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A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Molecular and Translational Medicine".

Deadline for manuscript submissions: 31 August 2026 | Viewed by 14440

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Dr. Anna De Blasio

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Guest Editor

Laboratory of Biochemistry, Department of Biological, Chemical and Pharmaceutical Sciences and Technologies (STEBICEF), University of Palermo, 90127 Palermo, Italy
Interests: TNBC; miRNA; cell death; cancer stem cells
Special Issues, Collections and Topics in MDPI journals

Dr. Daniela Carlisi

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Guest Editor

Section of Biochemistry, Department of Biomedicine, Neuroscience and Advanced Diagnostic, University of Palermo, 90127 Palermo, Italy
Interests: cancer; cancer stem cells; oxidative stress; antioxidant activity cell death; cancer therapy
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Breast cancer, one of the most common cancers affecting women worldwide, is classified based on its histological and molecular variability. This variability influences prognosis and treatment strategies, making breast cancer a complex disease to study and manage. One particularly heterogeneous subgroup is triple-negative breast cancer (TNBC), characterized by the absence of PR, ER, and HER2/NEU receptor expression. This molecular profile confers TNBC a particularly metastatic and invasive nature, along with drug resistance and a poor prognosis. Consequently, TNBC lacks specific molecular targets, making it difficult to establish effective therapeutic strategies, and conventional chemotherapy remains the primary treatment option.

The Special Issue, titled “Molecular Research in Breast Cancer”, aims to collect recent findings in this context, such as the following:

Genetic, epigenetic, and transcriptional profiles;
Descriptions of proteomic features and biochemical pathways;
Identification of cancer stem cells and their interactions with the microenvironment;
Metabolic reprogramming;
Effects induced by various drugs, in vitro and in vivo;
Breast cancer immunity and metabolic reprogramming;
Any evidence useful in identifying novel molecular targets to address the aggressive nature of TNBC.

We welcome contributions that enhance our understanding of breast cancer at the molecular level, providing insights that could lead to more effective treatments and improved patient outcomes.

Dr. Anna De Blasio
Dr. Daniela Carlisi
Guest Editors

Manuscript Submission Information

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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. Biomedicines is an international peer-reviewed open access monthly journal published by MDPI.

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Keywords

breast cancer
apoptosis
signaling pathways
drug resistance
metastasis
cancer stem cells
microRNA
biomarkers
drug target
tumor metabolism
tumor immunity

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Related Special Issue

Molecular Research of Triple-Negative Breast Cancer in Biomedicines (9 articles)

Published Papers (7 papers)

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Research

Jump to: Review

22 pages, 1254 KB

Open AccessArticle

Regulatory Variants in the KRAS 3′UTR and Intron 2 Are Associated with Breast Cancer Susceptibility Through Independent and Combinatorial Effects in a Mexican Population

by Asbiel Felipe Garibaldi-Ríos, Luis E. Figuera, Belinda Claudia Gómez-Meda, Guillermo Moisés Zúñiga-González, Ingrid Patricia Dávalos-Rodríguez, Patricia Montserrat García-Verdín, Ana María Puebla-Pérez, Irving Alejandro Carrillo-Dávila and Martha Patricia Gallegos-Arreola

Biomedicines 2026, 14(4), 948; https://doi.org/10.3390/biomedicines14040948 - 21 Apr 2026

Viewed by 287

Abstract

Background: Breast cancer (BC) is a leading cause of cancer-related mortality worldwide and a major public health concern in Mexico. Regulatory variants in KRAS, particularly within the 3′UTR and intronic regions, may influence gene expression through microRNA binding and transcriptional regulation. Methods: Five regulatory single-nucleotide variants (SNVs) in KRAS (rs12228277, rs1137196, rs8720, rs12587, and rs12245) were genotyped in BC patients and cancer-free controls. Associations were evaluated using odds ratios (ORs) with 95% confidence intervals (CIs), adjusting for age, alcohol, and tobacco use. Multiple testing was corrected using the Benjamini–Hochberg false discovery rate (FDR). Linkage disequilibrium (LD), multilocus combinations, and in silico functional analyses were also performed. Results: Variants rs12228277, rs1137196, rs8720, and rs12245 showed significant genotype-level associations with BC susceptibility, all remaining significant after FDR correction (pFDR < 0.05). No clinicopathological associations remained significant after correction in single-variant analyses. Multilocus analysis identified specific high-risk combinations (e.g., involving rs12228277, rs1137196, and rs8720) associated with increased BC susceptibility. At the nominal level, these combinations showed associations with clinicopathological features, including hormone receptor–positive status (PR and ER), proliferation markers, and Luminal B subtype; however, none remained significant after FDR correction. LD analysis indicated weak linkage among variants. In silico analyses suggested potential regulatory effects on microRNA binding and KRAS expression. Conclusions: Regulatory variants in KRAS are associated with BC susceptibility through independent effects and potential combinatorial patterns. These findings support the relevance of non-coding variation in cancer risk and warrant further functional and replication studies. Full article

(This article belongs to the Special Issue Molecular Research in Breast Cancer)

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27 pages, 2836 KB

Open AccessArticle

A Predictive Immunological Signature Associated with Pathological Response in Breast Cancer Treated with Neoadjuvant Chemotherapy

by Luis Arturo Palafox-Mariscal, Mariel García-Chagollán, Jesús García-Gómez, Fabiola Martín-Amaya-Barajas, Valeria Peña-Ruiz, Elizabeth Alvarez-Gonzalez, Eric Alfredo Aranda-Zuno, Jonathan Gallegos-Diaz-de-Leon, Aldo Antonio Alcaraz-Wong, Karina Ordoñez-Pantoja, Raquel Villegas-Pacheco, Adriana Aguilar-Lemarroy and Luis Felipe Jave-Suarez

Biomedicines 2026, 14(3), 663; https://doi.org/10.3390/biomedicines14030663 - 14 Mar 2026

Viewed by 618

Abstract

Background/Objectives: Breast cancer is a heterogeneous and complex disease with significant individual differences in molecular immunophenotype, biological behavior, histopathological morphology, and response to chemotherapy. The presence of tumor-infiltrating lymphocytes (TILs) has gained considerable attention due to growing evidence of their involvement in therapeutic efficacy, particularly in the response to neoadjuvant chemotherapy (NACT). Different immune cell subsets’ frequency, location, and functional orientation vary substantially between tumor types and individuals with apparently identical cancers. Currently, next-generation sequencing (NGS) has provided key insights into the composition of the tumor microenvironment. Simultaneously, immunohistochemistry (IHC) of paraffin-embedded biopsies allows the visualization of marker proteins within the immune infiltrate, thereby enhancing our understanding of the role of immune cells in cancer therapy. Methods: This exploratory study evaluated immune cell tumor infiltration using NGS with immune cell deconvolution, as well as automated IHC on Tru-Cut biopsies from 57 patients with locally advanced breast cancer. Image analysis was performed using Qupath v0.6.0 software. The percentage of infiltrating CD4+ or CD8+ T cells was determined, along with the expression of the markers FoxP3, LAG3, CTLA4, PD1, and TIM-3. We aimed to gain insights into the tumor microenvironment and its influence on the response to NACT in patients with breast cancer. Results: Transcriptomic immune deconvolution approaches suggested that a biased cytotoxic tumor environment is linked to chemosensitivity. IHC assays of individual markers reveal that baseline immune cell abundance and individual checkpoint expression did not differ significantly across the response groups. However, the functional organization and coordination of the tumor immune microenvironment showed distinct associations with chemosensitivity. Conclusions: Features representing immune balance, such as CD8/CD4 ratio and T cell-contextualized metrics, emerged as candidate predictors of pathological response to NACT, outperforming molecular phenotype alone in this exploratory cohort. Full article

(This article belongs to the Special Issue Molecular Research in Breast Cancer)

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18 pages, 2737 KB

Open AccessArticle

E-Cadherin Regulates HIF1-α In Vitro in Induced 3D Spheroid Models of Human Breast Cancer Through Both mTOR and Notch1 Signaling

by Yin Ye, Dollada Srisai and Sanford H. Barsky

Biomedicines 2025, 13(12), 2890; https://doi.org/10.3390/biomedicines13122890 - 26 Nov 2025

Viewed by 683

Abstract

Background: Both spontaneous and induced 3D spheroid models are among many in vitro models that recapitulate aspects of in vivo cancers. Although numerous studies have described the spatiotemporal relevance of these 3D models, there has been a paucity of studies investigating the signaling pathways that are activated during spheroidgenesis. Methods: Since in vitro 3D spheroidgenesis is thought to reflect at least some of the in vivo aspects of cancer biology (which undoubtedly involve cell adhesion, metabolism, and hypoxia-related pathways) and since we previously investigated these pathways in a model of spontaneous spheroidgenesis, this present study investigates these pathways in a model of induced spheroidgenesis with comparative studies involving a series of well-known E-cadherin-positive (MCF-7, HTB-126, HTB-27) and E-cadherin-negative (MDA-MB-468, MDA-MB-231, BT-549) human breast carcinoma cell lines. Results: Our findings demonstrate that during early induced spheroidgenesis, E-cadherin regulates hypoxia-inducible factor 1-alpha (HIF-1α) predominantly through PI3K/AKT/mTOR signaling and to a lesser extent through Notch1 signaling. Both the knockout of E-cadherin and calpain-mediated E-cadherin proteolysis result in a remarkable reduction in HIF-1α. Conclusions: 3D spheroid models recapitulate, in part, some of the in vivo stages of cancer progression, which include primary tumor clusters, lymphovascular emboli, and micrometastases, the signaling pathways present in these 3D spheroid models likely have relevance in vivo. Full article

(This article belongs to the Special Issue Molecular Research in Breast Cancer)

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18 pages, 2392 KB

Open AccessArticle

Synergistic Inhibition of Triple-Negative Breast Cancer by Acetylsalicylic Acid and Recombinant Human APE1/Ref-1 in a Mouse Xenograft Model

by Hao Jin, Yu Ran Lee, Sungmin Kim, Eunju Choi, Ka-Young Lee, Hee Kyoung Joo, Eun-Ok Lee, Cuk-Seong Kim, Je Ryong Kim, Sang Hun Lee and Byeong Hwa Jeon

Biomedicines 2025, 13(11), 2767; https://doi.org/10.3390/biomedicines13112767 - 12 Nov 2025

Cited by 1 | Viewed by 874

Abstract

Background: Triple-negative breast cancer (TNBC) is a highly aggressive subtype with limited therapeutic options due to the lack of estrogen, progesterone, and HER2 receptors. This study investigated the synergistic anticancer effects of recombinant human apurinic/apyrimidinic endonuclease 1/redox factor-1 (rhAPE1/Ref-1) and acetylsalicylic acid (ASA), a combination that has not been previously tested in vivo. Methods: We treated MDA-MB-231 TNBC cells with rhAPE1/Ref-1, ASA, or their combination to assess cell viability and apoptosis in vitro. In vivo, a murine xenograft model was established to evaluate the efficacy of the combination treatment on tumor growth, tumor-specific biomarkers, and key apoptotic proteins. The safety profile of the combination therapy was also assessed by monitoring hematological parameters. Results: While monotherapy with either rhAPE1/Ref-1 or ASA had minimal effects, their combination significantly reduced cell viability and enhanced apoptosis in vitro by increasing DNA fragmentation. These synergistic cytotoxic effects were significantly inhibited by the receptor for advanced glycation end-products (RAGE) siRNA, suggesting that RAGE acts as an important mediator. In the xenograft model, the combination treatment suppressed tumor growth by approximately 70%, an effect comparable to paclitaxel (PTX). This was confirmed by a significant reduction in the plasma levels of TNBC biomarkers (CEA, CA27-29, and CA15-3) and increased tumor apoptosis via the upregulation of p53 and Bax and downregulation of Bcl-2. Notably, ASA, alone or combined with rhAPE1/Ref-1, induced the expression of RAGE in MDA-MB-231 tumors. In contrast to PTX, the combination of rhAPE1/Ref-1 and ASA did not cause hematological toxicity, such as anemia or thrombocytopenia. Conclusions: The combination of rhAPE1/Ref-1 and ASA represents a promising new therapeutic strategy for TNBC by enhancing apoptosis and significantly inhibiting tumor progression in a mouse xenograft model. Full article

(This article belongs to the Special Issue Molecular Research in Breast Cancer)

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17 pages, 1302 KB

Open AccessArticle

DNA Methylation and Demethylation in Triple-Negative Breast Cancer: Associations with Clinicopathological Characteristics and the Chemotherapy Response

by Kateryna Tarhonska, Mateusz Wichtowski, Thomas Wow, Agnieszka Kołacińska-Wow, Katarzyna Płoszka, Wojciech Fendler, Izabela Zawlik, Sylwia Paszek, Alina Zuchowska and Ewa Jabłońska

Biomedicines 2025, 13(3), 585; https://doi.org/10.3390/biomedicines13030585 - 26 Feb 2025

Cited by 3 | Viewed by 4628

Abstract

Objectives: Triple-negative breast cancer (TNBC) is an aggressive cancer subtype with limited treatment options due to the absence of estrogen, progesterone receptors, and HER2 expression. This study examined the impact of DNA methylation and demethylation markers in tumor tissues on TNBC patients’ response to neoadjuvant chemotherapy (NACT) and analyzed the correlation between 5-methylcytosine (5-mC) and 5-hydroxymethylcytosine (5-hmC) and clinicopathological characteristics, offering new insights into the predictive value of these epigenetic markers. Methods: The study included 53 TNBC female patients, 19 of whom received neoadjuvant chemotherapy (NACT) before surgery. Global DNA methylation and demethylation levels were quantified using an ELISA-based method to measure 5-mC and 5-hmC content in DNA isolated from pre-treatment biopsy samples (in patients undergoing NACT) and postoperative tissues (in patients without NACT). Results: In patients who received NACT, those with disease progression had significantly higher pretreatment levels of 5-hmC (p = 0.028) and a trend toward higher 5-mC levels (p = 0.054) compared to those with pathological complete response, partial response, or stable disease. Higher 5-mC and 5-hmC levels were significantly associated with higher tumor grade (p = 0.039 and p = 0.017, respectively). Additionally, a positive correlation was observed between the Ki-67 proliferation marker and both 5-mC (r_S = 0.340, p = 0.049) and 5-hmC (r_S = 0.341, p = 0.048) levels in postoperative tissues. Conclusions: Our study highlights the potential of global DNA methylation and demethylation markers as predictors of tumor aggressiveness and chemotherapy response in TNBC. Further research in larger cohorts is necessary to validate these markers’ prognostic and predictive value. Full article

(This article belongs to the Special Issue Molecular Research in Breast Cancer)

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Review

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31 pages, 1646 KB

Open AccessReview

All the Way: A Decade of SIRT1 in Breast Cancer

by Giovanni Pratelli, Mauro Montalbano, Federica Affranchi, Chiara Occhipinti, Marianna Lauricella, Daniela Carlisi and Anna De Blasio

Biomedicines 2026, 14(3), 671; https://doi.org/10.3390/biomedicines14030671 - 15 Mar 2026

Viewed by 766

Abstract

Breast cancer (BC) is a highly heterogeneous genetic disease, comprising several subtypes with distinct features that significantly influence prognosis and treatment outcomes. Among these subtypes, triple-negative breast cancer (TNBC) is particularly aggressive and makes it resistant to many standard therapies. Epigenetic mechanisms, including acetylation and deacetylation, are crucial in regulating gene expression and maintaining normal cellular functions and are closely associated with BC progression. In this context, the histone deacetylases sirtuins (SIRT1-7) regulate key biological processes like genomic stability, inflammation, cellular senescence, and metabolic functions, increasingly linked to cancer. In particular, SIRT1 shows dual roles, functioning both as a tumor suppressor or an oncogene, contributing to cancer initiation, progression, and metastasis as well as chemotherapy resistance. Despite extensive research in the past decade, the exact role of SIRT1 in BC, especially in TNBC, remains controversial. Recent findings suggest that SIRT1 can be modulated not only through pharmacological approaches but also using natural extracts, offering potential alternative or complementary therapeutic strategies. Additionally, SIRT1 activity is regulated by a complex network of miRNAs, highlighting the need for further investigation. This review aims to summarize recent studies to identify key insights into the role of SIRT1 and explore it as a potential therapeutic target in BC. Full article

(This article belongs to the Special Issue Molecular Research in Breast Cancer)

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28 pages, 466 KB

Open AccessReview

Neoantigen-Driven Immunotherapy in Triple-Negative Breast Cancer: Emerging Strategies and Clinical Potential

by Peter A. Shatalov, Anna A. Bukaeva, Egor M. Veselovsky, Alexey A. Traspov, Daria V. Bagdasarova, Irina A. Leukhina, Anna P. Shinkarkina, Maria P. Raygorodskaya, Alena V. Murzaeva, Yulia A. Mechenici, Maria A. Revkova, Andrey D. Kaprin and Peter V. Shegai

Biomedicines 2025, 13(9), 2213; https://doi.org/10.3390/biomedicines13092213 - 9 Sep 2025

Cited by 3 | Viewed by 3420

Abstract

Triple-negative breast cancer (TNBC) is one of the most aggressive subtypes of breast cancer (BC), comprising approximately 20% of newly diagnosed BC cases. The poor prognosis, high recurrence rates, and inefficacy of hormone-based therapies make TNBC one of the greatest challenges in contemporary oncology. The unique immunological features of TNBC, including relatively high tumor mutational burden, abundance of tumor-infiltrating lymphocytes, and elevated PD-L1 expression, offer a wide range of opportunities for immunotherapeutic approaches, of which the most progressive and promising are neoantigen-driven ones. This review examines the current landscape of neoantigen-based therapeutic approaches in TNBC treatment, spanning from discovery methodologies to clinical applications. We provide a critical analysis of the tumor microenvironment (TME) in TNBC, highlighting the balance between its immunoactivating (CD8+ T-cells, dendritic cells) and immunosuppressive (regulatory T-cells, M2 macrophages) components as the key determinant of therapeutic success, as well as reviewing the emerging approaches to TME reprogramming and recruiting in favor of better outcomes. We also present state-of the-art methods in neoantigen identification and prioritization, covering the landscape of technological platforms and prediction algorithms, addressing the existing accuracy limitations along with emerging computational solutions, and comprehensively discussing the TNBC neoantigen spectrum. Our analysis shows the strong domination of patient-specific (“private”) neoantigens over shared variants in the TNBC, with TP53 as the only gene with recurrent variants. Finally, we extensively cover neoantigen-recruiting therapeutic modalities including adoptive cell therapies, personalized vaccine platforms (peptide-based, mRNA/DNA vaccines, dendritic cell vaccines), and oncolytic viruses-based approaches. Our study of current clinical trials demonstrates the substantial gap between early proof-of-concept experiments and further applicability of neoantigen-driven therapies. The major challenges hampering the success of such methods include neoantigen prediction inaccuracy rates, high manufacturing costs, and time consumption. Promising ways to overcome these difficulties include the development of combinational strategies, TME modeling and modifying, and improvement of the therapy delivery properties, along with the optimization of production workflows and cost-effectiveness of vaccine development. Full article

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