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The Role of Estrogen and Its Receptors in the Development and Therapy of Cancer

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Oncology".

Deadline for manuscript submissions: 20 December 2024 | Viewed by 15709

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Dr. Margalida Torrens-Mas

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Grupo Multidisciplinar de Oncología Traslacional, Universitat de les Illes Balears, 07120 Palma, Spain
Interests: mitochondria; breast cancer; oxidative stress; inflammation; metastasis
Special Issues, Collections and Topics in MDPI journals

Dr. Mercedes Nadal-Serrano

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1. Grupo Multidisciplinar de Oncología Traslacional, Institut Universitari d’Investigació en Ciències de la Salut (IUNICS), Universitat de les Illes Balears, Palma, Illes Balears, Spain
2. Instituto de Investigación Sanitaria de las Islas Baleares (IdISBa), Hospital Universitario Son Espases, Edificio S, Palma, Illes Balears, Spain
Interests: oncology; breast cancer; oxidative stress; mitochondria; senescence; antibody–drug conjugates; drug resistance
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Estrogens are steroid hormones that exert a wide variety of effects on the growth, development, and differentiation of different tissues. However, they also affect the oncogenic process and have a key role in several hormone-dependent cancers, such as breast and ovarian cancer. The action of estrogens is mediated through its binding to estrogen receptors (ER). Three different subtypes of ER have been described: ERα, ERβ, and G protein-coupled estrogen receptor 1 (GPER1). These receptors can either trigger a genomic response through the modulation of gene transcription or non-genomic effects through the modulation of several protein kinases. The molecular mechanisms underlying the role of ER remain to be elucidated. For instance, ERα has been associated with increased tumor cell proliferation, while ERβ seems to induce apoptosis and cell differentiation. Thus, the ratio between these two receptors becomes crucial to determine the effects of estrogens in cancer cells. Furthermore, GPER1 has been associated with the maintenance of cancer stem cells and resistance to anticancer therapies.

This Special Issue aims to gain insight into the roles of estrogens and estrogen receptors in different types of cancer, tumor development, progression, and metastasis. We welcome original research papers and reviews covering, but not limited to the following research questions:

Molecular mechanisms of estrogen–ER signaling and function in cancer cells;
Mechanisms of resistance to anticancer therapy modulated by estrogens and ER;
Modulation of ER expression and its influence on tumor progression.

Dr. Margalida Torrens-Mas
Dr. Mercedes Nadal-Serrano
Guest Editors

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Keywords

estrogen
estrogen receptor
breast cancer
anticancer therapy
cancer development
cancer progression
metastasis

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Published Papers (7 papers)

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13 pages, 3131 KiB

Open AccessArticle

by Firas Almouhanna and Jochen Hess

Int. J. Mol. Sci. 2024, 25(2), 1244; https://doi.org/10.3390/ijms25021244 - 19 Jan 2024

Viewed by 1405

Abstract

Head and neck squamous cell carcinoma (HNSCC) is associated with high morbidity and mortality. New personalized treatment strategies represent an unmet medical need to improve the overall survival and the quality of life of patients, which are often limited by the toxicity of established multimodal treatment protocols. Several studies have reported an increased expression of the estrogen receptor 1 (ESR1) in HNSCC, but its potential role in the disease outcome of these tumors remains elusive. Using an integrative analysis of multiomics and clinical data from The Cancer Genome Atlas (TCGA)-HNSC, we established a prognostic risk model based on an ESR1-related 25-gene set. The prognostic value was confirmed in an independent cohort of HNSCC and other solid tumors from TCGA. Finally, we performed in silico drug sensitivity modeling to explore potential vulnerabilities for both risk groups. This approach predicted a higher sensitivity for HNSCC, with prominent ESR1 pathway activity under treatment with specific estrogen receptor modulators. In conclusion, our data confirm the involvement of ESR1-related pathway activity in the progression of a defined subset of HNSCC, provide compelling evidence that these tumors share a specific vulnerability to endocrine therapy, and pave the way for preclinical studies and clinical trials to demonstrate the efficacy of this new therapeutic option. Full article

(This article belongs to the Special Issue The Role of Estrogen and Its Receptors in the Development and Therapy of Cancer)

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16 pages, 4571 KiB

Open AccessArticle

Association of SLC12A1 and GLUR4 Ion Transporters with Neoadjuvant Chemoresistance in Luminal Locally Advanced Breast Cancer

by Montserrat Justo-Garrido, Alejandro López-Saavedra, Nicolás Alcaraz, Carlo C. Cortés-González, Luis F. Oñate-Ocaña, Claudia Haydee Sarai Caro-Sánchez, Clementina Castro-Hernández, Cristian Arriaga-Canon, José Díaz-Chávez and Luis A. Herrera

Int. J. Mol. Sci. 2023, 24(22), 16104; https://doi.org/10.3390/ijms242216104 - 9 Nov 2023

Viewed by 2368

Abstract

Chemoresistance to standard neoadjuvant treatment commonly occurs in locally advanced breast cancer, particularly in the luminal subtype, which is hormone receptor-positive and represents the most common subtype of breast cancer associated with the worst outcomes. Identifying the genes associated with chemoresistance is crucial for understanding the underlying mechanisms and discovering effective treatments. In this study, we aimed to identify genes linked to neoadjuvant chemotherapy resistance in 62 retrospectively included patients with luminal breast cancer. Whole RNA sequencing of 12 patient biopsies revealed 269 differentially expressed genes in chemoresistant patients. We further validated eight highly correlated genes associated with resistance. Among these, solute carrier family 12 member 1 (SLC12A1) and glutamate ionotropic AMPA type subunit 4 (GRIA4), both implicated in ion transport, showed the strongest association with chemoresistance. Notably, SLC12A1 expression was downregulated, while protein levels of glutamate receptor 4 (GLUR4), encoded by GRIA4, were elevated in patients with a worse prognosis. Our results suggest a potential link between SLC12A1 gene expression and GLUR4 protein levels with chemoresistance in luminal breast cancer. In particular, GLUR4 protein could serve as a potential target for drug intervention to overcome chemoresistance. Full article

(This article belongs to the Special Issue The Role of Estrogen and Its Receptors in the Development and Therapy of Cancer)

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23 pages, 3810 KiB

Open AccessArticle

Quercetin and Its Fermented Extract as a Potential Inhibitor of Bisphenol A-Exposed HT-29 Colon Cancer Cells’ Viability

by Nataly García-Gutiérrez, Gabriel Luna-Bárcenas, Guadalupe Herrera-Hernández, Rocio Campos-Vega, Sara Julietta Lozano-Herrera, Ana Alicia Sánchez-Tusié, Pablo García-Solis and Haydé Azeneth Vergara-Castañeda

Int. J. Mol. Sci. 2023, 24(6), 5604; https://doi.org/10.3390/ijms24065604 - 15 Mar 2023

Cited by 9 | Viewed by 2470

Abstract

Bisphenol A (BPA) promotes colon cancer by altering the physiological functions of hormones. Quercetin (Q) can regulate signaling pathways through hormone receptors, inhibiting cancer cells. The antiproliferative effects of Q and its fermented extract (FEQ, obtained by Q gastrointestinal digestion and in vitro colonic fermentation) were analyzed in HT-29 cells exposed to BPA. Polyphenols were quantified in FEQ by HPLC and their antioxidant capacity by DPPH and ORAC. Q and 3,4-dihydroxyphenylacetic acid (DOPAC) were quantified in FEQ. Q and FEQ exhibited antioxidant capacity. Cell viability with Q+BPA and FEQ+BPA was 60% and 50%, respectively; less than 20% of dead cells were associated with the necrosis process (LDH). Treatments with Q and Q+BPA induced cell cycle arrest in the G0/G1 phase, and FEQ and FEQ+BPA in the S phase. Compared with other treatments, Q positively modulated ESR2 and GPR30 genes. Using a gene microarray of the p53 pathway, Q, Q+BPA, FEQ and FEQ+BPA positively modulated genes involved in apoptosis and cell cycle arrest; bisphenol inhibited the expression of pro-apoptotic and cell cycle repressor genes. In silico analyses demonstrated the binding affinity of Q > BPA > DOPAC molecules for ERα and ERβ. Further studies are needed to understand the role of disruptors in colon cancer. Full article

(This article belongs to the Special Issue The Role of Estrogen and Its Receptors in the Development and Therapy of Cancer)

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21 pages, 9959 KiB

Open AccessArticle

Radiosensitization of Breast Cancer Cells with a 2-Methoxyestradiol Analogue Affects DNA Damage and Repair Signaling In Vitro

by Elsie Magdalena Nolte, Anna Margaretha Joubert, Laurence Lafanechère and Anne Elisabeth Mercier

Int. J. Mol. Sci. 2023, 24(4), 3592; https://doi.org/10.3390/ijms24043592 - 10 Feb 2023

Cited by 3 | Viewed by 2305

Abstract

Radiation resistance and radiation-related side effects warrant research into alternative strategies in the application of this modality to cancer treatment. Designed in silico to improve the pharmacokinetics and anti-cancer properties of 2-methoxyestradiol, 2-ethyl-3-O-sulfamoyl-estra-1,3,5(10)16-tetraene (ESE-16) disrupts microtubule dynamics and induces apoptosis. Here, we investigated whether pre-exposure of breast cancer cells to low-dose ESE-16 would affect radiation-induced deoxyribonucleic acid (DNA) damage and the consequent repair pathways. MCF-7, MDA-MB-231, and BT-20 cells were exposed to sub-lethal doses of ESE-16 for 24 h before 8 Gy radiation. Flow cytometric quantification of Annexin V, clonogenic studies, micronuclei quantification, assessment of histone H2AX phosphorylation and Ku70 expression were performed to assess cell viability, DNA damage, and repair pathways, in both directly irradiated cells and cells treated with conditioned medium. A small increase in apoptosis was observed as an early consequence, with significant repercussions on long-term cell survival. Overall, a greater degree of DNA damage was detected. Moreover, initiation of the DNA-damage repair response was delayed, with a subsequent sustained elevation. Radiation-induced bystander effects induced similar pathways and were initiated via intercellular signaling. These results justify further investigation of ESE-16 as a radiation-sensitizing agent since pre-exposure appears to augment the response of tumor cells to radiation. Full article

(This article belongs to the Special Issue The Role of Estrogen and Its Receptors in the Development and Therapy of Cancer)

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23 pages, 3766 KiB

Open AccessArticle

The Co-Expression of Estrogen Receptors ERα, ERβ, and GPER in Endometrial Cancer

by Marko Hojnik, Maša Sinreih, Maja Anko, Neli Hevir-Kene, Tamara Knific, Boštjan Pirš, Snježana Frković Grazio and Tea Lanišnik Rižner

Int. J. Mol. Sci. 2023, 24(3), 3009; https://doi.org/10.3390/ijms24033009 - 3 Feb 2023

Cited by 7 | Viewed by 2768

Abstract

Estrogens have important roles in endometrial cancer (EC) and exert biological effects through the classical estrogen receptors (ERs) ERα and ERβ, and the G-protein–coupled ER, GPER. So far, the co-expression of these three types of ERs has not been studied in EC. We investigated ERα, ERβ, GPER mRNA and protein levels, and their intracellular protein distributions in EC tissue and in adjacent control endometrial tissue. Compared to control endometrial tissue, immunoreactivity for ERα in EC tissue was weaker for nuclei with minor, but unchanged, cytoplasmic staining; mRNA and protein levels showed decreased patterns for ERα in EC tissue. For ERβ, across both tissue types, the immunoreactivity was unchanged for nuclei and cytoplasm, although EC tissues again showed lower mRNA and protein levels compared to adjacent control endometrial tissue. The immunoreactivity of GPER as well as mRNA levels of GPER were unchanged across cancer and control endometrial tissues, while protein levels were lower in EC tissue. Statistically significant correlations of estrogen receptor α (ESR1) versus estrogen receptor β (ESR2) and GPER variant 3,4 versus ESR1 and ESR2 was seen at the mRNA level. At the protein level studied with Western blotting, there was significant correlation of ERα versus GPER, and ERβ versus GPER. While in clinical practice the expression of ERα is routinely tested in EC tissue, ERβ and GPER need to be further studied to examine their potential as prognostic markers, provided that specific and validated antibodies are available. Full article

(This article belongs to the Special Issue The Role of Estrogen and Its Receptors in the Development and Therapy of Cancer)

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14 pages, 18999 KiB

Open AccessArticle

Extracellular Acidosis Differentially Regulates Estrogen Receptor β-Dependent EMT Reprogramming in Female and Male Melanoma Cells

by Silvia Peppicelli, Jessica Ruzzolini, Matteo Lulli, Alessio Biagioni, Francesca Bianchini, Adele Caldarella, Chiara Nediani, Elena Andreucci and Lido Calorini

Int. J. Mol. Sci. 2022, 23(23), 15374; https://doi.org/10.3390/ijms232315374 - 6 Dec 2022

Cited by 7 | Viewed by 1729

Abstract

Clinical outcomes of melanoma patients pointed out a gender disparity that supports a correlation between sex hormone activity on estrogen receptors (ER) and melanoma development and progression. Here, we found that the epithelial-to-mesenchymal transition (EMT) of melanoma cells induced by extracellular acidosis, which is a crucial hallmark of solid cancers, correlates with the expression of ERβ, the most representative ER on melanoma cells. Extracellular acidosis induces an enhanced expression of ERβ in female cells and EMT markers remain unchanged, while extracellular acidosis did not induce the expression of ERβ in male cells and EMT was strongly promoted. An inverse relationship between ERβ expression and EMT markers in melanoma cells of different sex exposed to extracellular acidosis was revealed by two different technical approaches: florescence-activated cell sorting of high ERβ expressing cell subpopulations and ERβ receptor silencing. Finally, we found that ERβ regulates EMT through NF-κB activation. These results demonstrate that extracellular acidosis drives a differential ERβ regulation in male and female melanoma cells and that this gender disparity might open new perspectives for personalized therapeutic approaches. Full article

(This article belongs to the Special Issue The Role of Estrogen and Its Receptors in the Development and Therapy of Cancer)

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14 pages, 1144 KiB

Open AccessBrief Report

Kinesins Modify ERR1-Dependent Transcription Using a Conserved Nuclear Receptor Box Motif

by A. M. Pramodh Bandara Seneviratne, Sarah Lidagoster, Sofia Valbuena-Castor, Kareena Lashley, Sumit Saha, Aleksandra Alimova and Geri Kreitzer

Int. J. Mol. Sci. 2023, 24(4), 3795; https://doi.org/10.3390/ijms24043795 - 14 Feb 2023

Viewed by 1543

Abstract

Kinesin family motors are microtubule (MT)-stimulated ATPases known best as transporters of cellular cargoes through the cytoplasm, regulators of MT dynamics, organizers of the mitotic spindle, and for insuring equal division of DNA during mitosis. Several kinesins have also been shown to regulate transcription by interacting with transcriptional cofactors and regulators, nuclear receptors, or with specific promotor elements on DNA. We previously showed that an LxxLL nuclear receptor box motif in the kinesin-2 family motor KIF17 mediates binding to the orphan nuclear receptor estrogen related receptor alpha (ERR1) and is responsible for the suppression of ERR1-dependent transcription by KIF17. Analysis of all kinesin family proteins revealed that multiple kinesins contain this LxxLL motif, raising the question as to whether additional kinesin motors contribute to the regulation of ERR1. In this study, we interrogate the effects of multiple kinesins with LxxLL motifs on ERR1-mediated transcription. We demonstrate that the kinesin-3 family motor KIF1B contains two LxxLL motifs, one of which binds to ERR1. In addition, we show that expression of a KIF1B fragment containing this LxxLL motif inhibits ERR1-dependent transcription by regulating nuclear entry of ERR1. We also provide evidence that the effects of expressing the KIF1B-LxxLL fragment on ERR1 activity are mediated by a mechanism distinct from that of KIF17. Since LxxLL domains are found in many kinesins, our data suggest an expanded role for kinesins in nuclear receptor mediated transcriptional regulation. Full article

(This article belongs to the Special Issue The Role of Estrogen and Its Receptors in the Development and Therapy of Cancer)

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