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Predictive, Prognostic Biomarkers and Therapeutic Targets 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: closed (20 March 2025) | Viewed by 11142

Special Issue Editors


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Guest Editor
Department of Radiation Oncology, Ospedale San Filippo Neri, ASL Rome 1, Rome, Italy
Interests: radiotherapy; breast cancer; stereotactic body radiotherapy; palliative radiotherapy target therapy; immunotherapy; tailored systemic therapy

E-Mail Website
Guest Editor
1. Department of Radiation Oncology, Weill Cornell Medicine, New York, NY, USA
2. Department of Radiation Oncology, Miulli General Regional Hospital, Acquaviva delle Fonti, Bari, Italy
Interests: radiotherapy; breast cancer; stereotactic body radiotherapy; brain radiosurgery; target therapy; immunotherapy; tailored systemic therapy

Special Issue Information

Dear Colleagues,

Breast cancer is the most common cancer in women worldwide, with a high prevalence and incidence, configuring an important issue in cancer epidemiology. Over the years, new diagnostic, surgical and radiation techniques, more effective systemic treatments, and a better understanding of the disease biology and its complexity have improved both the survival and quality of life of breast cancer patients. However, the continuous research in the biological-molecular as well as clinical-translational fields constitute a projection towards the development of possible future treatments.

The scope of this Special Issue is to summarize and enlarge the knowledge in predictive, prognostic biomarkers and therapeutic targets in breast cancer, mostly focus on the interaction of radiotherapy (including stereotactic body radiotherapy and brain radiosurgery) and tailored systemic therapy.

Therefore, on these contexts, authors are invited to submit original research and review articles which address the progress and current standing of cellular signalling and molecular insights.

Dr. Antonella Ciabattoni
Dr. Fabiana Gregucci
Guest Editors

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Keywords

  • radiotherapy
  • breast cancer
  • stereotactic body radiotherapy
  • brain radiosurgery
  • target therapy
  • immunotherapy
  • tailored systemic therapy

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Published Papers (7 papers)

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Research

19 pages, 7417 KiB  
Article
Optimizing Detection of Circulating Tumor Cells in Breast Cancer: Unveiling New Markers for Clinical Applications
by Amira Mehtar, Janine Wechsler, Christophe Desterke, Julien Giron-Michel, Amira Bouzidi, Aude Burlion, Fawzia Louache, Samira Kahia-Tani, Georges Uzan and Sina Naserian
Int. J. Mol. Sci. 2025, 26(10), 4714; https://doi.org/10.3390/ijms26104714 - 14 May 2025
Viewed by 149
Abstract
Breast cancer (BC) is a heterogeneous disease with high metastasis potential, especially in the bones, liver, and lungs. Circulating tumor cells (CTCs), which emerge from active tumors, represent an early step toward metastasis and are associated with poor prognosis. CTCs of carcinoma origin [...] Read more.
Breast cancer (BC) is a heterogeneous disease with high metastasis potential, especially in the bones, liver, and lungs. Circulating tumor cells (CTCs), which emerge from active tumors, represent an early step toward metastasis and are associated with poor prognosis. CTCs of carcinoma origin are believed to express EpCAM and cytokeratins (CKs), common epithelial markers that are frequently used to identify them. However, in practice, the most aggressive CTCs lose the expression of those markers, leading to the partial loss of important information. Thus, finding some novel markers that identify CTCs regardless of their heterogeneity is crucial. A specific bioinformatics workflow integrating primary tumor and diverse BC cell lines transcriptomic expression analysis was developed and compared with single CTC transcriptomic analyses. We have identified a set of genes that are overexpressed in primary BC cells and are commonly upregulated among BC cell lines. Fifty of them were also found to be expressed in BC CTCs by single-cell transcriptomic analysis. Further in silico sorting narrowed this list to 12 genes. Using ScreenCell technology to isolate cancer cells spiked into normal blood, we tested the protein expression of all corresponding genes in vitro using the double immunocytochemistry method and validated MARCKSL1, SLC9A3R1, and RHOD as the most expressed markers. We then isolated the CTCs of 40 LN-invaded BC patients and 18 healthy donors using ScreenCell technology and showed that the combination of these three markers resulted in significantly better recognition of CTCs compared to EpCAM and CK conventional markers. Employing these novel markers, we found a clear distinction between blood samples from patients and healthy donors. In conclusion, through a specific bioinformatics workflow, in addition to in vitro and further clinical validations, we found three novel markers to precisely identify CTCs. These markers, when used together, enable a significantly more efficient identification of CTCs compared to conventional epithelial markers. Full article
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19 pages, 4184 KiB  
Article
Identification of Functional Immune Biomarkers in Breast Cancer Patients
by Roshanak Derakhshandeh, Yuyi Zhu, Junxin Li, Danubia Hester, Rania Younis, Rima Koka, Laundette P. Jones, Wenji Sun, Olga Goloubeva, Katherine Tkaczuk, Joshua Bates, Jocelyn Reader and Tonya J. Webb
Int. J. Mol. Sci. 2024, 25(22), 12309; https://doi.org/10.3390/ijms252212309 - 16 Nov 2024
Viewed by 1096
Abstract
Cancer immunotherapy has emerged as an effective, personalized treatment for certain patients, particularly for those with hematological malignancies. However, its efficacy in breast cancer has been marginal—perhaps due to cold, immune-excluded, or immune-desert tumors. Natural killer T (NKT) cells play a critical role [...] Read more.
Cancer immunotherapy has emerged as an effective, personalized treatment for certain patients, particularly for those with hematological malignancies. However, its efficacy in breast cancer has been marginal—perhaps due to cold, immune-excluded, or immune-desert tumors. Natural killer T (NKT) cells play a critical role in cancer immune surveillance and are reduced in cancer patients. Thus, we hypothesized that NKT cells could serve as a surrogate marker for immune function. In order to assess which breast cancer patients would likely benefit from immune cell-based therapies, we have developed a quantitative method to rapidly assess NKT function using stimulation with artificial antigen presenting cells followed by quantitative real-time PCR for IFN-γ. We observed a significant reduction in the percentage of circulating NKT cells in breast cancer patients, compared to healthy donors; however, the majority of patients had functional NKT cells. When we compared BC patients with highly functional NKT cells, as indicated by high IFN-γ induction, to those with little to no induction, following stimulation of NKT cells, there was no significant difference in NKT cell number between the groups, suggesting functional loss has more impact than physical loss of this subpopulation of T cells. In addition, we assessed the percentage of tumor-infiltrating lymphocytes and PD-L1 expression within the tumor microenvironment in the low and high responders. Further characterization of immune gene signatures in these groups identified a concomitant decrease in the induction of TNFα, LAG3, and LIGHT in the low responders. We next investigated the mechanisms by which breast cancers suppress NKT-mediated anti-tumor immune responses. We found that breast cancers secrete immunosuppressive lipids, and treatment with commonly prescribed medications that modulate lipid metabolism, can reduce tumor growth and restore NKT cell responses. Full article
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12 pages, 1504 KiB  
Article
Assessing the Prognostic Value of Cytoplasmic and Stromal Caveolin-1 in Early Triple-Negative Breast Cancer Undergoing Neoadjuvant Chemotherapy
by Iris Teruel, Eva Castellà, Sabela Recalde, Gemma Viñas, Anna Petit, Macedonia Trigueros, Eva Martínez-Balibrea, Eudald Felip, Milana Bergamino, Adrià Bernat-Peguera, Beatriz Cirauqui, Vanesa Quiroga, Angelica Ferrando-Díez, Anna Pous, Assumpció López, Laia Boronat, Gemma Soler, Jordi Recuero, Margarita Romeo, Pau Guillén, Ricard Mesía, Ester Ballana, Anna Martínez-Cardús and Mireia Margelíadd Show full author list remove Hide full author list
Int. J. Mol. Sci. 2024, 25(22), 12241; https://doi.org/10.3390/ijms252212241 - 14 Nov 2024
Viewed by 1324
Abstract
Triple-negative breast cancer (TNBC) is a highly aggressive subtype with limited therapeutic options, leading to higher relapse rates and mortality. Identifying prognostic biomarkers like caveolin-1 (CAV1) is crucial for personalized treatment. CAV1 influences tumor progression and chemotherapy response, particularly through its interaction with [...] Read more.
Triple-negative breast cancer (TNBC) is a highly aggressive subtype with limited therapeutic options, leading to higher relapse rates and mortality. Identifying prognostic biomarkers like caveolin-1 (CAV1) is crucial for personalized treatment. CAV1 influences tumor progression and chemotherapy response, particularly through its interaction with the tumor microenvironment (TME) and cancer metabolism. Understanding the prognostic value of CAV1 in different cellular compartments is essential for its clinical application in TNBC. In the methods section CAV1 gene expression in TNBC was evaluated using in silico analysis, followed by the immunohistochemical staining of tumor cytoplasm (cCAV1) and stromal cells (sCAV1) in 58 early-stage TNBC patients. Statistical analyses were performed to correlate CAV1 expression with clinicopathological features and survival. In the results section, in silico analysis revealed higher CAV1 expression in TNBC, correlating with shorter overall survival. In the patient samples, cCAV1 was observed in 10.3% of cases, and was associated with larger tumors, higher grades, and poorer prognoses. sCAV1 was detected in 42% of cases, associated with less proliferative and less aggressive tumors, but did not significantly impact prognoses. In conclusion, cCAV1 expression is a significant prognostic marker in early-stage TNBC, highlighting the importance of assessing CAV1 in different cellular compartments. Further research is needed to explore the mechanisms and clinical implications of cCAV1. Full article
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15 pages, 3974 KiB  
Article
Peri-Tumoural Lipid Composition and Hypoxia for Early Immune Response to Neoadjuvant Chemotherapy in Breast Cancer
by Sai Man Cheung, Kwok-Shing Chan, Nicholas Senn, Ehab Husain, Ravi Sharma, Trevor McGoldrick, Tanja Gagliardi, Yazan Masannat and Jiabao He
Int. J. Mol. Sci. 2024, 25(17), 9303; https://doi.org/10.3390/ijms25179303 - 28 Aug 2024
Viewed by 1370
Abstract
The deregulation of monounsaturated, polyunsaturated, and saturated fatty acids (MUFAs, PUFAs, SFAs) from de novo synthesis and hypoxia are central metabolic features of breast tumour. Early response markers for neoadjuvant chemotherapy (NACT) are critical for stratified treatment for patients with breast cancer, and [...] Read more.
The deregulation of monounsaturated, polyunsaturated, and saturated fatty acids (MUFAs, PUFAs, SFAs) from de novo synthesis and hypoxia are central metabolic features of breast tumour. Early response markers for neoadjuvant chemotherapy (NACT) are critical for stratified treatment for patients with breast cancer, and restoration of lipid metabolism and normoxia might precede observable structural change. In this study, we hypothesised that peri-tumoural lipid composition and hypoxia might be predictive and early response markers in patients with breast cancer undergoing NACT. Female patients with breast cancer were scanned on a 3T clinical MRI scanner at baseline and Cycle1, with acquisition of lipid composition maps of MUFAs, PUFAs, and SFAs, and hypoxia maps of effective transverse relaxation rate R2*. The percentage change in lipid composition and hypoxia at Cycle1 was calculated with reference to baseline. Tumour-associated macrophages were analysed based on immunostaining of CD163 from biopsy and resection, with the percentage change in the resected tumour calculated across the entire NACT. We found no significant difference in lipid composition and R2* between good and poor responders at baseline and Cycle1; however, the correlation between the percentage change in MUFAs and PUFAs against CD163 suggested the modulation in lipids with altered immune response might support the development of targeted therapies. Full article
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20 pages, 4224 KiB  
Article
Exploring the Relationship between MicroRNAs, Intratumoral Microbiota, and Breast Cancer Progression in Patients with and without Metastasis
by Aurora Laborda-Illanes, Lucía Aranega-Martín, Lidia Sánchez-Alcoholado, Soukaina Boutriq, Isaac Plaza-Andrades, Jesús Peralta-Linero, Guadalupe Garrido Ruiz, Bella Pajares-Hachero, Martina Álvarez, Emilio Alba, Alicia González-González and María Isabel Queipo-Ortuño
Int. J. Mol. Sci. 2024, 25(13), 7091; https://doi.org/10.3390/ijms25137091 - 28 Jun 2024
Cited by 3 | Viewed by 2090
Abstract
Breast cancer (BC) continues to pose a significant burden on global cancer-related morbidity and mortality, primarily driven by metastasis. However, the combined influence of microRNAs (miRNAs) and intratumoral microbiota on BC metastasis remains largely unexplored. In this study, we aimed to elucidate the [...] Read more.
Breast cancer (BC) continues to pose a significant burden on global cancer-related morbidity and mortality, primarily driven by metastasis. However, the combined influence of microRNAs (miRNAs) and intratumoral microbiota on BC metastasis remains largely unexplored. In this study, we aimed to elucidate the interplay between intratumoral microbiota composition, miRNA expression profiles, and their collective influence on metastasis development in BC patients by employing 16S rRNA sequencing and qPCR methodologies. Our findings revealed an increase in the expression of miR-149-5p, miR-20b-5p, and miR-342-5p in metastatic breast cancer (Met-BC) patients. The Met-BC patients exhibited heightened microbial richness and diversity, primarily attributed to diverse pathogenic bacteria. Taxonomic analysis identified several pathogenic and pro-inflammatory species enriched in Met-BC, contrasting with non-metastatic breast cancer (NonMet-BC) patients, which displayed an enrichment in potential probiotic and anti-inflammatory species. Notably, we identified and verified a baseline prognostic signature for metastasis in BC patients, with its clinical relevance further validated by its impact on overall survival. In conclusion, the observed disparities in miRNA expression and species-level bacterial abundance suggest their involvement in BC progression. The development of a prognostic signature holds promise for metastasis risk assessment, paving the way for personalized interventions and improved clinical outcomes in BC patients. Full article
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22 pages, 3595 KiB  
Article
Integrated Metabolomics and Transcriptomics Analysis of Anacardic Acid Inhibition of Breast Cancer Cell Viability
by Kellianne M. Piell, Claire C. Poulton, Christian G. Stanley, David J. Schultz and Carolyn M. Klinge
Int. J. Mol. Sci. 2024, 25(13), 7044; https://doi.org/10.3390/ijms25137044 - 27 Jun 2024
Cited by 2 | Viewed by 2645
Abstract
Anacardic acid (AnAc) inhibits the growth of estrogen receptor α (ERα)-positive MCF-7 breast cancer (BC) cells and MDA-MB-231 triple-negative BC (TNBC) cells, without affecting primary breast epithelial cells. RNA sequencing (seq) and network analysis of AnAc-treated MCF-7 and MDA-MB-231 cells suggested that AnAc [...] Read more.
Anacardic acid (AnAc) inhibits the growth of estrogen receptor α (ERα)-positive MCF-7 breast cancer (BC) cells and MDA-MB-231 triple-negative BC (TNBC) cells, without affecting primary breast epithelial cells. RNA sequencing (seq) and network analysis of AnAc-treated MCF-7 and MDA-MB-231 cells suggested that AnAc inhibited lipid biosynthesis and increased endoplasmic reticulum stress. To investigate the impact of AnAc on cellular metabolism, a comprehensive untargeted metabolomics analysis was performed in five independent replicates of control versus AnAc-treated MCF-7 and MDA-MB-231 cells and additional TNBC cell lines: MDA-MB-468, BT-20, and HCC1806. An analysis of the global metabolome identified key metabolic differences between control and AnAc-treated within each BC cell line and between MCF-7 and the TNBC cell lines as well as metabolic diversity among the four TNBC cell lines, reflecting TNBC heterogeneity. AnAc-regulated metabolites were involved in alanine, aspartate, glutamate, and glutathione metabolism; the pentose phosphate pathway; and the citric acid cycle. Integration of the transcriptome and metabolome data for MCF-7 and MDA-MB-231 identified Signal transduction: mTORC1 downstream signaling in both cell lines and additional cell-specific pathways. Together, these data suggest that AnAc treatment differentially alters multiple pools of cellular building blocks, nutrients, and transcripts resulting in reduced BC cell viability. Full article
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11 pages, 563 KiB  
Communication
The Diagnostic Value of microRNA Expression Analysis in Detecting Intraductal Papillomas in Patients with Pathological Nipple Discharge
by Seher Makineli, Menno R. Vriens, Arjen J. Witkamp, Paul J. van Diest and Cathy B. Moelans
Int. J. Mol. Sci. 2024, 25(3), 1812; https://doi.org/10.3390/ijms25031812 - 2 Feb 2024
Viewed by 1441
Abstract
Patients with pathological nipple discharge (PND) often undergo local surgical procedures because standard radiologic imaging fails to identify the underlying cause. MicroRNA (MiRNA) expression analysis of nipple fluid holds potential for distinguishing between breast diseases. This study aimed to compare miRNA expression levels [...] Read more.
Patients with pathological nipple discharge (PND) often undergo local surgical procedures because standard radiologic imaging fails to identify the underlying cause. MicroRNA (MiRNA) expression analysis of nipple fluid holds potential for distinguishing between breast diseases. This study aimed to compare miRNA expression levels between nipple fluids from patients with PND to identify possible relevant miRNAs that could differentiate between intraductal papillomas and no abnormalities in the breast tissue. Nipple fluid samples from patients with PND without radiological and pathological suspicion for malignancy who underwent a ductoscopy procedure were analyzed. We used univariate and multivariate regression analyses to identify nipple fluid miRNAs differing between pathologically confirmed papillomas and breast tissue without abnormalities. A total of 27 nipple fluid samples from patients with PND were included for miRNA expression analysis. Out of the 22 miRNAs examined, only miR-145-5p was significantly differentially expressed (upregulated) in nipple fluid from patients with an intraductal papilloma compared to patients showing no breast abnormalities (OR 4.76, p = 0.046), with a diagnostic accuracy of 92%. miR-145-5p expression in nipple fluid differs for intraductal papillomas and breast tissue without abnormalities and, therefore, has potential as a diagnostic marker to signal presence of papillomas in PND patients. However, further refinement and validation in clinical trials are necessary to establish its clinical applicability. Full article
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