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Breast Cancer: Molecular Pathology, Diagnosis, and Therapeutic Strategies
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Breast Cancer: Molecular Pathology, Diagnosis, and Therapeutic Strategies

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: 30 June 2025 | Viewed by 9322

Special Issue Editor

Dr. Rodrigo Sánchez-Bayona

E-Mail Website
Guest Editor
Medical Oncology Department, Hospital Universitario 12 de Octubre, 28041 Madrid, Spain
Interests: breast cancer; dairy products; sun cohort; Mediterranean population

Special Issue Information

Dear Colleagues,

The aim of this special issue is to address how the characterization and integration of molecular biomarkers have impacted the way we classify and treat breast cancer. The molecular landscape of breast cancer is vast, and there exists a gap between molecular research and its implications in clinical practice. We invite our colleague researchers to submit to this special issue their works focused on novel biomarkers, integration of molecular features in the treatment-decision process and therapeutic algorithms, and both the prognostic and predictive value of molecular assays in breast cancer. We will appreciate original research articles, and review articles will be only considered if they have a clear added value into the available literature body.

Dr. Rodrigo Sánchez-Bayona
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. 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

  • biomarker
  • breast
  • molecular assays
  • molecular characterization
  • molecular-driven treatment

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Published Papers (5 papers)

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Research

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15 pages, 3448 KiB  
Article
Breast Cancer Stem Cells and Immunogenicity Profile in High-Risk Early Triple-Negative Breast Cancer: A Pilot Study
by Ariadna Roqué-Lloveras, Ferran Pérez-Bueno, Xavier Pozo-Ariza, Emma Polonio-Alcalá, Sira Ausellé-Bosch, Glòria Oliveras, Gemma Viñas and Teresa Puig
Int. J. Mol. Sci. 2025, 26(9), 3960; https://doi.org/10.3390/ijms26093960 - 22 Apr 2025
Viewed by 220
Abstract
Triple-negative breast cancer (TNBC) is an aggressive subtype requiring further knowledge of biomarkers to improve targeted therapy. A major resistance mechanism involves breast cancer stem cells (BCSCs) evading the immune system. Neoadjuvant or adjuvant chemotherapy may alter BCSCs and the patients’ immune response. [...] Read more.
Triple-negative breast cancer (TNBC) is an aggressive subtype requiring further knowledge of biomarkers to improve targeted therapy. A major resistance mechanism involves breast cancer stem cells (BCSCs) evading the immune system. Neoadjuvant or adjuvant chemotherapy may alter BCSCs and the patients’ immune response. We conducted a retrospective study including 29 early-stage TNBC patients resistant to chemotherapy diagnosed at the Catalan Institute of Oncology (Girona, Spain) in 2010–2019. We obtained 44 paired tumor samples (pre- and post-chemotherapy) from the Tumor Biobank, assessing BCSC biomarkers (CD44, CD24, and ALDH1), PD-L1, and percentages of stromal tumor-infiltrating lymphocytes (TILs). Clinicopathological characteristics were also collected. At baseline, 68% of tumors had high CD44 expression, 55% showed low CD24 expression, 9% had high ALDH1 expression, 91% were PD-L1-negative (<1%), and 64% had a low percentage of stromal TILs. PD-L1 expression significantly increased post-chemotherapy, with 50% of initially negative tumors becoming PD-L1 positive (≥1%) (p = 0.006). No significant changes were observed in BCSC markers or TILs. No association was found between baseline BCSCs and increased PD-L1 expression post-chemotherapy. At a median follow-up of 58.9 months, 48.3% of patients were alive, with non-significant favorable trends in time to progression, disease-free survival, and overall survival in the PD-L1 positivization cohort post-chemotherapy. In conclusion, high-risk early-stage TNBC tumors increased PD-L1 expression after chemotherapy, potentially affecting clinical outcomes. BCSCs remained stable and independent of the tumor immunogenicity post-chemotherapy. Further studies are needed to explore the relationship between BCSCs and the immunogenicity profile, for development of new combined therapeutic strategies. Full article
(This article belongs to the Special Issue Breast Cancer: Molecular Pathology, Diagnosis, and Therapeutic Strategies)
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12 pages, 1358 KiB  
Communication
Pharmacological Inhibition of MDM2 Induces Apoptosis in p53-Mutated Triple-Negative Breast Cancer
by Jasmin Linh On, Sahel Ghaderi, Carina Rittmann, Greta Hoffmann, Franziska Gier, Vitalij Woloschin, Jia-Wey Tu, Sanil Bhatia, Andrea Kulik, Dieter Niederacher, Hans Neubauer, Thomas Kurz, Tanja Fehm and Knud Esser
Int. J. Mol. Sci. 2025, 26(3), 1078; https://doi.org/10.3390/ijms26031078 - 26 Jan 2025
Cited by 1 | Viewed by 1161
Abstract
Triple-negative breast cancer (TNBC) represents the most aggressive breast carcinoma subtype lacking efficient therapeutic options. A promising approach in cancer treatment is the pharmacological inhibition of murine double minute 2 (MDM2)-p53 interaction inducing apoptosis in p53 wild-type tumors. However, the role of MDM2 [...] Read more.
Triple-negative breast cancer (TNBC) represents the most aggressive breast carcinoma subtype lacking efficient therapeutic options. A promising approach in cancer treatment is the pharmacological inhibition of murine double minute 2 (MDM2)-p53 interaction inducing apoptosis in p53 wild-type tumors. However, the role of MDM2 in TNBC with primarily mutant p53 is not well understood. We here selected the clinical-stage MDM2 inhibitors Idasanutlin and Milademetan and investigated their anti-tumoral effects in TNBC. When we analyzed anti-tumor activity in the TNBC cell lines MDA-MB-231, MDA-MB-436, and MDA-MB-468, cellular viability was efficiently reduced, with half maximal inhibitory concentration (IC50) values ranging between 2.00 and 7.62 µM being up to 11-fold lower compared to the well-characterized non-clinical-stage MDM2 inhibitor Nutlin-3a. Furthermore, caspase-3/7 activity was efficiently induced. Importantly, the IC50 values for MDM2 inhibition were equally observed in HCT116 p53+/+ or HCT116 p53−/− cells. Finally, the IC50 was significantly higher in non-malignant MCF-10A cells than in TNBC cells. Taken together, Idasanutlin and Milademetan show a potent anti-tumor activity in TNBC cell culture models by efficiently inducing tumor cell death via apoptosis. This effect was observed despite an inactivating p53 mutation and was apparently independent of p53 expression. Our data suggest that MDM2 is a promising target in TNBC and clinical-stage MDM2 inhibitors should be further evaluated for their potential therapeutic application. Full article
(This article belongs to the Special Issue Breast Cancer: Molecular Pathology, Diagnosis, and Therapeutic Strategies)
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25 pages, 1049 KiB  
Article
Interferon-Gamma Secretion Is Significantly Decreased in Stage III Breast Cancer Patients
by Jung Im Yi, Jean Schneider, Seung Taek Lim, Byeongkwan Park and Young Jin Suh
Int. J. Mol. Sci. 2024, 25(8), 4561; https://doi.org/10.3390/ijms25084561 - 22 Apr 2024
Cited by 2 | Viewed by 1927
Abstract
Even though some studies have shown possible clinical relationship between molecular subtypes and tumor infiltrating natural killer (NK) cells around tumors, there are few studies showing the clinical relevance of peripheral NK cell activity at diagnosis in female patients with invasive breast cancer. [...] Read more.
Even though some studies have shown possible clinical relationship between molecular subtypes and tumor infiltrating natural killer (NK) cells around tumors, there are few studies showing the clinical relevance of peripheral NK cell activity at diagnosis in female patients with invasive breast cancer. A total of 396 female invasive breast cancer patients who received curative surgical treatment from March 2017 to July 2021 were retrospectively analyzed. NK cell activation-induced interferon-gamma (IFN-γ) secretion measured by enzyme-linked immunosorbent assay was used to measure the activity of peripheral NK cells. Statistical analyses were performed to determine clinical relationships with major clinicopathologic parameters. Quadripartite NK cell activity measured by induced interferon-gamma showed significant relevance with staging and body mass index, and some of the inflammatory serological markers, namely N/L (neutrophil/lymphocyte), P/N (platelet/neutrophil), and P/L (platelet/lymphocyte), showed significantly different NK activity in each interval by univariate analysis. A binary subgroup analysis, setting the IFN-γ secretion cut-off at 100 pg/mL, showed that stage III was significantly increased and axillary lymph node metastasis positivity was increased in the group of IFN-γ < 100 pg/mL, and IFN-γ secretion decreased with an increasing N stage, increased BMI (body mass index), and decreased production of IFN-γ. Following this, the same binary analysis, but with the IFN-γ secretion cut-off at 250 pg/mL, also showed that secretion in stage III was increased in those concentrations with <250 pg/mL, axillary lymph node positivity appeared to be correlated, and BMI ≥ 30 increased in prevalence. Additional ANOVA post hoc tests (Bonferroni) were performed on some serological markers that tended to be somewhat inconsistent. By subgroup analysis with Bonferroni adjustment between the IFN-γ secretion and TNM stage, no significant difference in IFN-γ secretion could be identified at stages I, II, and IV, but at stage III, the IFN-γ secretion < 100 pg/mL was significantly higher than 250 ≤ IFN-γ secretion < 500 pg/mL or IFN-γ secretion ≥ 500 pg/mL. According to this study, stage III was significantly associated with the lowest IFN-γ secretion. Compared to a higher level of IFN-γ secretion, a lower level of IFN-γ secretion seemed to be associated with increased body mass index. Unlike when IFN-γ secretion was analyzed in quartiles, as the IFN-γ secretion fell below 100 pg/mL, the correlation between axillary lymph node positivity and increased N stage, increased BMI, and increased N/L and P/L, which are suggested poor prognostic factors, became more pronounced. We think a peripheral IFN-γ secretion test might be convenient and useful tool for pretreatment risk assessment and selecting probable candidates for further treatment such as immunotherapy in some curable but high-risk invasive breast cancer patients, compared to other costly assaying of tissue NK cell activity at diagnosis. Full article
(This article belongs to the Special Issue Breast Cancer: Molecular Pathology, Diagnosis, and Therapeutic Strategies)
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Review

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11 pages, 858 KiB  
Review
Diagnostic Performance of Prostate-Specific Membrane Antigen-Targeted Positron Emission Tomography in Patients Diagnosed with Different Types of Breast Cancer: A Systematic Review
by Alessio Rizzo, Domenico Albano, Caterina Marchiò, Francesco Dondi, Manuela Racca, Francesco Bertagna, Francesco Fiz, Arnoldo Piccardo and Giorgio Treglia
Int. J. Mol. Sci. 2024, 25(21), 11413; https://doi.org/10.3390/ijms252111413 - 24 Oct 2024
Cited by 1 | Viewed by 1325
Abstract
Recent research has proposed using positron emission tomography/computed tomography (PET/CT) along with the administration of prostate-specific membrane antigen (PSMA)-targeting radiopharmaceuticals to identify breast cancer (BC) lesions. An extensive literature review to investigate the possible diagnostic utility of PET/CT with PSMA-targeting radiopharmaceuticals in BC [...] Read more.
Recent research has proposed using positron emission tomography/computed tomography (PET/CT) along with the administration of prostate-specific membrane antigen (PSMA)-targeting radiopharmaceuticals to identify breast cancer (BC) lesions. An extensive literature review to investigate the possible diagnostic utility of PET/CT with PSMA-targeting radiopharmaceuticals in BC patients was performed. The research comprised different clinical scenarios, including both newly diagnosed BC patients and those who had experienced disease relapse. This updated systematic review encompassed six studies investigating the diagnostic efficacy of PSMA-targeted PET/CT in BC. Throughout all clinical settings investigated, the papers presented data demonstrating a modest diagnostic performance of PSMA-targeted PET/CT in different subtypes of BC. In this setting, PSMA-guided PET/CT showed slightly higher accuracy in patients diagnosed with triple-negative BC. Based on the current literature, PSMA-targeted PET/CT cannot be suggested as a diagnostic tool to assess BC extent in any clinical scenario. However, based on the PSMA expression observed in triple-negative patients, it can be proposed as a tool to evaluate whether BC patients could benefit from PSMA-targeting radioligand therapy. Full article
(This article belongs to the Special Issue Breast Cancer: Molecular Pathology, Diagnosis, and Therapeutic Strategies)
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37 pages, 2073 KiB  
Review
Onco-Breastomics: An Eco-Evo-Devo Holistic Approach
by Anca-Narcisa Neagu, Danielle Whitham, Pathea Bruno, Aneeta Arshad, Logan Seymour, Hailey Morrissiey, Angiolina I. Hukovic and Costel C. Darie
Int. J. Mol. Sci. 2024, 25(3), 1628; https://doi.org/10.3390/ijms25031628 - 28 Jan 2024
Cited by 3 | Viewed by 3955
Abstract
Known as a diverse collection of neoplastic diseases, breast cancer (BC) can be hyperbolically characterized as a dynamic pseudo-organ, a living organism able to build a complex, open, hierarchically organized, self-sustainable, and self-renewable tumor system, a population, a species, a local community, a [...] Read more.
Known as a diverse collection of neoplastic diseases, breast cancer (BC) can be hyperbolically characterized as a dynamic pseudo-organ, a living organism able to build a complex, open, hierarchically organized, self-sustainable, and self-renewable tumor system, a population, a species, a local community, a biocenosis, or an evolving dynamical ecosystem (i.e., immune or metabolic ecosystem) that emphasizes both developmental continuity and spatio-temporal change. Moreover, a cancer cell community, also known as an oncobiota, has been described as non-sexually reproducing species, as well as a migratory or invasive species that expresses intelligent behavior, or an endangered or parasite species that fights to survive, to optimize its features inside the host’s ecosystem, or that is able to exploit or to disrupt its host circadian cycle for improving the own proliferation and spreading. BC tumorigenesis has also been compared with the early embryo and placenta development that may suggest new strategies for research and therapy. Furthermore, BC has also been characterized as an environmental disease or as an ecological disorder. Many mechanisms of cancer progression have been explained by principles of ecology, developmental biology, and evolutionary paradigms. Many authors have discussed ecological, developmental, and evolutionary strategies for more successful anti-cancer therapies, or for understanding the ecological, developmental, and evolutionary bases of BC exploitable vulnerabilities. Herein, we used the integrated framework of three well known ecological theories: the Bronfenbrenner’s theory of human development, the Vannote’s River Continuum Concept (RCC), and the Ecological Evolutionary Developmental Biology (Eco-Evo-Devo) theory, to explain and understand several eco-evo-devo-based principles that govern BC progression. Multi-omics fields, taken together as onco-breastomics, offer better opportunities to integrate, analyze, and interpret large amounts of complex heterogeneous data, such as various and big-omics data obtained by multiple investigative modalities, for understanding the eco-evo-devo-based principles that drive BC progression and treatment. These integrative eco-evo-devo theories can help clinicians better diagnose and treat BC, for example, by using non-invasive biomarkers in liquid-biopsies that have emerged from integrated omics-based data that accurately reflect the biomolecular landscape of the primary tumor in order to avoid mutilating preventive surgery, like bilateral mastectomy. From the perspective of preventive, personalized, and participatory medicine, these hypotheses may help patients to think about this disease as a process governed by natural rules, to understand the possible causes of the disease, and to gain control on their own health. Full article
(This article belongs to the Special Issue Breast Cancer: Molecular Pathology, Diagnosis, and Therapeutic Strategies)
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