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Molecular Research and Cellular Biology of Breast Cancer
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Molecular Research and Cellular Biology of Breast Cancer

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: 20 July 2025 | Viewed by 5758

Special Issue Editors

Prof. Dr. Andrea Nicolini

E-Mail Website
Guest Editor
Department of Internal Medicine, Santa Chiara Hospital, University of Pisa, Via Roma 67, 56126 Pisa, Italy
Interests: breast and gastrointestinal cancer
Special Issues, Collections and Topics in MDPI journals
Dr. Cristian Scatena

E-Mail Website
Guest Editor
1. Division of Pathology, Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, 56126 Pisa, Italy
2. Department of Laboratory Medicine, Pisa University Hospital, 56126 Pisa, Italy
Interests: pathology; tumour microenvironment; molecular genetics; breast cancer
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Enhanced environmental pollution and life prolongation account for the tremendous cancer increase over the last century. Cancer is a significant hurdle and is one of the largest causes of death worldwide. Moreover, it is a substantial social problem due to its diffusion in the overall population and the high cost of biological drugs of the “targeted therapies” era, which prolong survival without providing a definitive cure. Cancer is a genetic and epigenetic disease involving a complex landscape of molecular mechanisms that take part in the biology of cancer and other cells in the tumor microenvironment (TME). Therefore, despite extensive efforts and progress, further research is required. The principal aim of this Special Issue is to collect potential contributions, research or review articles, to improve our knowledge of subjects related to cancer disease. We expect this Special Issue will be helpful in stimulating new ideas for translational research.

This Special Issue is supervised by Prof. Dr. Andrea Nicolini and Dr. Cristian Scatena, assisted by our Topical Advisory Panel Member, Dr. Margherita Puppo (Physiopathologie, Diagnostic et Traitements des Maladies Osseuses, Lyon, France).

Prof. Dr. Andrea Nicolini
Dr. Cristian Scatena
Guest Editors

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Keywords

  • molecular mechanisms of tumor growth and diffusion
  • cancer cell biology
  • biology of tumor micro-environmental cells
  • MDR
  • hormone dependency
  • HER2 positive breast cancer
  • TNBC
  • genetic and epigenetic alterations
  • pro-tumor and anti-tumor immune responses
  • conventional and biological therapies
  • blood and tissue biomarkers

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Published Papers (6 papers)

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Research

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19 pages, 4308 KiB  
Article
Disruption of P2Y2 Signaling Promotes Breast Tumor Cell Dissemination by Reducing ATP-Dependent Calcium Elevation and Actin Localization to Cell Junctions
by Makenzy L. Mull, Stephen J. P. Pratt, Keyata N. Thompson, David A. Annis, Rachel M. Lee, Julia A. Ju, Darin E. Gilchrist, Megan B. Stemberger, Liron Boyman, William J. Lederer, Michele I. Vitolo and Stuart S. Martin
Int. J. Mol. Sci. 2025, 26(9), 4286; https://doi.org/10.3390/ijms26094286 - 1 May 2025
Viewed by 210
Abstract
The tumor microenvironment and healing wounds both contain extremely high concentrations of adenosine triphosphate (ATP) compared to normal tissue. The P2Y2 receptor, an ATP-activated purinergic receptor, is typically associated with pulmonary, endothelial, and neurological cell signaling. Here, we examine ATP-dependent signaling in breast [...] Read more.
The tumor microenvironment and healing wounds both contain extremely high concentrations of adenosine triphosphate (ATP) compared to normal tissue. The P2Y2 receptor, an ATP-activated purinergic receptor, is typically associated with pulmonary, endothelial, and neurological cell signaling. Here, we examine ATP-dependent signaling in breast epithelial cells and how it is altered in metastatic breast cancer. Using rapid imaging techniques, we show how ATP-activated P2Y2 signaling causes an increase in intracellular Ca2+ in non-tumorigenic breast epithelial cells, approximately 3-fold higher than their tumorigenic and metastatic counterparts. The non-tumorigenic cells respond to increased Ca2+ with actin polymerization and localization to the cell edges after phalloidin staining, while the metastatic cells remain unaffected. The increase in intracellular Ca2+ after ATP stimulation was blunted to control levels using a P2Y2 antagonist, which also prevented actin mobilization and significantly increased cell dissemination from spheroids in non-tumorigenic cells. Furthermore, the lack of Ca2+ changes and actin mobilization in metastatic breast cancer cells could be due to the reduced P2Y2 expression, which correlates with poorer overall survival in breast cancer patients. This study elucidates the rapid changes that occur after elevated intracellular Ca2+ in breast epithelial cells and how metastatic cancer cells have adapted to evade this cellular response. Full article
(This article belongs to the Special Issue Molecular Research and Cellular Biology of Breast Cancer)
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17 pages, 2589 KiB  
Article
Impact of Patient Profile on CDK4/6 Inhibitor Therapy Outcomes: A Real-World Data Analysis
by Ioana-Miruna Stanciu, Maria-Cristina Orlov-Slavu, Andreea-Ioana Parosanu and Cornelia Nitipir
Int. J. Mol. Sci. 2025, 26(7), 3357; https://doi.org/10.3390/ijms26073357 - 3 Apr 2025
Viewed by 558
Abstract
Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors have transformed the treatment landscape for patients with hormone receptor-positive (HR+)/HER2-negative (HER2−) breast cancer. However, their efficacy is influenced by various clinical and biological factors, including patient age, tumor biology, and treatment-related toxicities. The aim of [...] Read more.
Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors have transformed the treatment landscape for patients with hormone receptor-positive (HR+)/HER2-negative (HER2−) breast cancer. However, their efficacy is influenced by various clinical and biological factors, including patient age, tumor biology, and treatment-related toxicities. The aim of this study is to evaluate the impact of demographic, clinical, and tumor-related characteristics on the efficacy of CDK4/6 inhibitors in a cohort of patients with metastatic HR+/HER2− breast cancer. We conducted a retrospective cohort study analyzing the outcomes of 95 patients with metastatic ER-positive, HER2-negative breast cancer (BC) treated with CDK4/6 inhibitors (ribociclib, palbociclib, and abemaciclib) in combination with endocrine therapy. The patient demographics, tumor characteristics, and treatment regimens were examined, with a primary focus on progression-free survival (PFS), overall survival (OS), time on treatment (TOT), and the influence of clinical and biological factors. Younger patients (under 50 years) demonstrated higher tumor aggressiveness, reflected by higher Ki67 levels and histological grades, which negatively impacted their survival outcomes. Ribociclib was associated with the highest survival benefit, particularly in younger patients. Older patients (over 50 years) showed greater rates of comorbidities and toxicity, with dose reductions correlated with improved survival outcomes. This study highlights the significance of personalized treatment strategies based on patient age, comorbidities, and tumor biology. Ribociclib shows superior efficacy in younger, less comorbid patients, while palbociclib remains a viable option for older patients with higher comorbidity burdens. Full article
(This article belongs to the Special Issue Molecular Research and Cellular Biology of Breast Cancer)
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19 pages, 2146 KiB  
Article
Synergistic Effects of Oxaliplatin, 5-Fluorouracil, and Novel Synthetic Uracil Analog U-359 on Breast Cancer Cell Carcinogenesis
by Angelika Długosz-Pokorska, Tomasz Janecki, Anna Janecka and Katarzyna Gach-Janczak
Int. J. Mol. Sci. 2025, 26(7), 2964; https://doi.org/10.3390/ijms26072964 - 25 Mar 2025
Viewed by 443
Abstract
Breast cancer presents significant global challenges, necessitating effective treatments to combat drug resistance and minimize chemotherapy side effects. This study evaluated the cytotoxic effects of U-359, Oxaliplatin (Ox), and 5-Fluorouracil (5-FU) in MCF-7 and MCF-10A cells using MTT and RealTime-GLO assays. Morphological changes [...] Read more.
Breast cancer presents significant global challenges, necessitating effective treatments to combat drug resistance and minimize chemotherapy side effects. This study evaluated the cytotoxic effects of U-359, Oxaliplatin (Ox), and 5-Fluorouracil (5-FU) in MCF-7 and MCF-10A cells using MTT and RealTime-GLO assays. Morphological changes were assessed by light microscopy following Wright–Giemsa staining. Apoptosis induction was studied using qPCR for apoptotic markers, the RealTime-Glo™ Annexin V assay, and the cleaved PARP1 ELISA assay. Caspase 8 and 9 activities, ABCB1, ABCG2, and NF-κB protein levels were quantified using ELISA. Synergy was analyzed using the Bliss Independence Model. The results indicated that combining U-359 with Ox and 5-FU enhanced cytotoxicity compared to individual treatments. U-359 induced apoptosis-associated morphological changes in MCF-7 cells, which were augmented with the Ox and 5-FU treatment. Apoptosis assays confirmed the up-regulation of pro-apoptotic markers and the down-regulation of anti-apoptotic markers with U-359 alone or in combination. Elevated cleaved PARP1 levels suggested robust apoptosis induction with U-359 and Ox or 5-FU. Caspase activity assays demonstrated a significant activation of caspase 8 and 9, implicating both apoptotic pathways. Furthermore, U-359 down-regulated ABCB1, ABCG2, and NF-κB in MCF-7 cells, which were up-regulated by Ox and 5-FU alone. The Bliss Independence Model revealed strong synergistic interactions (SI < 1) between U-359 and Ox or 5-FU, particularly in reducing ABCB1 and NF-κB levels. U-359 combined with Ox and 5-FU shows potential for overcoming chemotherapy resistance in breast cancer by enhancing apoptosis and modulating drug resistance. Further clinical studies are needed to optimize treatment and improve outcomes. Full article
(This article belongs to the Special Issue Molecular Research and Cellular Biology of Breast Cancer)
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12 pages, 243 KiB  
Article
Prognostic Significance of Peripheral Blood Parameters as Predictor of Neoadjuvant Chemotherapy Response in Breast Cancer
by Ionut Flaviu Faur, Amadeus Dobrescu, Ioana Adelina Clim, Paul Pasca, Cosmin Burta, Cristi Tarta, Dan Brebu, Andreea-Adriana Neamtu, Vlad Braicu, Ciprian Duta and Bogdan Totolici
Int. J. Mol. Sci. 2025, 26(6), 2541; https://doi.org/10.3390/ijms26062541 - 12 Mar 2025
Viewed by 1871
Abstract
The standard treatment for breast cancer typically includes surgery, often followed by systemic therapy and individualized treatment regimens. However, there is growing interest in identifying pre-therapeutic biomarkers that can predict tumor response to neoadjuvant chemotherapy (NACT). This study systematically evaluated various analytical parameters, [...] Read more.
The standard treatment for breast cancer typically includes surgery, often followed by systemic therapy and individualized treatment regimens. However, there is growing interest in identifying pre-therapeutic biomarkers that can predict tumor response to neoadjuvant chemotherapy (NACT). This study systematically evaluated various analytical parameters, including age, TNM stage, histological type, molecular subtype, and several biomarker ratios, such as the platelet-to-lymphocyte ratio (PLR), neutrophil-to-lymphocyte ratio (NLR), lymphocyte-to-monocyte ratio (LMR), systemic immune-inflammatory index (SII), and prognostic nutritional index (PNI). We aimed to assess the predictive value of these parameters regarding the tumor’s response rate to NACT. The analysis revealed a statistically significant association between the pathological complete response—pCR (absence of any detectable cancer cells in the tissue following neoadjuvant chemotherapy (NACT))—rate and NLR in the subgroup with values between 1 and 3 (p = 0.001). The optimal cut-off for PLR was determined to be 120.45, with 80.55% of patients achieving pCR showing PLR values below this threshold (p = 0.000). Similarly, the LMR cut-off was found to be 12.34, with 77.77% of patients with pCR having LMR values below this threshold (p = 0.002). Additionally, lower pre-therapeutic values of NLR (p < 0.001), PLR (p = 0.002), SII (p = 0.001), and LMR (p = 0.001) were significantly correlated with pCR compared to the non-pCR subgroup (p < 0.005). These findings highlight the predictive potential of these biomarkers for achieving pCR following NACT. Our study supports the hypothesis that pre-therapeutic values of NLR, PLR, SII, and LMR can serve as predictive biomarkers for pCR in breast cancer patients undergoing NACT. However, the PNI did not demonstrate predictive potential in relation to pCR. These biomarkers may provide valuable insights into patient prognosis and guide personalized treatment strategies. Full article
(This article belongs to the Special Issue Molecular Research and Cellular Biology of Breast Cancer)
19 pages, 12268 KiB  
Article
Potential Drug Synergy Through the ERBB2 Pathway in HER2+ Breast Tumors
by Yareli Rojas-Salazar, Emiliano Gómez-Montañez, Jorge Rojas-Salazar, Guillermo de Anda-Jáuregui and Enrique Hernández-Lemus
Int. J. Mol. Sci. 2024, 25(23), 12840; https://doi.org/10.3390/ijms252312840 - 29 Nov 2024
Viewed by 1137
Abstract
HER2-positive (HER2+) breast cancer is characterized by the overexpression of the ERBB2 (HER2) gene, which promotes aggressive tumor growth and poor prognosis. Targeting the ERBB2 pathway with single-agent therapies has shown limited efficacy due to resistance mechanisms and the complexity of gene interactions [...] Read more.
HER2-positive (HER2+) breast cancer is characterized by the overexpression of the ERBB2 (HER2) gene, which promotes aggressive tumor growth and poor prognosis. Targeting the ERBB2 pathway with single-agent therapies has shown limited efficacy due to resistance mechanisms and the complexity of gene interactions within the tumor microenvironment. This study aims to explore potential drug synergies by analyzing gene–drug interactions and combination therapies that target the ERBB2 pathway in HER2+ breast tumors. Using gene co-expression network analysis, we identified 23 metabolic pathways with significant cross-linking of gene interactions, including those involving EGFR tyrosine kinase inhibitors, PI3K, mTOR, and others. We visualized these interactions using Cytoscape to generate individual and combined drug–gene networks, focusing on frequently used drugs such as Erlotinib, Gefitinib, Lapatinib, and Cetuximab. Individual networks highlighted the direct effects of these drugs on their target genes and neighboring genes within the ERBB2 pathway. Combined drug networks, such as those for Cetuximab with Lapatinib, Cetuximab with Erlotinib, and Erlotinib with Lapatinib, revealed potential synergies that could enhance therapeutic efficacy by simultaneously influencing multiple genes and pathways. Our findings suggest that a network-based approach to analyzing drug combinations provides valuable insights into the molecular mechanisms of HER2+ breast cancer and offers promising strategies for overcoming drug resistance and improving treatment outcomes. Full article
(This article belongs to the Special Issue Molecular Research and Cellular Biology of Breast Cancer)
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Review

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37 pages, 1374 KiB  
Review
Molecular Mechanisms and Therapeutic Strategies to Overcome Resistance to Endocrine Therapy and CDK4/6 Inhibitors in Advanced ER+/HER2− Breast Cancer
by Paola Ferrari, Maria Luisa Schiavone, Cristian Scatena and Andrea Nicolini
Int. J. Mol. Sci. 2025, 26(7), 3438; https://doi.org/10.3390/ijms26073438 - 7 Apr 2025
Viewed by 897
Abstract
Approximately 70–80% of breast cancers are estrogen receptor-positive (ER+), with 65% of these cases also being progesterone receptor-positive (ER+PR+). In most cases of ER+ advanced breast cancer, endocrine therapy (ET) serves as the first-line treatment, utilizing various drugs that inhibit ER signaling. These [...] Read more.
Approximately 70–80% of breast cancers are estrogen receptor-positive (ER+), with 65% of these cases also being progesterone receptor-positive (ER+PR+). In most cases of ER+ advanced breast cancer, endocrine therapy (ET) serves as the first-line treatment, utilizing various drugs that inhibit ER signaling. These include tamoxifen, a selective estrogen receptor modulator (SERM); fulvestrant, a selective estrogen receptor degrader (SERD); and aromatase inhibitors (AIs), which block estrogen synthesis. However, intrinsic or acquired hormone resistance eventually develops, leading to disease progression. The combination of ET with cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6is) has been shown to significantly increase progression-free survival (PFS) and, in some cases, overall survival (OS). CDK4/6is works by arresting the cell cycle in the G1 phase, preventing DNA synthesis, and enhancing the efficacy of ET. This review highlights the key mechanisms of resistance to ET, whether used alone or in combination with biological agents, as well as emerging therapeutic strategies aimed at overcoming resistance. Addressing ET resistance remains a work in progress, and in the near future, better patient selection for different therapeutic approaches is expected through the identification of more precise biological and genetic markers. In particular, liquid biopsy may provide a real-time portrait of the disease, offering insights into mechanisms driving ET resistance and cancer progression. Full article
(This article belongs to the Special Issue Molecular Research and Cellular Biology of Breast Cancer)
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