International Journal of Molecular Sciences

Research

17 pages, 3293 KiB

Open AccessArticle

Epicatechin Decreases UCP2 Gene Expression in MDA-MB-231 Breast Cancer Cells by the Presence of a Regulatory Element in the Promoter

by Fernando Pereyra-Vergara, Ivonne María Olivares-Corichi, Juan Pedro Luna-Arias, David Méndez-Luna and José Rubén García-Sánchez

Int. J. Mol. Sci. 2025, 26(9), 4102; https://doi.org/10.3390/ijms26094102 - 25 Apr 2025

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Abstract

Uncoupling protein 2 (UCP2) plays an important role in normal cells because it mitigates the cytotoxic effect of reactive oxygen species (ROS). However, its overexpression in cancer cells is related to drug resistance and increased cell proliferation due to a decrease in ROS [...] Read more.

Uncoupling protein 2 (UCP2) plays an important role in normal cells because it mitigates the cytotoxic effect of reactive oxygen species (ROS). However, its overexpression in cancer cells is related to drug resistance and increased cell proliferation due to a decrease in ROS production. In this context, molecules that regulate or block UCP2 have potential as anticancer agents. (-)-Epicatechin, a flavonoid that inhibits cell proliferation, increases ROS, and induces apoptosis in cancerous cells, was evaluated for its effects on UCP2 gene expression. For this purpose, the real-time quantitative polymerase chain reaction (qRT–PCR) and Western blotting were performed in MDA-MB-231 and MCF-10A cells to determine the effects of (-)-epicatechin on UCP2 expression. Furthermore, the impact of (-)-epicatechin on cell viability was also determined. To analyze the transcriptional regulation of the UCP2 gene by (-)-epicatechin, a 5′-region of the human UCP2 gene (−2093/+297) was amplified, sequenced, cloned, and inserted into a reporter plasmid. To analyze the promoter activity and regulatory motif involved in the effects of (-)-epicatechin, several deletions of the UCP2 promoter were generated and transfected into MDA-MB-231 and MCF-10A cells. An electrophoretic mobility shift assay (EMSA) was carried out to detect the interaction between DNA and proteins involved in the effect of (-)-epicatechin. The increased expression of the UCP2 gene in MDA-MB-231 cells was decreased by (-)-epicatechin, and the opposite effect was observed in MCF-10A cells. The promoter region of the human UCP2 gene (−2093/+297) showed activity, which was decreased by (-)-epicatechin. A sequence of 117 bp located at position −109 b to +8 b has a fragment of 90 bp that is related to the (-)-epicatechin effect. Bioinformatics analysis and EMSA of this sequence revealed the presence of a regulatory site for a protein with zinc fingers. The presence of a response element to (-)-epicatechin in the human UCP2 promoter revealed that the inhibition of this gene in MDA-MB-231 breast cancer cells occurred at the transcriptional level. In this study, we propose the mechanism of action of (-)-epicatechin that could aid in cancer treatment. Full article

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

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27 pages, 9672 KiB

Open AccessArticle

miRNAs from Zebrafish Embryo Extracts Inhibit Breast Cancer Invasiveness and Migration by Modulating miR-218-5p/PI3K Pathway

by Noemi Monti, Daniele Antinori, Sara Proietti, Aurora Piombarolo, Alessandro Querqui, Guglielmo Lentini, Domenico Liguoro, Michele Aventaggiato, Marco Lucarelli, Andrea Pensotti, Alessandro Giuliani, Marco Tafani, Andrea Fuso and Mariano Bizzarri

Int. J. Mol. Sci. 2025, 26(8), 3812; https://doi.org/10.3390/ijms26083812 - 17 Apr 2025

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Abstract

Herein, we demonstrate that soluble factors extracted from the distinct phases of the development of zebrafish embryos (ZFEs) exhibit a specific miRNA profile. We removed proteins and concentrated miRNAs in different phase-related samples, which we investigated further. We observed that ZFEs modulate miRNA [...] Read more.

Herein, we demonstrate that soluble factors extracted from the distinct phases of the development of zebrafish embryos (ZFEs) exhibit a specific miRNA profile. We removed proteins and concentrated miRNAs in different phase-related samples, which we investigated further. We observed that ZFEs modulate miRNA expression in both normal and cancerous breast cells, significantly inhibiting the invasiveness and motility of triple-negative breast cancer cells. Namely, ZFEs reactivate the synthesis of miR-218-5p in cancerous cells, leading to the downregulation of PI3K, which consequently alters the distribution of phosphoinositides (such as PIP2/PIP3). Moreover, the silencing of miR-218-5p abolished the ZFE effects. Restoring a proper PIP2/PIP3 ratio is crucial for promoting the regression of the malignant phenotype. Phenotypic reversion follows the extensive cytoskeleton rearrangement and the re-emergence of E-cadherin/β-catenin complexes. In addition, ZFEs antagonize the Epithelial Mesenchymal Transition (EMT) by modulating several pathways, including the TCTP-p53 axis. Overall, these results show that embryo extracts enriched with fish miRNAs reactivate endogenous miR-218-5p in cancerous cells, which in turn downregulates critical pathways involved in tumor progression and metastasis. Full article

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

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25 pages, 4374 KiB

Open AccessArticle

Identifying Genes Associated with the Anticancer Activity of a Fluorinated Chalcone in Triple-Negative Breast Cancer Cells Using Bioinformatics Tools

by Eduardo De la Cruz-Cano, José Ángel González-Díaz, Ivonne María Olivares-Corichi, Jorge Tonatiuh Ayala-Sumuano, José Alfredo Díaz-Gandarilla, Quirino Torres-Sauret, Violeta Larios-Serrato, Miguel Ángel Vilchis-Reyes, Carlos Javier López-Victorio, José Arnold González-Garrido and José Rubén García-Sánchez

Int. J. Mol. Sci. 2025, 26(8), 3662; https://doi.org/10.3390/ijms26083662 - 12 Apr 2025

Viewed by 726

Abstract

Fluorinated chalcones are molecules reported to possess potent anticancer properties against triple-negative breast cancer (TNBC) cells. However, their molecular mechanisms have not yet been fully explored. Using bioinformatics tools, we analyzed the transcriptomes of MDA-MB-231 cells treated with either a novel fluorinated chalcone [...] Read more.

Fluorinated chalcones are molecules reported to possess potent anticancer properties against triple-negative breast cancer (TNBC) cells. However, their molecular mechanisms have not yet been fully explored. Using bioinformatics tools, we analyzed the transcriptomes of MDA-MB-231 cells treated with either a novel fluorinated chalcone (compound 3) or a control in order to identify differentially expressed (DE) genes associated with its anticancer activity and determine the biological processes in which these genes are involved. A fluorinated chalcone was synthesized using the Claisen–Schmidt method. The transcriptome of MDA-MB-231 cells was then analyzed on an Illumina NextSeq500, and DE genes with significant changes in expression were identified using the DESeq2 v1.38.0 bioinformatics tool under the strict detection criteria of |log2FC| ≥ 2 and adjusted p < 0.05. We identified 504 DE genes, which were enriched in terms related to “regulation of cell death”, “cation transport”, “response to topologically incorrect proteins”, and “response to unfolded proteins”. Surprisingly, these genes were involved in “the HSF1-dependent transactivation pathway” and “the attenuation phase pathway”. This bioinformatics-based study suggests that the tested fluorinated chalcone could influence HSF-1 silencing in addition to promoting the up-regulation of several genes involved in stress-induced apoptosis. Therefore, the tested compound could have enormous potential as a novel approach for TNBC treatment. Full article

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

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23 pages, 10599 KiB

Open AccessArticle

Microbubble-Protected Oncolytic Virotherapy Targeted by Sonoporation Induces Tumor Necrosis and T-Lymphocyte Infiltration in Humanized Mice Bearing Triple-Negative Breast Cancer

by Juliana Sitta, Flavia De Carlo, Imani Kirven, John H. Tackett, Patrice Penfornis, George Clement Dobbins, Mallory Barbier, Luis Del Valle, Clayton T. Larsen, Ernest G. Schutt, Rhodemann Li, Candace M. Howard and Pier Paolo Claudio

Int. J. Mol. Sci. 2024, 25(24), 13697; https://doi.org/10.3390/ijms252413697 - 21 Dec 2024

Cited by 2 | Viewed by 1392

Abstract

Oncolytic virotherapy has shown great promise in mediating targeted tumor destruction through tumor-selective replication and induction of anti-tumor immunity; however, obstacles remain for virus candidates to reach the clinic. These include avoiding neutralizing antibodies, preventing stimulation of the adaptive immune response during intravenous [...] Read more.

Oncolytic virotherapy has shown great promise in mediating targeted tumor destruction through tumor-selective replication and induction of anti-tumor immunity; however, obstacles remain for virus candidates to reach the clinic. These include avoiding neutralizing antibodies, preventing stimulation of the adaptive immune response during intravenous administration, and inducing sufficient apoptosis and immune activation so that the body’s defense can work to eradicate systemic disease. We have developed a co-formulation of oncolytic viruses (OVs) with Imagent^® lipid-encapsulated, perfluorocarbon microbubbles (MBs) to protect the OVs from the innate and adaptive immune system. Once inside the MB, the viral particles become acoustically active such that external ultrasound can target the delivery of the virus locally within the tumor. Humanized NSG female mice (Hu-CD34⁺ NSG-SGM3) engrafted in their flanks with MDA-MB-231-Luc triple-negative breast cancer (TNBC) cells were transduced with MB/OVs, with or without adjuvant Pembrolizumab treatment, and tumor sizes and tumor necrosis were assessed. The presence of CD8⁺ (cytotoxic T-cells), CD4⁺ (helper T-cells), and CD25⁺ (Tregs) tumor-infiltrating lymphocytes (TILs) was quantified in the tumor samples by immunohistochemistry. In an in vivo model of humanized mice engrafted with a human immune system, we observed significantly greater tumor necrosis and smaller tumor mass in human TNBC xenografts systemically treated with MB/OV complexes in the presence or absence of pembrolizumab adjuvant treatment, compared to controls. Additionally, we observed a low ratio of CD4⁺/CD8⁺ TILs and a high ratio of CD8⁺/CD25⁺ TILs in the MDA-MB-231 xenografts treated with MB/OVs complexes with or without pembrolizumab adjuvant treatment, compared to controls. Our study demonstrated the feasibility of using MBs to target OVs to TNBC through diagnostic ultrasound, which decreased tumor mass by increasing tumor necrosis and stimulated a local and systemic antitumoral immune response by increasing intratumoral CD8⁺ T-cytotoxic lymphocyte infiltration and decreasing CD25⁺ Treg cells. Full article

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

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16 pages, 1384 KiB

Open AccessArticle

Explainable Machine Learning Models Using Robust Cancer Biomarkers Identification from Paired Differential Gene Expression

by Elisa Díaz de la Guardia-Bolívar, Juan Emilio Martínez Manjón, David Pérez-Filgueiras, Igor Zwir and Coral del Val

Int. J. Mol. Sci. 2024, 25(22), 12419; https://doi.org/10.3390/ijms252212419 - 19 Nov 2024

Cited by 1 | Viewed by 1456

Abstract

In oncology, there is a critical need for robust biomarkers that can be easily translated into the clinic. We introduce a novel approach using paired differential gene expression analysis for biological feature selection in machine learning models, enhancing robustness and interpretability while accounting [...] Read more.

In oncology, there is a critical need for robust biomarkers that can be easily translated into the clinic. We introduce a novel approach using paired differential gene expression analysis for biological feature selection in machine learning models, enhancing robustness and interpretability while accounting for patient variability. This method compares primary tumor tissue with the same patient’s healthy tissue, improving gene selection by eliminating individual-specific artifacts. A focus on carcinoma was selected due to its prevalence and the availability of the data; we aim to identify biomarkers involved in general carcinoma progression, including less-researched types. Our findings identified 27 pivotal genes that can distinguish between healthy and carcinoma tissue, even in unseen carcinoma types. Additionally, the panel could precisely identify the tissue-of-origin in the eight carcinoma types used in the discovery phase. Notably, in a proof of concept, the model accurately identified the primary tissue origin in metastatic samples despite limited sample availability. Functional annotation reveals these genes’ involvement in cancer hallmarks, detecting subtle variations across carcinoma types. We propose paired differential gene expression analysis as a reference method for the discovering of robust biomarkers. Full article

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

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17 pages, 3434 KiB

Open AccessArticle

Prognostic Markers in Tyrosine Kinases Specific to Basal-like 2 Subtype of Triple-Negative Breast Cancer

by Praopim Limsakul, Pongsakorn Choochuen, Thawirasm Jungrungrueang and Krit Charupanit

Int. J. Mol. Sci. 2024, 25(3), 1405; https://doi.org/10.3390/ijms25031405 - 24 Jan 2024

Cited by 2 | Viewed by 2830

Abstract

Triple-negative breast cancer (TNBC), a heterogeneous and therapeutically challenging subtype, comprises over 50% of patients categorized into basal-like 1 (BL1) and basal-like 2 (BL2) intrinsic molecular subtypes. Despite their shared basal-like classification, BL2 is associated with a poor response to neoadjuvant chemotherapy and [...] Read more.

Triple-negative breast cancer (TNBC), a heterogeneous and therapeutically challenging subtype, comprises over 50% of patients categorized into basal-like 1 (BL1) and basal-like 2 (BL2) intrinsic molecular subtypes. Despite their shared basal-like classification, BL2 is associated with a poor response to neoadjuvant chemotherapy and reduced relapse-free survival compared to BL1. Here, the study focused on identifying subtype-specific markers for BL2 through transcriptomic analysis of TNBC patients using RNA-seq and clinical integration. Six receptor tyrosine kinase (TK) genes, including EGFR, EPHA4, EPHB2, PDGFRA, PDGFRB, and ROR1, were identified as potential differentiators for BL2. Correlations between TK mRNA expression and TNBC prognosis, particularly EGFR, PDGFRA, and PDGFRB, revealed potential synergistic interactions in pathways related to cell survival and proliferation. Our findings also suggest promising dual markers for predicting disease prognosis. Furthermore, RT-qPCR validation demonstrated that identified BL2-specific TKs were expressed at a higher level in BL2 than in BL1 cell lines, providing insights into unique characteristics. This study advances the understanding of TNBC heterogeneity within the basal-like subtypes, which could lead to novel clinical treatment approaches and the development of targeted therapies. Full article

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

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17 pages, 7111 KiB

Open AccessArticle

miR-877-5p as a Potential Link between Triple-Negative Breast Cancer Development and Metabolic Syndrome

by Juana Moro, Agustina Grinpelc, Paula Lucía Farré, Rocío Belén Duca, Ezequiel Lacunza, Karen Daniela Graña, Georgina Daniela Scalise, Guillermo Nicolás Dalton, Cintia Massillo, Flavia Piccioni, Federico Dimase, Emilio Batagelj, Adriana De Siervi and Paola De Luca

Int. J. Mol. Sci. 2023, 24(23), 16758; https://doi.org/10.3390/ijms242316758 - 25 Nov 2023

Cited by 3 | Viewed by 2379

Abstract

Metabolic syndrome (MS) is a risk factor for breast cancer (BC) that increases its aggressiveness and metastasis. The prevalence of MS is higher in triple-negative breast cancer (TNBC), which is the molecular subtype with the worst prognosis. The molecular mechanisms underlying this association [...] Read more.

Metabolic syndrome (MS) is a risk factor for breast cancer (BC) that increases its aggressiveness and metastasis. The prevalence of MS is higher in triple-negative breast cancer (TNBC), which is the molecular subtype with the worst prognosis. The molecular mechanisms underlying this association have not been fully elucidated. MiRNAs are small, non-coding RNAs that regulate gene expression. Aberrant expression of miRNAs in both tissues and fluids are linked to several pathologies. The aim of this work was to identify circulating miRNAs in patients with alterations associated with MS (AAMS) that also impact on BC. Using microarray technology, we detected 23 miRNAs altered in the plasma of women with AAMS that modulate processes linked to cancer. We found that let-7b-5p and miR-28-3p were decreased in plasma from patients with AAMS and also in BC tumors, while miR-877-5p was increased. Interestingly, miR-877-5p expression was associated with lower patient survival, and its expression was higher in PAM50 basal-like BC tumors compared to the other molecular subtypes. Analyses from public databases revealed that miR-877-5p was also increased in plasma from BC patients compared to plasma from healthy donors. We identified IGF2 and TIMP3 as validated target genes of miR-877-5p whose expression was decreased in BC tissue and moreover, was negatively correlated with the levels of this miRNA in the tumors. Finally, a miRNA inhibitor against miR-877-5p diminished viability and tumor growth of the TNBC model 4T1. These results reveal that miR-877-5p inhibition could be a therapeutic option for the treatment of TNBC. Further studies are needed to investigate the role of this miRNA in TNBC progression. Full article

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

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14 pages, 2009 KiB

Open AccessArticle

Kinesin Family Member C1 (KIFC1/HSET) Underlies Aggressive Disease in Androgen Receptor-Low and Basal-Like Triple-Negative Breast Cancers

by Nikita Jinna, Yate-Ching Yuan and Padmashree Rida

Int. J. Mol. Sci. 2023, 24(22), 16072; https://doi.org/10.3390/ijms242216072 - 8 Nov 2023

Cited by 3 | Viewed by 1528

Abstract

Quadruple-negative breast cancer (QNBC) lacks traditional actionable targets, including androgen receptor (AR). QNBC disproportionately afflicts and impacts patients of African genetic ancestry. Kinesin family member C1 (KIFC1/HSET), a centrosome clustering protein that prevents cancer cells from undergoing centrosome-amplification-induced apoptosis, has been reported to [...] Read more.

Quadruple-negative breast cancer (QNBC) lacks traditional actionable targets, including androgen receptor (AR). QNBC disproportionately afflicts and impacts patients of African genetic ancestry. Kinesin family member C1 (KIFC1/HSET), a centrosome clustering protein that prevents cancer cells from undergoing centrosome-amplification-induced apoptosis, has been reported to be upregulated in TNBCs and African-American (AA) TNBCs. Herein, we analyzed KIFC1 RNA levels and their associations with clinical features and outcomes among AR-low and AR-high TNBC tumors in three distinct publicly available gene expression datasets and in the breast cancer gene expression database (bc-GenExMiner). KIFC1 levels were significantly higher in AR-low and basal-like TNBCs than in AR-high and non-basal-like TNBCs, irrespective of the stage, grade, tumor size, and lymph node status. KIFC1 levels were also upregulated in AR-low tumors relative to AR-high tumors among Black and premenopausal women with TNBC. High KIFC1 levels conferred significantly shorter overall survival, disease-free survival, and distant metastasis-free survival among AR-low and basal-like TNBC patients in Kaplan–Meier analyses. In conclusion, KIFC1 levels may be upregulated in AR-low tumors and, specifically, in those of African descent, wherein it may promote poor outcomes. KIFC1 may be an actionable cancer-cell-specific target for the AR-low TNBC subpopulation and could aid in alleviating racial disparities in TNBC outcomes. Full article

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

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18 pages, 1110 KiB

Open AccessArticle

Untargeted LC-MS/MS Metabolomics Study of HO-AAVPA and VPA on Breast Cancer Cell Lines

by Alan Rubén Estrada-Pérez, Juan Benjamín García-Vázquez, Humberto L. Mendoza-Figueroa, Martha Cecilia Rosales-Hernández, Cynthia Fernández-Pomares and José Correa-Basurto

Int. J. Mol. Sci. 2023, 24(19), 14543; https://doi.org/10.3390/ijms241914543 - 26 Sep 2023

Cited by 2 | Viewed by 2035

Abstract

Breast cancer (BC) is one of the biggest health problems worldwide, characterized by intricate metabolic and biochemical complexities stemming from pronounced variations across dysregulated molecular pathways. If BC is not diagnosed early, complications may lead to death. Thus, the pursuit of novel therapeutic [...] Read more.

Breast cancer (BC) is one of the biggest health problems worldwide, characterized by intricate metabolic and biochemical complexities stemming from pronounced variations across dysregulated molecular pathways. If BC is not diagnosed early, complications may lead to death. Thus, the pursuit of novel therapeutic avenues persists, notably focusing on epigenetic pathways such as histone deacetylases (HDACs). The compound N-(2-hydroxyphenyl)-2-propylpentanamide (HO-AAVPA), a derivative of valproic acid (VPA), has emerged as a promising candidate warranting pre-clinical investigation. HO-AAVPA is an HDAC inhibitor with antiproliferative effects on BC, but its molecular mechanism has yet to be deciphered. Furthermore, in the present study, we determined the metabolomic effects of HO-AAVPA and VPA on cells of luminal breast cancer (MCF-7) and triple-negative breast cancer (MDA-MB-231) subtypes. The LC-MS untargeted metabolomic study allowed for the simultaneous measurement of multiple metabolites and pathways, identifying that both compounds affect glycerophospholipid and sphingolipid metabolism in the MCF-7 and MDA-MB-231 cell lines, suggesting that other biological targets were different from HDACs. In addition, there are different dysregulate metabolites, possibly due to the physicochemical differences between HO-AAVPA and VPA. Full article

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

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Review

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35 pages, 1849 KiB

Open AccessReview

Overcoming Challenges in Small-Molecule Drug Bioavailability: A Review of Key Factors and Approaches

by Ke Wu, Soon Hwan Kwon, Xuhan Zhou, Claire Fuller, Xianyi Wang, Jaydutt Vadgama and Yong Wu

Int. J. Mol. Sci. 2024, 25(23), 13121; https://doi.org/10.3390/ijms252313121 - 6 Dec 2024

Cited by 8 | Viewed by 4864

Abstract

The bioavailability of small-molecule drugs remains a critical challenge in pharmaceutical development, significantly impacting therapeutic efficacy and commercial viability. This review synthesizes recent advances in understanding and overcoming bioavailability limitations, focusing on key physicochemical and biological factors influencing drug absorption and distribution. We [...] Read more.

The bioavailability of small-molecule drugs remains a critical challenge in pharmaceutical development, significantly impacting therapeutic efficacy and commercial viability. This review synthesizes recent advances in understanding and overcoming bioavailability limitations, focusing on key physicochemical and biological factors influencing drug absorption and distribution. We examine cutting-edge strategies for enhancing bioavailability, including innovative formulation approaches, rational structural modifications, and the application of artificial intelligence in drug design. The integration of nanotechnology, 3D printing, and stimuli-responsive delivery systems are highlighted as promising avenues for improving drug delivery. We discuss the importance of a holistic, multidisciplinary approach to bioavailability optimization, emphasizing early-stage consideration of ADME properties and the need for patient-centric design. This review also explores emerging technologies such as CRISPR-Cas9-mediated personalization and microbiome modulation for tailored bioavailability enhancement. Finally, we outline future research directions, including advanced predictive modeling, overcoming biological barriers, and addressing the challenges of emerging therapeutic modalities. By elucidating the complex interplay of factors affecting bioavailability, this review aims to guide future efforts in developing more effective and accessible small-molecule therapeutics. Full article

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

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13 pages, 3537 KiB

Open AccessReview

Local Production of Acute Phase Proteins: A Defense Reaction of Cancer Cells to Injury with Focus on Fibrinogen

by Péter Hamar

Int. J. Mol. Sci. 2024, 25(6), 3435; https://doi.org/10.3390/ijms25063435 - 19 Mar 2024

Cited by 2 | Viewed by 1983

Abstract

This review is intended to demonstrate that the local production of acute phase proteins (termed local acute phase response (lAPR)) and especially fibrin/fibrinogen (FN) is a defense mechanism of cancer cells to therapy, and inhibition of the lAPR can augment the effectiveness of [...] Read more.

This review is intended to demonstrate that the local production of acute phase proteins (termed local acute phase response (lAPR)) and especially fibrin/fibrinogen (FN) is a defense mechanism of cancer cells to therapy, and inhibition of the lAPR can augment the effectiveness of cancer therapy. Previously we detected a lAPR accompanying tumor cell death during the treatment of triple-negative breast cancer (TNBC) with modulated electro-hyperthermia (mEHT) in mice. We observed a similar lAPR in in hypoxic mouse kidneys. In both models, production of FN chains was predominant among the locally produced acute phase proteins. The production and extracellular release of FN into the tumor microenvironment is a known method of self-defense in tumor cells. We propose that the lAPR is a new, novel cellular defense mechanism like the heat shock response (HSR). In this review, we demonstrate a potential synergism between FN inhibition and mEHT in cancer treatment, suggesting that the effectiveness of mEHT and chemotherapy can be enhanced by inhibiting the HSR and/or the lAPR. Non-anticoagulant inhibition of FN offers potential new therapeutic options for cancer treatment. Full article

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

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20 pages, 730 KiB

Open AccessReview

Advances in the Management of Early-Stage Triple-Negative Breast Cancer

by Prarthna V. Bhardwaj, Yue Wang, Elizabeth Brunk, Philip M. Spanheimer and Yara G. Abdou

Int. J. Mol. Sci. 2023, 24(15), 12478; https://doi.org/10.3390/ijms241512478 - 5 Aug 2023

Cited by 5 | Viewed by 3176

Abstract

Triple-negative breast cancer (TNBC) is a subtype of breast cancer with both inter- and intratumor heterogeneity, thought to result in a more aggressive course and worse outcomes. Neoadjuvant therapy (NAT) has become the preferred treatment modality of early-stage TNBC as it allows for [...] Read more.

Triple-negative breast cancer (TNBC) is a subtype of breast cancer with both inter- and intratumor heterogeneity, thought to result in a more aggressive course and worse outcomes. Neoadjuvant therapy (NAT) has become the preferred treatment modality of early-stage TNBC as it allows for the downstaging of tumors in the breast and axilla, monitoring early treatment response, and most importantly, provides important prognostic information that is essential to determining post-surgical therapies to improve outcomes. It focuses on combinations of systemic drugs to optimize pathologic complete response (pCR). Excellent response to NAT has allowed surgical de-escalation in ideal candidates. Further, treatment algorithms guide the systemic management of patients based on their pCR status following surgery. The expanding knowledge of molecular pathways, genomic sequencing, and the immunological profile of TNBC has led to the use of immune checkpoint inhibitors and targeted agents, including PARP inhibitors, further revolutionizing the therapeutic landscape of this clinical entity. However, subgroups most likely to benefit from these novel approaches in TNBC remain elusive and are being extensively studied. In this review, we describe current practices and promising therapeutic options on the horizon for TNBC, surgical advances, and future trends in molecular determinants of response to therapy in early-stage TNBC. Full article

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

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Other

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10 pages, 1602 KiB

Open AccessBrief Report

Matrix Metalloproteinase-9 Expression Is Associated with the Absence of Response to Neoadjuvant Chemotherapy in Triple-Negative Breast Cancer Patients

by Marylène Lejeune, Laia Reverté, Noèlia Gallardo, Esther Sauras, Ramon Bosch, Daniel Mata, Albert Roso, Anna Petit, Vicente Peg, Francisco Riu, Joan García-Fontgivell, Fernanda Relea, Begoña Vieites, Luis de la Cruz-Merino, Meritxell Arenas, Valeri Rodriguez, Juana Galera, Anna Korzynska, Benoît Plancoulaine, Tomás Álvaro and Carlos López Show full author list Hide full author list

Int. J. Mol. Sci. 2023, 24(14), 11297; https://doi.org/10.3390/ijms241411297 - 11 Jul 2023

Cited by 5 | Viewed by 2089

Abstract

Triple-negative breast cancer (TNBC) is particularly challenging due to the weak or absent response to therapeutics and its poor prognosis. The effectiveness of neoadjuvant chemotherapy (NAC) response is strongly influenced by changes in elements of the tumor microenvironment (TME). This work aimed to [...] Read more.

Triple-negative breast cancer (TNBC) is particularly challenging due to the weak or absent response to therapeutics and its poor prognosis. The effectiveness of neoadjuvant chemotherapy (NAC) response is strongly influenced by changes in elements of the tumor microenvironment (TME). This work aimed to characterize the residual TME composition in 96 TNBC patients using immunohistochemistry and in situ hybridization techniques and evaluate its prognostic implications for partial responders vs. non-responders. Compared with non-responders, partial responders containing higher levels of CD83+ mature dendritic cells, FOXP3+ regulatory T cells, and IL-15 expression but lower CD138+ cell concentration exhibited better OS and RFS. However, along with tumor diameter and positive nodal status at diagnosis, matrix metalloproteinase-9 (MMP-9) expression in the residual TME was identified as an independent factor associated with the impaired response to NAC. This study yields new insights into the key components of the residual tumor bed, such as MMP-9, which is strictly associated with the lack of a pathological response to NAC. This knowledge might help early identification of TNBC patients less likely to respond to NAC and allow the establishment of new therapeutic targets. Full article

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

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