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Special Issue "Novel Insights on the Molecular Bases of Hormone-Responsive Breast Cancer Biology"

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: 31 October 2020.

Special Issue Editor

Prof. Dr. Roberta Tarallo
Website
Guest Editor
Department of Medicine, Surgery and Dentistry "Scuola Medica Salernitana", University of Salerno, Salerno, Italy
Interests: cancer biology; functional genomics; epigenomics; chromatin remodelling; endocrine-resistance; interaction proteomics

Special Issue Information

Dear Colleagues,

Breast cancer (BC) is one of the most frequent neoplasia in women and presents multiple patterns of disease progression and response to therapies, mainly relying on the expression of hormone receptors.

Approximately 70% of breast tumors express estrogen receptor α (ERα), most showing hormone dependence and responding to adjuvant endocrine therapies. Although ER blockade is effective in the majority of cases, intrinsic or de novo resistance to endocrine therapy of receptor-positive tumors is a key problem in clinical management of BC patients.

This Special Issue “Novel Insights on the Molecular Bases of Hormone-Responsive Breast Cancer Biology” of the International Journal of Molecular Sciences aims to provide an updated overview of basic and translational research focusing on hormone-responsive and/or endocrine-therapy resistant breast cancer at the molecular level. In vitro, in vivo, and ex vivo experimental models, multi-omics, and genome-wide approaches are welcome.  

The formats for submissions include original research articles, brief communications, and reviews.

Prof. Dr. Roberta Tarallo
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 papers will be 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. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. 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

  • breast cancer
  • hormone-responsiveness
  • estrogen signaling
  • endocrine resistance
  • molecular mechanisms
  • epigenetic modifications
  • chromatin remodeling
  • omics approaches

Published Papers (7 papers)

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Research

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Open AccessArticle
Fatty Acid Synthase Is a Key Enabler for Endocrine Resistance in Heregulin-Overexpressing Luminal B-Like Breast Cancer
Int. J. Mol. Sci. 2020, 21(20), 7661; https://doi.org/10.3390/ijms21207661 - 16 Oct 2020
Abstract
HER2 transactivation by the HER3 ligand heregulin (HRG) promotes an endocrine-resistant phenotype in the estrogen receptor-positive (ER+) luminal-B subtype of breast cancer. The underlying biological mechanisms that link them are, however, incompletely understood. Here, we evaluated the putative role of the lipogenic enzyme [...] Read more.
HER2 transactivation by the HER3 ligand heregulin (HRG) promotes an endocrine-resistant phenotype in the estrogen receptor-positive (ER+) luminal-B subtype of breast cancer. The underlying biological mechanisms that link them are, however, incompletely understood. Here, we evaluated the putative role of the lipogenic enzyme fatty acid synthase (FASN) as a major cause of HRG-driven endocrine resistance in ER+/HER2-negative breast cancer cells. MCF-7 cells engineered to stably overexpress HRG (MCF-7/HRG), an in vitro model of tamoxifen/fulvestrant-resistant luminal B-like breast cancer, showed a pronounced up-regulation of FASN gene/FASN protein expression. Autocrine HRG up-regulated FASN expression via HER2 transactivation and downstream activation of PI-3K/AKT and MAPK-ERK1/2 signaling pathways. The HRG-driven FASN-overexpressing phenotype was fully prevented in MCF-7 cells expressing a structural deletion mutant of HRG that is sequestered in a cellular compartment and lacks the ability to promote endocrine-resistance in an autocrine manner. Pharmacological inhibition of FASN activity blocked the estradiol-independent and tamoxifen/fulvestrant-refractory ability of MCF-7/HRG cells to anchorage-independently grow in soft-agar. In vivo treatment with a FASN inhibitor restored the anti-tumor activity of tamoxifen and fulvestrant against fast-growing, hormone-resistant MCF-7/HRG xenograft tumors in mice. Overall, these findings implicate FASN as a key enabler for endocrine resistance in HRG+/HER2- breast cancer and highlight the therapeutic potential of FASN inhibitors for the treatment of endocrine therapy-resistant luminal-B breast cancer. Full article
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Open AccessArticle
Estrogen Induces Selective Transcription of Caveolin1 Variants in Human Breast Cancer through Estrogen Responsive Element-Dependent Mechanisms
Int. J. Mol. Sci. 2020, 21(17), 5989; https://doi.org/10.3390/ijms21175989 - 20 Aug 2020
Abstract
The estrogen receptor (ER) signaling regulates numerous physiological processes mainly through activation of gene transcription (genomic pathways). Caveolin1 (CAV1) is a membrane-resident protein that behaves as platform to enable different signaling molecules and receptors for membrane-initiated pathways. CAV1 directly interacts with ERs and [...] Read more.
The estrogen receptor (ER) signaling regulates numerous physiological processes mainly through activation of gene transcription (genomic pathways). Caveolin1 (CAV1) is a membrane-resident protein that behaves as platform to enable different signaling molecules and receptors for membrane-initiated pathways. CAV1 directly interacts with ERs and allows their localization on membrane with consequent activation of ER-non-genomic pathways. Loss of CAV1 function is a common feature of different types of cancers, including breast cancer. Two protein isoforms, CAV1α and CAV1β, derived from two alternative translation initiation sites, are commonly described for this gene. However, the exact transcriptional regulation underlying CAV1 expression pattern is poorly elucidated. In this study, we dissect the molecular mechanism involved in selective expression of CAV1β isoform, induced by estrogens and downregulated in breast cancer. Luciferase assays and Chromatin immunoprecipitation demonstrate that transcriptional activation is triggered by estrogen-responsive elements embedded in CAV1 intragenic regions and DNA-binding of estrogen-ER complexes. This regulatory control is dynamically established by local chromatin changes, as proved by the occurrence of histone H3 methylation/demethylation events and association of modifier proteins as well as modification of H3 acetylation status. Thus, we demonstrate for the first time, an estrogen-ERs-dependent regulatory circuit sustaining selective CAV1β expression. Full article
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Open AccessArticle
Unexpected Impact of a Hepatitis C Virus Inhibitor on 17β-Estradiol Signaling in Breast Cancer
Int. J. Mol. Sci. 2020, 21(10), 3418; https://doi.org/10.3390/ijms21103418 - 12 May 2020
Abstract
17β-Estradiol (E2) controls diverse physiological processes, including cell proliferation, through its binding to estrogen receptor α (ERα). E2:ERα signaling depends on both the receptor subcellular localization (e.g., nucleus, plasma membrane) and intracellular ERα abundance. Indeed, the control of ERα levels is necessary for [...] Read more.
17β-Estradiol (E2) controls diverse physiological processes, including cell proliferation, through its binding to estrogen receptor α (ERα). E2:ERα signaling depends on both the receptor subcellular localization (e.g., nucleus, plasma membrane) and intracellular ERα abundance. Indeed, the control of ERα levels is necessary for the effects of E2, and E2 itself induces ERα degradation and cell proliferation in parallel. Thus, the modulation of intracellular ERα levels is a critical parameter for E2-induced cell proliferation. Therefore, we used this parameter as a bait to identify compounds that influence ERα levels and E2-dependent proliferation in breast cancer (BC) cells from a library of Food and Drug Administration (FDA)-approved drugs. We found that telaprevir (Tel) reduces ERα levels and inhibits BC cell proliferation. Tel is an inhibitor of the hepatitis C virus (HCV) NS3/4A serine protease, but its effect on E2:ERα signaling has not been investigated. Here, for the first time, we analyzed the effects of Tel on intracellular ERα levels and E2:ERα signaling to cell proliferation in different ERα-expressing BC cell lines. Overall, our findings demonstrate that Tel reduces intracellular ERα levels, deregulates E2:ERα signaling and inhibits E2-induced proliferation in BC cells and suggest the potential drug repurposing of Tel for the treatment of BC. Full article
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Open AccessArticle
Blockade of CDK7 Reverses Endocrine Therapy Resistance in Breast Cancer
Int. J. Mol. Sci. 2020, 21(8), 2974; https://doi.org/10.3390/ijms21082974 - 23 Apr 2020
Cited by 1
Abstract
Cyclin-dependent kinase (CDK)-7 inhibitors are emerging as promising drugs for the treatment of different types of cancer that show chemotherapy resistance. Evaluation of the effects of CDK7 inhibitor, THZ1, alone and combined with tamoxifen is of paramount importance. Thus, in the current work, [...] Read more.
Cyclin-dependent kinase (CDK)-7 inhibitors are emerging as promising drugs for the treatment of different types of cancer that show chemotherapy resistance. Evaluation of the effects of CDK7 inhibitor, THZ1, alone and combined with tamoxifen is of paramount importance. Thus, in the current work, we assessed the effects of THZ1 and/or tamoxifen in two estrogen receptor-positive (ER+) breast cancer cell lines (MCF7) and its tamoxifen resistant counterpart (LCC2) in vitro and in xenograft mouse models of breast cancer. Furthermore, we evaluated the expression of CDK7 in clinical samples from breast cancer patients. Cell viability, apoptosis, and genes involved in cell cycle regulation and tamoxifen resistance were determined. Tumor volume and weight, proliferation marker (Ki67), angiogenic marker (CD31), and apoptotic markers were assayed. Bioinformatic data indicated CDK7 expression was associated with negative prognosis, enhanced pro-oncogenic pathways, and decreased response to tamoxifen. Treatment with THZ1 enhanced tamoxifen-induced cytotoxicity, while it inhibited genes involved in tumor progression in MCF-7 and LCC2 cells. In vivo, THZ1 boosted the effect of tamoxifen on tumor weight and tumor volume, reduced Ki67 and CD31 expression, and increased apoptotic cell death. Our findings identify CDK7 as a possible therapeutic target for breast cancer whether it is sensitive or resistant to tamoxifen therapy. Full article
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Review

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Open AccessReview
miRNA Expression Profiles in Luminal A Breast Cancer—Implications in Biology, Prognosis, and Prediction of Response to Hormonal Treatment
Int. J. Mol. Sci. 2020, 21(20), 7691; https://doi.org/10.3390/ijms21207691 - 17 Oct 2020
Abstract
Breast cancer, which is the most common malignancy in women, does not form a uniform nosological unit but represents a group of malignant diseases with specific clinical, histopathological, and molecular characteristics. The increasing knowledge of the complex pathophysiological web of processes connected with [...] Read more.
Breast cancer, which is the most common malignancy in women, does not form a uniform nosological unit but represents a group of malignant diseases with specific clinical, histopathological, and molecular characteristics. The increasing knowledge of the complex pathophysiological web of processes connected with breast cancercarcinogenesis allows the development of predictive and prognostic gene expressionand molecular classification systems with improved risk assessment, which could be used for individualized treatment. In our review article, we present the up-to-date knowledge about the role of miRNAs and their prognostic and predictive value in luminal A breast cancer. Indeed, an altered expression profile of miRNAs can distinguish not only between cancer and healthy samples, but they can classify specific molecular subtypes of breast cancer including HER2, Luminal A, Luminal B, and TNBC. Early identification and classification of breast cancer subtypes using miRNA expression profilescharacterize a promising approach in the field of personalized medicine. A detection of sensitive and specific biomarkers to distinguish between healthy and early breast cancer patients can be achieved by an evaluation of the different expression of several miRNAs. Consequently, miRNAs represent a potential as good diagnostic, prognostic, predictive, and therapeutic biomarkers for patients with luminal A in the early stage of BC. Full article
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Open AccessReview
The Importance of Breast Adipose Tissue in Breast Cancer
Int. J. Mol. Sci. 2020, 21(16), 5760; https://doi.org/10.3390/ijms21165760 - 11 Aug 2020
Abstract
Adipose tissue is a complex endocrine organ, with a role in obesity and cancer. Adipose tissue is generally linked to excessive body fat, and it is well known that the female breast is rich in adipose tissue. Hence, one can wonder: what is [...] Read more.
Adipose tissue is a complex endocrine organ, with a role in obesity and cancer. Adipose tissue is generally linked to excessive body fat, and it is well known that the female breast is rich in adipose tissue. Hence, one can wonder: what is the role of adipose tissue in the breast and why is it required? Adipose tissue as an organ consists of adipocytes, an extracellular matrix (ECM) and immune cells, with a significant role in the dynamics of breast changes throughout the life span of a female breast from puberty, pregnancy, lactation and involution. In this review, we will discuss the importance of breast adipose tissue in breast development and its involvement in breast changes happening during pregnancy, lactation and involution. We will focus on understanding the biology of breast adipose tissue, with an overview on its involvement in the various steps of breast cancer development and progression. The interaction between the breast adipose tissue surrounding cancer cells and vice-versa modifies the tumor microenvironment in favor of cancer. Understanding this mutual interaction and the role of breast adipose tissue in the tumor microenvironment could potentially raise the possibility of overcoming breast adipose tissue mediated resistance to therapies and finding novel candidates to target breast cancer. Full article
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Open AccessReview
Global View of Candidate Therapeutic Target Genes in Hormone-Responsive Breast Cancer
Int. J. Mol. Sci. 2020, 21(11), 4068; https://doi.org/10.3390/ijms21114068 - 06 Jun 2020
Cited by 1
Abstract
Breast cancer (BC) is a heterogeneous disease characterized by different biopathological features, differential response to therapy and substantial variability in long-term-survival. BC heterogeneity recapitulates genetic and epigenetic alterations affecting transformed cell behavior. The estrogen receptor alpha positive (ERα+) is the most common BC [...] Read more.
Breast cancer (BC) is a heterogeneous disease characterized by different biopathological features, differential response to therapy and substantial variability in long-term-survival. BC heterogeneity recapitulates genetic and epigenetic alterations affecting transformed cell behavior. The estrogen receptor alpha positive (ERα+) is the most common BC subtype, generally associated with a better prognosis and improved long-term survival, when compared to ERα-tumors. This is mainly due to the efficacy of endocrine therapy, that interfering with estrogen biosynthesis and actions blocks ER-mediated cell proliferation and tumor spread. Acquired resistance to endocrine therapy, however, represents a great challenge in the clinical management of ERα+ BC, causing tumor growth and recurrence irrespective of estrogen blockade. Improving overall survival in such cases requires new and effective anticancer drugs, allowing adjuvant treatments able to overcome resistance to first-line endocrine therapy. To date, several studies focus on the application of loss-of-function genome-wide screenings to identify key (hub) “fitness” genes essential for BC progression and representing candidate drug targets to overcome lack of response, or acquired resistance, to current therapies. Here, we review the biological significance of essential genes and relative functional pathways affected in ERα+ BC, most of which are strictly interconnected with each other and represent potential effective targets for novel molecular therapies. Full article
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Planned Papers

The below list represents only planned manuscripts. Some of these manuscripts have not been received by the Editorial Office yet. Papers submitted to MDPI journals are subject to peer-review.

Title: An unexpected impact of an HCV inhibitor on estradiol signaling in breast cancer
Authors: Filippo Acconcia, etc.

Title: MiRNA signatures in ER positive breast cancer - implications in biology, prognosis, preventive and personalised medicine
Authors: Erik Kudela, etc.

Title: Adipose tissue and breast cancer: a bibliometric analysis of expression and variation of some important adipose biomarkers
Authors: Dinh-Toi Chu, Thuy Nguyen Thi Phuong, Thien Chu Dinh, etc.

Title: The importance of breast adipose tissue in breast cancer
Authors: Charu Kothari, Caroline Diorio and Francine Durocher

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