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Breast Cancers: From Molecular Basis to Therapy
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Breast Cancers: From Molecular Basis to Therapy

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 December 2024 | Viewed by 13422

Special Issue Editor

Dr. Carlo Greco

E-Mail Website
Guest Editor
Radiation Oncology, Campus Bio-Medico University, 00128 Rome, Italy
Interests: molecular biology of cancer

Special Issue Information

Dear Colleagues,

Breast cancer is the most frequent malignancy among females, and its incidence is continuously increasing. According to the World Health Organization, it is expected to increase from 2.26 million diagnoses in 2020 to 3.03 million cases in 2040, representing an important global health problem. Advances in the field of molecular research have offered insights into the cellular mechanisms and genetic changes that characterize breast cancer subtypes.

IJMS has organized a series of Special Issues to highlight the latest advancements in order to be at the forefront of science in different fields of research. This editorial initiative, led by Dr. Carlo Greco, is focused on new insights, novel developments, current challenges, latest discoveries, recent advances, and future perspectives in the field of breast cancer.

The present Special Issue, entitled “Breast Cancers: From Molecular Basis to Therapy”, aims to present recent research developments to the wider community. We welcome contributions in this field.

Dr. Carlo Greco
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.

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Keywords

  • breast cancer
  • molecular biology

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Published Papers (6 papers)

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Research

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22 pages, 9046 KiB  
Article
Single-Sample Networks Reveal Intra-Cytoband Co-Expression Hotspots in Breast Cancer Subtypes
by Richard Ponce-Cusi, Patricio López-Sánchez, Vinicius Maracaja-Coutinho and Jesús Espinal-Enríquez
Int. J. Mol. Sci. 2024, 25(22), 12163; https://doi.org/10.3390/ijms252212163 - 13 Nov 2024
Viewed by 384
Abstract
Breast cancer is a heterogeneous disease comprising various subtypes with distinct molecular characteristics, clinical outcomes, and therapeutic responses. This heterogeneity evidences significant challenges for diagnosis, prognosis, and treatment. Traditional genomic co-expression network analyses often overlook individual-specific interactions critical for personalized medicine. In this [...] Read more.
Breast cancer is a heterogeneous disease comprising various subtypes with distinct molecular characteristics, clinical outcomes, and therapeutic responses. This heterogeneity evidences significant challenges for diagnosis, prognosis, and treatment. Traditional genomic co-expression network analyses often overlook individual-specific interactions critical for personalized medicine. In this study, we employed single-sample gene co-expression network analysis to investigate the structural and functional genomic alterations across breast cancer subtypes (Luminal A, Luminal B, Her2-enriched, and Basal-like) and compared them with normal breast tissue. We utilized RNA-Seq gene expression data to infer gene co-expression networks. The LIONESS algorithm allowed us to construct individual networks for each patient, capturing unique co-expression patterns. We focused on the top 10,000 gene interactions to ensure consistency and robustness in our analysis. Network metrics were calculated to characterize the topological properties of both aggregated and single-sample networks. Our findings reveal significant fragmentation in the co-expression networks of breast cancer subtypes, marked by a change from interchromosomal (TRANS) to intrachromosomal (CIS) interactions. This transition indicates disrupted long-range genomic communication, leading to localized genomic regulation and increased genomic instability. Single-sample analyses confirmed that these patterns are consistent at the individual level, highlighting the molecular heterogeneity of breast cancer. Despite these pronounced alterations, the proportion of CIS interactions did not significantly correlate with patient survival outcomes across subtypes, suggesting limited prognostic value. Furthermore, we identified high-degree genes and critical cytobands specific to each subtype, providing insights into subtype-specific regulatory networks and potential therapeutic targets. These genes play pivotal roles in oncogenic processes and may represent important keys for targeted interventions. The application of single-sample co-expression network analysis proves to be a powerful tool for uncovering individual-specific genomic interactions. Full article
(This article belongs to the Special Issue Breast Cancers: From Molecular Basis to Therapy)
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13 pages, 2903 KiB  
Article
In-Depth Analysis of the Peripheral Immune Profile of HER2+ Breast Cancer Patients on Neoadjuvant Treatment with Chemotherapy Plus Trastuzumab Plus Pertuzumab
by Ayelén Ivana Pesce Viglietti, María Belén Bordignon, Alexis Ostinelli, Manglio Miguel Rizzo, Gerardo Cueto, María Belén Sanchez, Florencia Perazzo, Mora Amat, Federico Coló, María Victoria Costanzo, Adrián Nervo, Jorge Nadal, Gabriel Crimi, Ignacio Mc Lean, Eunice Amancay Spengler, José Mordoh, Pablo Mandó and Estrella Mariel Levy
Int. J. Mol. Sci. 2024, 25(17), 9268; https://doi.org/10.3390/ijms25179268 - 27 Aug 2024
Viewed by 1162
Abstract
Currently, therapy for early-stage human epidermal growth factor receptor 2-positive (HER2+) breast cancer (BC) is based on the combination of trastuzumab and pertuzumab plus chemotherapy in a neoadjuvant regimen. The INMUNOHER study aimed to detect immunological markers in peripheral blood and their association [...] Read more.
Currently, therapy for early-stage human epidermal growth factor receptor 2-positive (HER2+) breast cancer (BC) is based on the combination of trastuzumab and pertuzumab plus chemotherapy in a neoadjuvant regimen. The INMUNOHER study aimed to detect immunological markers in peripheral blood and their association with treatment response. Sixty-two HER2+ BC patients were recruited. Pre-treatment samples were obtained before the start of treatment, while post-treatment samples were obtained after completing therapy and before surgery and were analyzed by flow cytometry. The pathologic complete response (pCR) rate achieved was 82.3%. The expression of the NKp30, PD-1, and TIM-3 receptors was reduced in the Natural Killer (NK)-CD56dim subset of patients who did not achieve pCR. Following therapy, many changes were found in leukocytes, including alterations in T cell lymphocyte proportions. Also, the percentage of NK cells decreased, and several phenotypic changes were observed in this population. After treatment, IFN-γ production by NK cells against HER2+-cells with or without trastuzumab was significantly reduced. HER2-targeted therapy plus chemotherapy demonstrated high efficacy in most patients, reducing the statistical power for finding immunological markers. However, NK subset phenotypes correlated better with response groups, and numerous changes in the percentage of leukocytes and T and NK cells, as well as changes in the functionality of NK cells, were observed in most patients after treatment, encouraging further research into these immune populations. Full article
(This article belongs to the Special Issue Breast Cancers: From Molecular Basis to Therapy)
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12 pages, 1802 KiB  
Article
Comparing the HER2 Status of the Primary Tumor to That of Disseminated Tumor Cells in Early Breast Cancer
by Léa Louise Volmer, Dominik Dannehl, Sabine Matovina, Florin-Andrei Taran, Christina Barbara Walter, Markus Wallwiener, Sara Yvonne Brucker, Andreas Daniel Hartkopf and Tobias Engler
Int. J. Mol. Sci. 2024, 25(11), 5910; https://doi.org/10.3390/ijms25115910 - 29 May 2024
Viewed by 1027
Abstract
Breast cancer remains a leading cause of cancer mortality in women globally. Despite advancements in systemic therapy, the risk of distant recurrence persists even after such treatment and may be linked to disseminated tumor cells (DTCs). Variability in molecular characteristics between primary tumors [...] Read more.
Breast cancer remains a leading cause of cancer mortality in women globally. Despite advancements in systemic therapy, the risk of distant recurrence persists even after such treatment and may be linked to disseminated tumor cells (DTCs). Variability in molecular characteristics between primary tumors (PTs) and distant metastases underscores the need to comprehensively understand metastatic pathways. This retrospective study investigated discrepancies between HER2 expression in PTs and DTCs and their implications for survival outcomes in 201 early breast cancer (EBC) patients. We found a significant association between HER2 expression in PTs and DTCs when classifying tumors as HER2-high/low/negative. Patients whose HER2 status was discordant between PTs and DTCs exhibited worse distant disease-free survival than those with concordant status. Multivariate analysis confirmed the HER2 status of DTCs as an independent prognostic factor for distant DFS. These findings emphasize the importance of assessing HER2 expression in DTCs and its potential implications for tailored therapy strategies in EBC. Furthermore, prospective trials are needed to validate these findings and explore targeted therapies based on the molecular characteristics of DTCs. Full article
(This article belongs to the Special Issue Breast Cancers: From Molecular Basis to Therapy)
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23 pages, 3059 KiB  
Article
Tamoxifen Activates Transcription Factor EB and Triggers Protective Autophagy in Breast Cancer Cells by Inducing Lysosomal Calcium Release: A Gateway to the Onset of Endocrine Resistance
by Cecilia Boretto, Chiara Actis, Pawan Faris, Francesca Cordero, Marco Beccuti, Giulio Ferrero, Giuliana Muzio, Francesco Moccia and Riccardo Autelli
Int. J. Mol. Sci. 2024, 25(1), 458; https://doi.org/10.3390/ijms25010458 - 29 Dec 2023
Cited by 3 | Viewed by 1584
Abstract
Among the several mechanisms accounting for endocrine resistance in breast cancer, autophagy has emerged as an important player. Previous reports have evidenced that tamoxifen (Tam) induces autophagy and activates transcription factor EB (TFEB), which regulates the expression of genes controlling autophagy and lysosomal [...] Read more.
Among the several mechanisms accounting for endocrine resistance in breast cancer, autophagy has emerged as an important player. Previous reports have evidenced that tamoxifen (Tam) induces autophagy and activates transcription factor EB (TFEB), which regulates the expression of genes controlling autophagy and lysosomal biogenesis. However, the mechanisms by which this occurs have not been elucidated as yet. This investigation aims at dissecting how TFEB is activated and contributes to Tam resistance in luminal A breast cancer cells. TFEB was overexpressed and prominently nuclear in Tam-resistant MCF7 cells (MCF7-TamR) compared with their parental counterpart, and this was not dependent on alterations of its nucleo-cytoplasmic shuttling. Tam promoted the release of lysosomal Ca2+ through the major transient receptor potential cation channel mucolipin subfamily member 1 (TRPML1) and two-pore channels (TPCs), which caused the nuclear translocation and activation of TFEB. Consistently, inhibiting lysosomal calcium release restored the susceptibility of MCF7-TamR cells to Tam. Our findings demonstrate that Tam drives the nuclear relocation and transcriptional activation of TFEB by triggering the release of Ca2+ from the acidic compartment, and they suggest that lysosomal Ca2+ channels may represent new druggable targets to counteract the onset of autophagy-mediated endocrine resistance in luminal A breast cancer cells. Full article
(This article belongs to the Special Issue Breast Cancers: From Molecular Basis to Therapy)
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12 pages, 866 KiB  
Article
The Clinical Relevance of the NATALEE Study: Application of the NATALEE Criteria to a Real-World Cohort from Two Large German Breast Cancer Centers
by Henning Schäffler, Franziska Mergel, Kerstin Pfister, Stephan Lukac, Angelina Fink, Kristina Veselinovic, Brigitte Rack, Visnja Fink, Elena Leinert, Moritz Dimpfl, Alexander Englisch, Christian Martin Tegeler, Anna Seller, Eva-Maria Grischke, Markus Hahn, Léa Louise Volmer, Tobias Engler, Marie Louise Frevert, Florin Andrei Taran, Wolfgang Janni, Sara Yvonne Brucker, Andreas Daniel Hartkopf and Dominik Dannehladd Show full author list remove Hide full author list
Int. J. Mol. Sci. 2023, 24(22), 16366; https://doi.org/10.3390/ijms242216366 - 15 Nov 2023
Cited by 9 | Viewed by 3791
Abstract
The NATALEE study showed a significant benefit in invasive disease-free survival (iDFS) for patients with HR+/HER2− early breast cancer (eBC) at intermediate and high risk of recurrence who were treated with the CDK4/6 inhibitor Ribociclib in combination with endocrine therapy (ET). This retrospective [...] Read more.
The NATALEE study showed a significant benefit in invasive disease-free survival (iDFS) for patients with HR+/HER2− early breast cancer (eBC) at intermediate and high risk of recurrence who were treated with the CDK4/6 inhibitor Ribociclib in combination with endocrine therapy (ET). This retrospective study aims to apply the NATALEE inclusion criteria to a representative real-world cohort to estimate the proportion of HR+/HER2− breast cancer patients eligible for adjuvant Ribociclib therapy. Patients who underwent full surgical treatment for eBC between January 2018 and December 2020 at two large German university breast cancer centers (University of Ulm, University of Tuebingen) were included. Descriptive statistics were used to characterize the patient population eligible for Ribociclib treatment based on the NATALEE study’s inclusion criteria. Out of 2384 enrolled patients, 1738 had HR+/HER2− eBC, of whom 43% (747/1738) met the NATALEE inclusion criteria. Of note, these patients were older, received less chemotherapy and presented with less advanced tumor stages compared to the NATALEE study cohort. Additionally, compared to the NATALEE study cohort, fewer patients had lymph node involvement (72.4% vs. 88.7%). Our analysis suggests that approximately 43% of all HR+/HER2− breast cancer patients will qualify for Ribociclib treatment. Given the numerous treatment options for patients with HR+/HER2− eBC, as well as the differences between the NATALEE cohort and patients in the real-world clinical setting, future analyses will be needed to determine which patients would benefit most from adjuvant CDK4/6 inhibitor treatment. Full article
(This article belongs to the Special Issue Breast Cancers: From Molecular Basis to Therapy)
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Review

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13 pages, 880 KiB  
Review
CDK4/6 Inhibitor Resistance in Hormone Receptor-Positive Metastatic Breast Cancer: Translational Research, Clinical Trials, and Future Directions
by Jin Sun Lee, Hannah Hackbart, Xiaojiang Cui and Yuan Yuan
Int. J. Mol. Sci. 2023, 24(14), 11791; https://doi.org/10.3390/ijms241411791 - 22 Jul 2023
Cited by 7 | Viewed by 4124
Abstract
The emergence of CDK4/6 inhibitors, such as palbociclib, ribociclib, and abemaciclib, has revolutionized the treatment landscape for hormone receptor-positive breast cancer. These agents have demonstrated significant clinical benefits in terms of both progression-free survival and overall survival. However, resistance to CDK4/6 inhibitors remains [...] Read more.
The emergence of CDK4/6 inhibitors, such as palbociclib, ribociclib, and abemaciclib, has revolutionized the treatment landscape for hormone receptor-positive breast cancer. These agents have demonstrated significant clinical benefits in terms of both progression-free survival and overall survival. However, resistance to CDK4/6 inhibitors remains a challenge, limiting their long-term efficacy. Understanding the complex mechanisms driving resistance is crucial for the development of novel therapeutic strategies and the improvement of patient outcomes. Translational research efforts, such as preclinical models and biomarker studies, offer valuable insight into resistance mechanisms and may guide the identification of novel combination therapies. This review paper aims to outline the reported mechanisms underlying CDK4/6 inhibitor resistance, drawing insights from both clinical data and translational research in order to help direct the future of treatment for hormone receptor-positive metastatic breast cancer. Full article
(This article belongs to the Special Issue Breast Cancers: From Molecular Basis to Therapy)
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