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Cancers
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Estrogens and Estrogen Receptor Modulators in Cancer Research and Therapy
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Estrogens and Estrogen Receptor Modulators in Cancer Research and Therapy

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Cancer Therapy".

Deadline for manuscript submissions: closed (31 July 2023) | Viewed by 11260

Special Issue Editor

Prof. Dr. Oliver Treeck

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Guest Editor
Department of Gynecology and Obstetrics I, Molecular Gynecologic Oncology, University Medical Center Regensburg, Caritas KH St. Josef, 93053 Regensburg, Germany
Interests: hormone-dependent cancer; tumors of the breast; ovary and endometrium; estrogen receptor signaling; estrogen receptor; G-protein coupled estrogen receptor 1; transcriptome analysis
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Estrogens affect oncogenesis and tumor progression in a variety of cancer entities such as prostate cancer, colorectal cancer, breast cancer, and gynecological tumors of the endometrium and ovary. Three primary mediators of estrogen actions are currently known: estrogen receptor (ER)α, ERβ, and G-protein coupled estrogen receptor 1 (GPER1). ERα triggers tumor growth in breast cancer (and other cancer types) and is thereby an established therapy target in this cancer entity. ERβ, whose function in cancer is less understood, particularly due to former problems regarding antibody specificity, is suggested to act as a partial ERα antagonist and tumor suppressor in various cancer types such as breast and prostate cancer, although further research on the function of ERβ in these and other cancer entities is required. Another level of complexity was added by the realization that the ESR1 and ESR2 genes code for multiple splice variants, which are partially translated into proteins with altered function. Increasing evidence suggests that GPER1 contributes to endocrine therapy resistance in breast cancer while also playing a complex role in a number of other cancers including melanoma. Further efforts are needed to elucidate the pleiotropic function of GPER1 in cancer. Additionally, recent evidence suggests that estrogens not only act on tumor cells but also on the function of multiple cells of the tumor microenvironment, including fibroblasts, immune cells, and adipocytes, which can greatly affect carcinogenesis. This is another important mechanism of estrogen effects in cancer, which needs further investigation.

In this Special Issue of Cancers, we aim to stimulate discussions on these topics by bringing together expert opinions from across the field. We welcome submissions (original research papers and comprehensive reviews) that cover any relevant topic, such as estrogen signaling and function in less-studied cancer types, the function of receptor splice variants in cancer, the role of ER and GPER1 in any cancer entity, the effect of ER modulators and their combinations on cancer cells, the significance of the interaction between estrogen- and growth factor signaling, or the effect of estrogens on the efficacy of targeted cancer therapy drugs.

Prof. Dr. Oliver Treeck
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-dependent cancer
  • estrogens
  • estrogen receptors
  • estrogen receptor splice variants
  • estrogen receptor modulators
  • estrogen signaling
  • cancer therapy

Published Papers (6 papers)

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Editorial

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3 pages, 172 KiB  
Editorial
Estrogens and Estrogen Receptor Modulators in Cancer Research and Therapy
by Oliver Treeck
Cancers 2023, 15(17), 4318; https://doi.org/10.3390/cancers15174318 - 29 Aug 2023
Cited by 1 | Viewed by 869
Abstract
Estrogens affect oncogenesis and tumor progression in a variety of cancer entities [...] Full article
(This article belongs to the Special Issue Estrogens and Estrogen Receptor Modulators in Cancer Research and Therapy)

Research

Jump to: Editorial, Review

14 pages, 2841 KiB  
Article
Genomic Alterations Associated with Estrogen Receptor Pathway Activity in Metastatic Breast Cancer Have a Differential Impact on Downstream ER Signaling
by Lindsay Angus, Marcel Smid, Saskia M. Wilting, Manouk K. Bos, Neeltje Steeghs, Inge R. H. M. Konings, Vivianne C. G. Tjan-Heijnen, Johanna M. G. H. van Riel, Agnes J. van de Wouw, CPCT Consortium, Edwin Cuppen, Martijn P. Lolkema, Agnes Jager, Stefan Sleijfer and John W. M. Martens
Cancers 2023, 15(17), 4416; https://doi.org/10.3390/cancers15174416 - 4 Sep 2023
Viewed by 1268
Abstract
Mutations in the estrogen receptor gene (ESR1), its transcriptional regulators, and the mitogen-activated protein kinase (MAPK) pathway are enriched in patients with endocrine-resistant metastatic breast cancer (MBC). Here, we integrated whole genome sequencing with RNA sequencing data from the same samples [...] Read more.
Mutations in the estrogen receptor gene (ESR1), its transcriptional regulators, and the mitogen-activated protein kinase (MAPK) pathway are enriched in patients with endocrine-resistant metastatic breast cancer (MBC). Here, we integrated whole genome sequencing with RNA sequencing data from the same samples of 101 ER-positive/HER2-negative MBC patients who underwent a tumor biopsy prior to the start of a new line of treatment for MBC (CPCT-02 study, NCT01855477) to analyze the downstream effects of DNA alterations previously linked to endocrine resistance, thereby gaining a better understanding of the associated mechanisms. Hierarchical clustering was performed using expression of ESR1 target genes. Genomic alterations at the DNA level, gene expression levels, and last administered therapy were compared between the identified clusters. Hierarchical clustering revealed two distinct clusters, one of which was characterized by increased expression of ESR1 and its target genes. Samples in this cluster were significantly enriched for mutations in ESR1 and amplifications in FGFR1 and TSPYL. Patients in the other cluster showed relatively lower expression levels of ESR1 and its target genes, comparable to ER-negative samples, and more often received endocrine therapy as their last treatment before biopsy. Genes in the MAPK-pathway, including NF1, and ESR1 transcriptional regulators were evenly distributed. In conclusion, RNA sequencing identified a subgroup of patients with clear expression of ESR1 and its downstream targets, probably still benefiting from ER-targeting agents. The lower ER expression in the other subgroup might be partially explained by ER activity still being blocked by recently administered endocrine treatment, indicating that biopsy timing relative to endocrine treatment needs to be considered when interpreting transcriptomic data. Full article
(This article belongs to the Special Issue Estrogens and Estrogen Receptor Modulators in Cancer Research and Therapy)
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22 pages, 3922 KiB  
Article
Cannabidiol as a Promising Adjuvant Therapy for Estrogen Receptor-Positive Breast Tumors: Unveiling Its Benefits with Aromatase Inhibitors
by Cristina Ferreira Almeida, Natércia Teixeira, Maria João Valente, Anne Marie Vinggaard, Georgina Correia-da-Silva and Cristina Amaral
Cancers 2023, 15(9), 2517; https://doi.org/10.3390/cancers15092517 - 27 Apr 2023
Cited by 3 | Viewed by 2520
Abstract
Background: Estrogen receptor-positive (ER+) breast cancer is the most diagnosed subtype, with aromatase inhibitors (AIs) being one of the therapeutic drug types used in the clinic. However, endocrine resistance may develop after prolonged treatment, and different approaches, such as combining endocrine [...] Read more.
Background: Estrogen receptor-positive (ER+) breast cancer is the most diagnosed subtype, with aromatase inhibitors (AIs) being one of the therapeutic drug types used in the clinic. However, endocrine resistance may develop after prolonged treatment, and different approaches, such as combining endocrine and targeted therapies, have been applied. Recently, we demonstrated that cannabidiol (CBD) induces anti-tumor actions in ER+ breast cancer cells by targeting aromatase and ERs. Considering this, we studied, in vitro, whether CBD when combined with AIs could improve their effectiveness. Methods: MCF-7aro cells were used and the effects on cell viability and on the modulation of specific targets were investigated. Results: CBD when combined with anastrozole (Ana) and letrozole (Let) caused no beneficial effect in comparison to the isolated AIs. In contrast, when combined with the AI exemestane (Exe), CBD potentiated its pro-cell death effects, abolished its estrogen-like effect, impaired ERα activation, and prevented its oncogenic role on the androgen receptor (AR). Moreover, this combination inhibited ERK1/2 activation, promoting apoptosis. The study of the hormonal microenvironment suggests that this combination should not be applied in early stages of ER+ breast tumors. Conclusions: Contrary to Ana and Let, this study highlights the potential benefits of combining CBD with Exe to improve breast cancer treatment and opens up the possibility of new therapeutic approaches comprising the use of cannabinoids. Full article
(This article belongs to the Special Issue Estrogens and Estrogen Receptor Modulators in Cancer Research and Therapy)
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14 pages, 2686 KiB  
Article
Sex- and Female Age-Dependent Differences in Gene Expression in Diffuse Large B-Cell Lymphoma—Possible Estrogen Effects
by Dan Huang, Mattias Berglund, Anastasios Damdimopoulos, Per Antonson, Cecilia Lindskog, Gunilla Enblad, Rose-Marie Amini and Sam Okret
Cancers 2023, 15(4), 1298; https://doi.org/10.3390/cancers15041298 - 17 Feb 2023
Cited by 2 | Viewed by 1773
Abstract
For most lymphomas, including diffuse large B-cell lymphoma (DLBCL), the male incidence is higher, and the prognosis is worse compared to females. The reasons are unclear; however, epidemiological and experimental data suggest that estrogens are involved. With this in mind, we analyzed gene [...] Read more.
For most lymphomas, including diffuse large B-cell lymphoma (DLBCL), the male incidence is higher, and the prognosis is worse compared to females. The reasons are unclear; however, epidemiological and experimental data suggest that estrogens are involved. With this in mind, we analyzed gene expression data from a publicly available cohort (EGAD00001003600) of 746 DLBCL samples based on RNA sequencing. We found 1293 genes to be differentially expressed between males and females (adj. p-value < 0.05). Few autosomal genes and pathways showed common sex-regulated expression between germinal center B-cell (GCB) and activated B-cell lymphoma (ABC) DLBCL. Analysis of differentially expressed genes between pre- vs. postmenopausal females identified 208 GCB and 345 ABC genes, with only 5 being shared. When combining the differentially expressed genes between females vs. males and pre- vs. postmenopausal females, nine putative estrogen-regulated genes were identified in ABC DLBCL. Two of them, NR4A2 and MUC5B, showed induced and repressed expression, respectively. Interestingly, NR4A2 has been reported as a tumor suppressor in lymphoma. We show that ABC DLBCL females with a high NR4A2 expression showed better survival. Inversely, MUC5B expression causes a more malignant phenotype in several cancers. NR4A2 and MUC5B were confirmed to be estrogen-regulated when the ABC cell line U2932 was grafted to mice. The results demonstrate sex- and female reproductive age-dependent differences in gene expression between DLBCL subtypes, likely due to estrogens. This may contribute to the sex differences in incidence and prognosis. Full article
(This article belongs to the Special Issue Estrogens and Estrogen Receptor Modulators in Cancer Research and Therapy)
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13 pages, 1748 KiB  
Article
E3 Ubiquitin Ligase NEDD4 Affects Estrogen Receptor α Expression and the Prognosis of Patients with Hormone Receptor-Positive Breast Cancer
by Yutaka Natori, Junko Suga, Emi Tokuda, Kazunoshin Tachibana, Jun-ichi Imai, Reiko Honma, Yusuke Azami, Masaru Noda, Eisaku Sasaki, Shinya Watanabe, Tohru Ohtake and Shigehira Saji
Cancers 2023, 15(2), 539; https://doi.org/10.3390/cancers15020539 - 16 Jan 2023
Cited by 1 | Viewed by 1929
Abstract
Neural precursor cell-expressed developmentally downregulated 4–1 (NEDD4) is an E3 ligase that leads to the degradation of proteins, including estrogen receptor α. We evaluated whether the expression level of NEDD4 affected the outcome of breast cancer patients. We performed a retrospective cohort study [...] Read more.
Neural precursor cell-expressed developmentally downregulated 4–1 (NEDD4) is an E3 ligase that leads to the degradation of proteins, including estrogen receptor α. We evaluated whether the expression level of NEDD4 affected the outcome of breast cancer patients. We performed a retrospective cohort study enrolling 143 patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative early breast cancer. Of the 66 patients with high NEDD4 mRNA levels (high NEDD4 group) and 77 patients with low NEDD4 mRNA levels (low NEDD4 group), 98.4% and 96.1%, respectively, of the patients had received neoadjuvant/adjuvant hormone therapy. Disease-free survival and overall survival were significantly longer in the low NEDD4 group than in the high NEDD4 group (p = 0.048 and p = 0.022, respectively). Western blotting revealed a high expression of estrogen receptor α in the NEDD4-knockdown culture cells. The proliferation of NEDD4-knockdown cells treated with tamoxifen or estradiol deprivation was suppressed, compared with that of NEDD4-expressing cells. Knockdown of NEDD4 in breast cancer cells induced the accumulation of estrogen receptor α and increased sensitivity to hormone therapy. In summary, this mechanism may lead to a better prognosis in hormone receptor-positive breast cancer patients with a low expression of NEDD4. Full article
(This article belongs to the Special Issue Estrogens and Estrogen Receptor Modulators in Cancer Research and Therapy)
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Review

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30 pages, 879 KiB  
Review
Non-Coding RNAs Modulating Estrogen Signaling and Response to Endocrine Therapy in Breast Cancer
by Oliver Treeck, Silke Haerteis and Olaf Ortmann
Cancers 2023, 15(6), 1632; https://doi.org/10.3390/cancers15061632 - 7 Mar 2023
Cited by 7 | Viewed by 2068
Abstract
The largest part of human DNA is transcribed into RNA that does not code for proteins. These non-coding RNAs (ncRNAs) are key regulators of protein-coding gene expression and have been shown to play important roles in health, disease and therapy response. Today, endocrine [...] Read more.
The largest part of human DNA is transcribed into RNA that does not code for proteins. These non-coding RNAs (ncRNAs) are key regulators of protein-coding gene expression and have been shown to play important roles in health, disease and therapy response. Today, endocrine therapy of ERα-positive breast cancer (BC) is a successful treatment approach, but resistance to this therapy is a major clinical problem. Therefore, a deeper understanding of resistance mechanisms is important to overcome this resistance. An increasing amount of evidence demonstrate that ncRNAs affect the response to endocrine therapy. Thus, ncRNAs are considered versatile biomarkers to predict or monitor therapy response. In this review article, we intend to give a summary and update on the effects of microRNAs (miRNAs), long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs) on estrogen signaling in BC cells, this pathway being the target of endocrine therapy, and their role in therapy resistance. For this purpose, we reviewed articles on these topics listed in the PubMed database. Finally, we provide an assessment regarding the clinical use of these ncRNA types, particularly their circulating forms, as predictive BC biomarkers and their potential role as therapy targets to overcome endocrine resistance. Full article
(This article belongs to the Special Issue Estrogens and Estrogen Receptor Modulators in Cancer Research and Therapy)
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