reported. We discuss here the findings on the role of estrogen/estrogen receptor (ER) axis in epithelial versus mesenchymal transition of prostate cancer cells. The pending questions concerning this issue are presented, together with the impact of the available data in clinical management of prostate cancer patients. Full article
(This article belongs to the Special Issue Estrogen Receptor (ER) Signalling Pathway in Cancers)
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