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Targeting Breast Cancer: Strategies and Hopes

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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 (31 July 2023) | Viewed by 20514

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Special Issue Editors

Prof. Dr. Christos Papadimitriou

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Second Department of Surgery, Aretaieion Hospital, Medical School, National and Kapodistrian University of Athens, 11528 Athens, Greece
Interests: early breast cancer; adjuvant chemotherapy; chemotherapy for metastatic breast cancer; clinical trials; mTOR inhibitors; CDK4/6 inhibitors; endocrine therapy
Special Issues, Collections and Topics in MDPI journals

Prof. Dr. Flora Zagouri

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Department of Clinical Therapeutics, Alexandra Hospital, Medical School, 11528 Athens, Greece
Interests: tumors; prognostic markers; antineoplastic agents; cancer biomarkers; tumor biology
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Dr. Michalis Liontos

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Department of Clinical Therapeutics, Division of Oncology, Alexandra Hospital, National and Kapodistrian University of Athens, 10679 Athens, Greece
Interests: ovarian cancer; personalized medicine; DNA damage response; DNA repair mechanisms; uterine cancer
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Breast cancer therapeutics has evolved rapidly within the last decade as a result of the improvements in the understanding of the molecular biology of the disease. Novel drugs have significantly increased rates of disease-free survival and overall survival of the patients. In parallel, we have recognized categories of patients where de-intensification of treatment results to similar oncological outcomes while sparing patients from toxicities related to treatment. However, there is still an unmet need to improve treatments, especially for more aggressive histologies of the disease.

Regarding hormone receptor positive patients, CDK4/6 inhibitors have revolutionized treatment of metastatic as well as locally advanced disease. Unfortunately, mechanisms of primary and secondary resistance to these agents and hormonal therapy lead to disease recurrence. Further research on molecular alterations that lead to treatment failure as well as proper selection of group of patients is necessary to improve the benefits of this class of drugs. In addition, molecular data that could guide us regarding treatment sequence and possible combinatorial approaches could be of benefit.

For the Her-2 positive group of patients, antibody drug conjugates have significantly extended overall survival in patients with metastatic disease and are currently tested in the adjuvant setting as well. In addition, the efficacy of trastuzumab deruxtacan in patients with low expression of Her-2 triggers scientific research on redefining the population of patients that derive benefit from such agents. Finally, mechanisms of resistance in these drugs as well as biomarkers that could determine proper sequencing of anti-Her2 treatment are of utmost importance.

Finally, in patients with triple negative breast cancer, immunotherapy has provided novel therapeutic opportunities and increased overall survival. Despite early success, though, further understanding of the molecular biology of the disease could provide insight for combinations of immunotherapeutic and targeted agents that could further improve responses and prolong survival. It is also crucial to recognize molecular subtypes of TNBC and guide proper management with the existing agents.

All the above denote that a new, fascinating era has begun regarding the molecular research of breast cancer. The current Special Issue welcomes innovative research that could further promote our knowledge in this field and lead to the development of novel therapeutic agents. Since molecular biology and basic scientific studies are indispensable for the development of our journal, we will prioritize basic research over clinical trials/data.

Dr. Christos Papadimitriou
Prof. Dr. Flora Zagouri
Dr. Michalis Liontos
Guest Editors

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.

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Keywords

breast cancer
novel drugs
hormone receptor
inhibitor
immunotherapy
targeted agents

Published Papers (9 papers)

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Research

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14 pages, 2852 KiB

Open AccessArticle

Brk/PTK6 and Involucrin Expression May Predict Breast Cancer Cell Responses to Vitamin D3

by Carol Box, Caroline Pennington, Stephen Hare, Sarah Porter, Dylan Edwards, Suzanne Eccles, Mark Crompton and Amanda Harvey

Int. J. Mol. Sci. 2023, 24(13), 10757; https://doi.org/10.3390/ijms241310757 - 28 Jun 2023

Cited by 2 | Viewed by 1093

Abstract

The process of human embryonic mammary development gives rise to the structures in which mammary cells share a developmental lineage with skin epithelial cells such as keratinocytes. As some breast carcinomas have previously been shown to express high levels of involucrin, a marker of keratinocyte differentiation, we hypothesised that some breast tumours may de-differentiate to a keratinocyte-derived ‘evolutionary history’. To confirm our hypothesis, we investigated the frequency of involucrin expression along with that of Brk, a tyrosine kinase expressed in up to 86% of breast carcinomas whose normal expression patterns are restricted to differentiating epithelial cells, most notably those in the skin (keratinocytes) and the gastrointestinal tract. We found that involucrin, a keratinocyte differentiation marker, was expressed in a high proportion (78%) of breast carcinoma samples and cell lines. Interestingly, tumour samples found to express high levels of involucrin were also shown to express Brk. 1,25-dihydroxyvitamin D3, a known differentiation agent and potential anti-cancer agent, decreased proliferation in the breast cancer cell lines that expressed both involucrin and Brk, whereas the Brk/involucrin negative cell lines tested were less susceptible. In addition, responses to 1,25-dihydroxyvitamin D3 were not correlated with vitamin D receptor expression. These data contribute to the growing body of evidence suggesting that cellular responses to 1,25-dihydroxyvitamin D3 are potentially independent of vitamin D receptor status and provide an insight into potential markers, such as Brk and/or involucrin that could predict therapeutic responses to 1,25-dihydroxyvitamin D3. Full article

(This article belongs to the Special Issue Targeting Breast Cancer: Strategies and Hopes)

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16 pages, 3568 KiB

Open AccessArticle

Comparative Proteomics Analysis of Exosomes Identifies Key Pathways and Protein Markers Related to Breast Cancer Metastasis

by Shichen Shen, Chengjian Tu, He Shen, Jun Li, Costa Frangou, Jianmin Zhang and Jun Qu

Int. J. Mol. Sci. 2023, 24(4), 4033; https://doi.org/10.3390/ijms24044033 - 17 Feb 2023

Cited by 1 | Viewed by 2726

Abstract

Proteomics analysis of circulating exosomes derived from cancer cells represents a promising approach to the elucidation of cell–cell communication and the discovery of putative biomarker candidates for cancer diagnosis and treatment. Nonetheless, the proteome of exosomes derived from cell lines with different metastatic capabilities still warrants further investigation. Here, we present a comprehensive quantitative proteomics investigation of exosomes isolated from immortalized mammary epithelial cells and matched tumor lines with different metastatic potentials in an attempt to discover exosome markers specific to breast cancer (BC) metastasis. A total of 2135 unique proteins were quantified with a high confidence level from 20 isolated exosome samples, including 94 of the TOP 100 exosome markers archived by ExoCarta. Moreover, 348 altered proteins were observed, among which several metastasis-specific markers, including cathepsin W (CATW), magnesium transporter MRS2 (MRS2), syntenin-2 (SDCB2), reticulon-4 (RTN), and UV excision repair protein RAD23 homolog (RAD23B), were also identified. Notably, the abundance of these metastasis-specific markers corresponds well with the overall survival of BC patients in clinical settings. Together, these data provide a valuable dataset for BC exosome proteomics investigation and prominently facilitate the elucidation of the molecular mechanisms underlying primary tumor development and progression. Full article

(This article belongs to the Special Issue Targeting Breast Cancer: Strategies and Hopes)

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29 pages, 17897 KiB

Open AccessArticle

LC-PDA-MS and GC-MS Analysis of Scorzonera hispanica Seeds and Their Effects on Human Breast Cancer Cell Lines

by Karolina Lendzion, Agnieszka Gornowicz, Jakub W. Strawa, Katarzyna Bielawska, Robert Czarnomysy, Bożena Popławska, Krzysztof Bielawski, Michał Tomczyk, Wojciech Miltyk and Anna Bielawska

Int. J. Mol. Sci. 2022, 23(19), 11584; https://doi.org/10.3390/ijms231911584 - 30 Sep 2022

Cited by 5 | Viewed by 1787

Abstract

Scorzonera hispanica is an herbaceous perennial cultivated in Central and Southern Europe. This study aimed to qualitatively and quantitatively evaluate the composition of oil, extracts, and fractions (SH1-SH12) obtained from S. hispanica seeds. Furthermore, an evaluation of biological activities in breast cancer cell lines was also performed. GC-MS analysis revealed that the primary components of the seed oil (SH12) were fatty acids and β-sitosterol. In the evaluation of extracts (SH1-SH3, SH8-SH10) and fractions (SH4-SH7, SH11) composition, the presence of apigenin, derivatives of p-coumaric and caffeic acids, was reported. In the biological assays, methanolic extract (SH1), diethyl ether (SH4), and chloroform (SH11) fractions exhibited cytotoxicity toward cells. The highest activity was observed for fatty acids- and 3,4-dimethoxycinnamate-rich SH11 (IC₅₀: 399.18 μg/mL for MCF-7, 781.26 μg/mL for MDA-MB-231). SH11 was also observed to induce apoptosis in MCF-7 cells (52.4%). SH1, SH4, and SH11 attenuate signaling pathways and affect the expression of apoptosis-, autophagy-, and inflammation-related proteins. SH12 was non-toxic toward either cancer or normal cell lines in concentrations up to 1 mg/mL. The results suggest that S. hispanica seeds exhibit a wide range of potential uses as a source of oil and bioactive compounds for complementary therapy of breast cancer. Full article

(This article belongs to the Special Issue Targeting Breast Cancer: Strategies and Hopes)

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20 pages, 6511 KiB

Open AccessArticle

The Reduced Graphene Oxide (rGO) Induces Apoptosis, Autophagy and Cell Cycle Arrest in Breast Cancer Cells

by Rafał Krętowski and Marzanna Cechowska-Pasko

Int. J. Mol. Sci. 2022, 23(16), 9285; https://doi.org/10.3390/ijms23169285 - 18 Aug 2022

Cited by 8 | Viewed by 1721

Abstract

Reduced graphene oxide (rGO) has already been reported as a potential cytostatic agent in various cancers. However, the mechanisms underlying rGO’s cytotoxicity are still insufficiently understood. Thus, the aim of the study was to investigate the molecular and cellular effects of rGO in breast cancer. Given this, two cell lines, MDA-MB-231 and ZR-75-1, were analyzed using MTT test, flow cytometry and Western blot assay. Incubation with rGO resulted in a multitude of effects, including the stimulation of autophagy, cell cycle arrest and, finally, the apoptotic death of cancer cells. Notably, rGO had minimal effect on normal human fibroblasts. Apoptosis in cancer cells was accompanied by decreased mitochondrial membrane potential, the deregulated expression of mitochondrial proteins and the activation of caspase 9 and caspase 3, suggesting that rGO predominantly induced apoptosis via intrinsic pathway. The analysis of LC3 protein expression revealed that rGO also caused autophagy in breast cancer cells. Moreover, rGO treatment resulted in cell cycle arrest, which was accompanied by deregulated p21 expression. Altogether, rGO seems to have multidirectional cytostatic and cytotoxic effects in breast cancer cells, making it a promising agent worthy of further investigation. Full article

(This article belongs to the Special Issue Targeting Breast Cancer: Strategies and Hopes)

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Review

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14 pages, 1059 KiB

Open AccessReview

Anti-Tumor Immunity and Preoperative Radiovaccination: Emerging New Concepts in the Treatment of Breast Cancer

by Ioannis M. Koukourakis, Marios Papadimitriou, Dimitra Desse, Anna Zygogianni and Christos Papadimitriou

Int. J. Mol. Sci. 2023, 24(11), 9310; https://doi.org/10.3390/ijms24119310 - 26 May 2023

Cited by 1 | Viewed by 1313

Abstract

Neoadjuvant chemotherapy (NACT) for certain breast cancer (BC) subtypes confers significant tumor regression rates and a survival benefit for patients with a complete pathologic response. Clinical and preclinical studies have demonstrated that immune-related factors are responsible for better treatment outcomes, and thus, neoadjuvant immunotherapy (IO) has emerged as a means to further improve patient survival rates. Innate immunological “coldness”, however, of specific BC subtypes, especially of the luminal ones, due to their immunosuppressive tumor microenvironment, hinders the efficacy of immune checkpoint inhibitors. Treatment policies aiming to reverse this immunological inertia are, therefore, needed. Moreover, radiotherapy (RT) has been proven to have a significant interplay with the immune system and promote anti-tumor immunity. This “radiovaccination” effect could be exploited in the neoadjuvant setting of BC and significantly enhance the effects of the already established clinical practice. Modern stereotactic irradiation techniques directed to the primary tumor and involved lymph nodes may prove important for the RT-NACT-IO combination. In this review, we provide an overview and critically discuss the biological rationale, clinical experience, and ongoing research underlying the interplay between neoadjuvant chemotherapy, anti-tumor immune response, and the emerging role of RT as a preoperative adjunct with immunological therapeutic implications in BC. Full article

(This article belongs to the Special Issue Targeting Breast Cancer: Strategies and Hopes)

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19 pages, 1320 KiB

Open AccessReview

Clinical and Translational Applications of Serological and Histopathological Biomarkers in Metastatic Breast Cancer: A Comprehensive Review

by Leonel Pekarek, Alicia Sánchez Cendra, Eduardo D. Roberts Cervantes, Cristina Sánchez Cendra, Oscar Fraile-Martinez, Cielo García-Montero, Raul Diaz-Pedrero, Diego Torres-Carranza, Laura Lopez-Gonzalez, Soledad Aguado-Henche, Antonio Rios-Parra, Luis M. García-Puente, Natalio García-Honduvilla, Julia Bujan, Melchor Alvarez-Mon, Miguel A. Saez and Miguel A. Ortega

Int. J. Mol. Sci. 2023, 24(9), 8396; https://doi.org/10.3390/ijms24098396 - 07 May 2023

Cited by 3 | Viewed by 2187

Abstract

Breast cancer is one of the most common malignancies worldwide and the most common form of cancer in women. A large proportion of patients begin with localized disease and undergo treatment with curative intent, while another large proportion of patients debuts with disseminated metastatic disease. In the last subgroup of patients, the prognosis in recent years has changed radically, given the existence of different targeted therapies thanks to the discovery of different biomarkers. Serological, histological, and genetic biomarkers have demonstrated their usefulness in the initial diagnosis, in the follow-up to detect relapses, to guide targeted treatment, and to stratify the prognosis of the most aggressive tumors in those with breast cancer. Molecular markers are currently the basis for the diagnosis of metastatic disease, given the wide variety of chemotherapy regions and existing therapies. These markers have been a real revolution in the therapeutic arsenal for breast cancer, and their diagnostic validity allows the classification of tumors with higher rates of relapse, aggressiveness, and mortality. In this sense, the existence of therapies targeting different molecular alterations causes a series of changes in tumor biology that can be assessed throughout the course of the disease to provide information on the underlying pathophysiology of metastatic disease, which allows us to broaden our knowledge of the different mechanisms of tissue invasion. Therefore, the aim of the present article is to review the clinical, diagnostic, predictive, prognostic utility and limitations of the main biomarkers available and under development in metastatic breast cancer. Full article

(This article belongs to the Special Issue Targeting Breast Cancer: Strategies and Hopes)

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24 pages, 1073 KiB

Open AccessReview

Regulation of Inflammasome by microRNAs in Triple-Negative Breast Cancer: New Opportunities for Therapy

by Liliana-Roxana Balahura (Stămat), Sorina Dinescu and Marieta Costache

Int. J. Mol. Sci. 2023, 24(4), 3245; https://doi.org/10.3390/ijms24043245 - 07 Feb 2023

Cited by 1 | Viewed by 2292

Abstract

During the past decade, researchers have investigated the molecular mechanisms of breast cancer initiation and progression, especially triple-negative breast cancer (TNBC), in order to identify specific biomarkers that could serve as feasible targets for innovative therapeutic strategies development. TNBC is characterized by a dynamic and aggressive nature, due to the absence of estrogen, progesterone and human epidermal growth factor 2 receptors. TNBC progression is associated with the dysregulation of nucleotide-binding oligomerization domain-like receptor and pyrin domain-containing protein 3 (NLRP3) inflammasome, followed by the release of pro-inflammatory cytokines and caspase-1 dependent cell death, termed pyroptosis. The heterogeneity of the breast tumor microenvironment triggers the interest of non-coding RNAs’ involvement in NLRP3 inflammasome assembly, TNBC progression and metastasis. Non-coding RNAs are paramount regulators of carcinogenesis and inflammasome pathways, which could help in the development of efficient treatments. This review aims to highlight the contribution of non-coding RNAs that support inflammasome activation and TNBC progression, pointing up their potential for clinical applications as biomarkers for diagnosis and therapy. Full article

(This article belongs to the Special Issue Targeting Breast Cancer: Strategies and Hopes)

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20 pages, 402 KiB

Open AccessReview

Genetic Heterogeneity, Tumor Microenvironment and Immunotherapy in Triple-Negative Breast Cancer

by Eva Kudelova, Marek Smolar, Veronika Holubekova, Andrea Hornakova, Dana Dvorska, Vincent Lucansky, Lenka Koklesova, Erik Kudela and Peter Kubatka

Int. J. Mol. Sci. 2022, 23(23), 14937; https://doi.org/10.3390/ijms232314937 - 29 Nov 2022

Cited by 22 | Viewed by 3727

Abstract

Heterogeneity of triple-negative breast cancer is well known at clinical, histopathological, and molecular levels. Genomic instability and greater mutation rates, which may result in the creation of neoantigens and enhanced immunogenicity, are additional characteristics of this breast cancer type. Clinical outcome is poor due to early age of onset, high metastatic potential, and increased likelihood of distant recurrence. Consequently, efforts to elucidate molecular mechanisms of breast cancer development, progression, and metastatic spread have been initiated to improve treatment options and improve outcomes for these patients. The extremely complex and heterogeneous tumor immune microenvironment is made up of several cell types and commonly possesses disorganized gene expression. Altered signaling pathways are mainly associated with mutated genes including p53, PIK3CA, and MAPK, and which are positively correlated with genes regulating immune response. Of note, particular immunity-associated genes could be used in prognostic indexes to assess the most effective management. Recent findings highlight the fact that long non-coding RNAs also play an important role in shaping tumor microenvironment formation, and can mediate tumor immune evasion. Identification of molecular signatures, through the use of multi-omics approaches, and effector pathways that drive early stages of the carcinogenic process are important steps in developing new strategies for targeted cancer treatment and prevention. Advances in immunotherapy by remodeling the host immune system to eradicate tumor cells have great promise to lead to novel therapeutic strategies. Current research is focused on combining immune checkpoint inhibition with chemotherapy, PARP inhibitors, cancer vaccines, or natural killer cell therapy. Targeted therapies may improve therapeutic response, eliminate therapeutic resistance, and improve overall patient survival. In the future, these evolving advancements should be implemented for personalized medicine and state-of-art management of cancer patients. Full article

(This article belongs to the Special Issue Targeting Breast Cancer: Strategies and Hopes)

22 pages, 1096 KiB

Open AccessReview

Advances in the Management of Central Nervous System Metastases from Breast Cancer

by Jorge Avila and José Pablo Leone

Int. J. Mol. Sci. 2022, 23(20), 12525; https://doi.org/10.3390/ijms232012525 - 19 Oct 2022

Cited by 1 | Viewed by 2506

Abstract

Central nervous system (CNS) metastases are common in breast cancer (BC) patients and are particularly relevant as new treatments for BC are prolonging survival. Here, we review advances in the treatment of CNS metastases from BC, including radiotherapy, systemic therapies, and the evolving role of immunotherapy. The use of radiotherapy and chemotherapy is the cornerstone of treatment for CNS metastases. However, new targeted therapies have recently been developed, including anti-HER2 agents and antibody–drug conjugates that have presented promising results for the treatment of these patients. Full article

(This article belongs to the Special Issue Targeting Breast Cancer: Strategies and Hopes)

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