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Hormone Receptors and Signaling in Breast 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 Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (15 April 2024) | Viewed by 17554

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Special Issue Editor

Dr. Farzad Pakdel

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Guest Editor

Research Institute in Health, Environment and Occupation (Irset), Inserm U1085, Transcription, Environment and Cancer Group, University of Rennes 1, 35000 Rennes, France
Interests: estrogen receptor; gene expression; transcription mechanisms; endocrine disrupter chemicals; breast cancer
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Breast cancer is a serious health problem worldwide, representing the second cause of death through malignancies among women in developed countries. Environmental factors, endogenous and exogenous hormones, as well as physiological and genetic factors are involved in the pathogenesis of breast cancer.

It is classified into a few major molecular subtypes according to hormone and growth factor receptor expression. Approximately 70% of breast tumors express estrogen receptor α (ERα), most showing hormone dependence and responding to adjuvant endocrine therapies. The phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) is a signaling pathway involved in cell proliferation, survival, invasion, migration, apoptosis, glucose metabolism and DNA repair. Aberrations in the PI3K/AKT/mTOR pathway are common in breast cancer. Preclinical data support the notion that these aberrations predict the inhibition of breast cancer by targeted agents.

This Special Issue aims to provide a timely peer-reviewed and open access platform for original research and review articles, focused on the latest findings relating to hormone receptor activation in breast cancer progression and metastasis, as well as the applications of this knowledge for disease therapeutics.

Dr. Farzad Pakdel
Guest Editor

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Keywords

breast cancer
hormone receptor
growth factor receptor
estrogen receptor
endocrine therapies
PI3K
AKT
mTOR
signaling

Published Papers (5 papers)

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Research

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18 pages, 5403 KiB

Open AccessArticle

In Silico Identification of a BRCA1:miR-29:DNMT3 Axis Involved in the Control of Hormone Receptors in BRCA1-Associated Breast Cancers

by Manuela Santarosa, Davide Baldazzi, Michela Armellin and Roberta Maestro

Int. J. Mol. Sci. 2023, 24(12), 9916; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24129916 - 08 Jun 2023

Viewed by 1204

Abstract

Germline inactivating mutations in the BRCA1 gene lead to an increased lifetime risk of ovarian and breast cancer (BC). Most BRCA1-associated BC are triple-negative tumors (TNBC), aggressive forms of BC characterized by a lack of expression of estrogen and progesterone hormone receptors (HR) and HER2. How BRCA1 inactivation may favor the development of such a specific BC phenotype remains to be elucidated. To address this question, we focused on the role of miRNAs and their networks in mediating BRCA1 functions. miRNA, mRNA, and methylation data were retrieved from the BRCA cohort of the TCGA project. The cohort was divided into a discovery set (Hi-TCGA) and a validation set (GA-TCGA) based on the platform used for miRNA analyses. The METABRIC, GSE81002, and GSE59248 studies were used as additional validation data sets. BCs were differentiated into BRCA1-like and non-BRCA1-like based on an established signature of BRCA1 pathway inactivation. Differential expression of miRNAs, gene enrichment analysis, functional annotation, and methylation correlation analyses were performed. The miRNAs downregulated in BRCA1-associated BC were identified by comparing the miRNome of BRCA1-like with non-BRCA1-like tumors from the Hi-TCGA discovery cohort. miRNAs:gene-target anticorrelation analyses were then performed. The target genes of miRNAs downregulated in the Hi-TCGA series were enriched in the BRCA1-like tumors from the GA-TCGA and METABRIC validation data sets. Functional annotation of these genes revealed an over-representation of several biological processes ascribable to BRCA1 activity. The enrichment of genes related to DNA methylation was particularly intriguing, as this is an aspect of BRCA1 functions that has been poorly explored. We then focused on the miR-29:DNA methyltransferase network and showed that the miR-29 family, which was downregulated in BRCA1-like tumors, was associated with poor prognosis in these BCs and inversely correlated with the expression of the DNA methyltransferases DNMT3A and DNMT3B. This, in turn, correlated with the methylation extent of the promoter of HR genes. These results suggest that BRCA1 may control the expression of HR via a miR-29:DNMT3:HR axis and that disruption of this network may contribute to the receptor negative phenotype of tumors with dysfunctional BRCA1. Full article

(This article belongs to the Special Issue Hormone Receptors and Signaling in Breast Cancer)

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22 pages, 4600 KiB

Open AccessArticle

Cell Uptake of Steroid-BODIPY Conjugates and Their Internalization Mechanisms: Cancer Theranostic Dyes

by Ana F. Amendoeira, André Luz, Ruben Valente, Catarina Roma-Rodrigues, Hasrat Ali, Johan E. van Lier, Fernanda Marques, Pedro V. Baptista and Alexandra R. Fernandes

Int. J. Mol. Sci. 2023, 24(4), 3600; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24043600 - 10 Feb 2023

Cited by 2 | Viewed by 1841

Abstract

Estradiol-BODIPY linked via an 8-carbon spacer chain and 19-nortestosterone- and testosterone-BODIPY linked via an ethynyl spacer group were evaluated for cell uptake in the breast cancer cell lines MCF-7 and MDA-MB-231 and prostate cancer cell lines PC-3 and LNCaP, as well as in normal dermal fibroblasts, using fluorescence microscopy. The highest level of internalization was observed with 11β-OMe-estradiol-BODIPY 2 and 7α-Me-19-nortestosterone-BODIPY 4 towards cells expressing their specific receptors. Blocking experiments showed changes in non-specific cell uptake in the cancer and normal cells, which likely reflect differences in the lipophilicity of the conjugates. The internalization of the conjugates was shown to be an energy-dependent process that is likely mediated by clathrin- and caveolae-endocytosis. Studies using 2D co-cultures of cancer cells and normal fibroblasts showed that the conjugates are more selective towards cancer cells. Cell viability assays showed that the conjugates are non-toxic for cancer and/or normal cells. Visible light irradiation of cells incubated with estradiol-BODIPYs 1 and 2 and 7α-Me-19-nortestosterone-BODIPY 4 induced cell death, suggesting their potential for use as PDT agents. Full article

(This article belongs to the Special Issue Hormone Receptors and Signaling in Breast Cancer)

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Review

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19 pages, 2232 KiB

Open AccessReview

Hormone Receptor Signaling and Breast Cancer Resistance to Anti-Tumor Immunity

by Alexandra Moisand, Mathilde Madéry, Thomas Boyer, Charlotte Domblides, Céline Blaye and Nicolas Larmonier

Int. J. Mol. Sci. 2023, 24(20), 15048; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms242015048 - 10 Oct 2023

Cited by 4 | Viewed by 1574

Abstract

Breast cancers regroup many heterogeneous diseases unevenly responding to currently available therapies. Approximately 70–80% of breast cancers express hormone (estrogen or progesterone) receptors. Patients with these hormone-dependent breast malignancies benefit from therapies targeting endocrine pathways. Nevertheless, metastatic disease remains a major challenge despite available treatments, and relapses frequently ensue. By improving patient survival and quality of life, cancer immunotherapies have sparked considerable enthusiasm and hope in the last decade but have led to only limited success in breast cancers. In addition, only patients with hormone-independent breast cancers seem to benefit from these immune-based approaches. The present review examines and discusses the current literature related to the role of hormone receptor signaling (specifically, an estrogen receptor) and the impact of its modulation on the sensitivity of breast cancer cells to the effector mechanisms of anti-tumor immune responses and on the capability of breast cancers to escape from protective anti-cancer immunity. Future research prospects related to the possibility of promoting the efficacy of immune-based interventions using hormone therapy agents are considered. Full article

(This article belongs to the Special Issue Hormone Receptors and Signaling in Breast Cancer)

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19 pages, 1640 KiB

Open AccessReview

A Basic Review on Estrogen Receptor Signaling Pathways in Breast Cancer

by Léa Clusan, François Ferrière, Gilles Flouriot and Farzad Pakdel

Int. J. Mol. Sci. 2023, 24(7), 6834; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24076834 - 06 Apr 2023

Cited by 31 | Viewed by 8624

Abstract

Breast cancer is the most common cancer and the deadliest among women worldwide. Estrogen signaling is closely associated with hormone-dependent breast cancer (estrogen and progesterone receptor positive), which accounts for two-thirds of tumors. Hormone therapy using antiestrogens is the gold standard, but resistance to these treatments invariably occurs through various biological mechanisms, such as changes in estrogen receptor activity, mutations in the ESR1 gene, aberrant activation of the PI3K pathway or cell cycle dysregulations. All these factors have led to the development of new therapies, such as selective estrogen receptor degraders (SERDs), or combination therapies with cyclin-dependent kinases (CDK) 4/6 or PI3K inhibitors. Therefore, understanding the estrogen pathway is essential for the treatment and new drug development of hormone-dependent cancers. This mini-review summarizes current literature on the signalization, mechanisms of action and clinical implications of estrogen receptors in breast cancer. Full article

(This article belongs to the Special Issue Hormone Receptors and Signaling in Breast Cancer)

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17 pages, 1620 KiB

Open AccessReview

Drugging the PI3K/AKT/mTOR Pathway in ER+ Breast Cancer

by Carla L. Alves and Henrik J. Ditzel

Int. J. Mol. Sci. 2023, 24(5), 4522; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24054522 - 24 Feb 2023

Cited by 15 | Viewed by 3493

Abstract

The frequent activation of the PI3K/AKT/mTOR pathway and its crucial role in estrogen receptor-positive (ER+) breast cancer tumorigenesis and drug resistance has made it a highly attractive therapeutic target in this breast cancer subtype. Consequently, the number of new inhibitors in clinical development targeting this pathway has drastically increased. Among these, the PIK3CA isoform-specific inhibitor alpelisib and the pan-AKT inhibitor capivasertib were recently approved in combination with the estrogen receptor degrader fulvestrant for the treatment of ER+ advanced breast cancer after progression on an aromatase inhibitor. Nevertheless, the clinical development of multiple inhibitors of the PI3K/AKT/mTOR pathway, in parallel with the incorporation of CDK4/6 inhibitors into the standard of care treatment in ER+ advanced breast cancer, has led to a multitude of available therapeutic agents and many possible combined strategies which complicate personalizing treatment. Here, we review the role of the PI3K/AKT/mTOR pathway in ER+ advanced breast cancer, highlighting the genomic contexts in which the various inhibitors of this pathway may have superior activity. We also discuss selected trials with agents targeting the PI3K/AKT/mTOR and related pathways as well as the rationale supporting the clinical development of triple combination therapy targeting ER, CDK4/6 and PI3K/AKT/mTOR in ER+ advanced breast cancer. Full article

(This article belongs to the Special Issue Hormone Receptors and Signaling in Breast Cancer)

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