Molecular Research of Triple-Negative Breast Cancer

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

Deadline for manuscript submissions: 31 May 2024 | Viewed by 14684

Special Issue Editors


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Guest Editor
Department of Biological, Chemical and Pharmaceutical Sciences and Technologies (STEBICEF), Laboratory of Biochemistry, University of Palermo, Viale delle Scienze, ed. 16, 90128 Palermo, Italy
Interests: TNBC; miRNA; cell death; cancer stem cells
Special Issues, Collections and Topics in MDPI journals

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Guest Editor
Department of Biomedicine, Neurosciences and Advanced Diagnostics (BIND), Institute of Biochemistry, University of Palermo, Via del Vespro, 131, 90127 Palermo, Italy
Interests: breast cancer; chemotherapy resistance; cancer stem cells; NAFLD; natural drugs
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Breast cancer is classified on the basis of histological and molecular variability; a subgroup equally heterogeneous is triple-negative breast cancer (TNBC), which shows lost expression of PR, ER and HER2/NEU receptors and a general molecular expression that confers it a particularly metastatic and invasive nature, drug resistance and poor prognosis. Therefore, several subtypes that actually have no specific molecular targets characterize TNBC and, consequently, a feature that makes it difficult to set a valid therapeutic strategy and so, to date, conventional chemotherapy is the only choice.

The Special Issue, entitled “Molecular Research of Triple-Negative Breast Cancer”, aims to collect recent results in this context, as:

  • Genetic, epigenetic, transcriptional profiles;
  • Description of proteomic features and/or biochemical pathways;
  • Identification of cancer stem cells and their cross-talk with microenvironment; metabolic reprogramming;
  • Effect induced in vitro/in vivo of any (or combination of) drugs;
  • Triple-negative breast cancer immunity and metabolic reprogramming;
  • Any evidence useful to suggest and define novel molecular target to challenge the aggressive character of TNBC.

Dr. Anna De Blasio
Dr. Daniela Carlisi
Guest Editors

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Keywords

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

Published Papers (8 papers)

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Research

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21 pages, 3271 KiB  
Article
Low-Density Lipoproteins Increase Proliferation, Invasion, and Chemoresistance via an Exosome Autocrine Mechanism in MDA-MB-231 Chemoresistant Cells
by César Y. Castañeda-Sánchez, Brenda Chimal-Vega, Roberto León-Gutiérrez, Adrián Ernesto Araiza-Robles, Nicolás Serafín-Higuera, Angel Pulido-Capiz, Ignacio A. Rivero, Raúl Díaz-Molina, Manuel Alatorre-Meda, Eustolia Rodríguez-Velázquez and Victor García-González
Biomedicines 2024, 12(4), 742; https://doi.org/10.3390/biomedicines12040742 - 27 Mar 2024
Viewed by 1007
Abstract
Dyslipidemias involving high concentrations of low-density lipoproteins (LDLs) increase the risk of developing triple-negative breast cancer (TNBC), wherein cholesterol metabolism and protein translation initiation mechanisms have been linked with chemoresistance. Doxorubicin (Dox) treatment, a member of the anthracycline family, represents a typical therapeutic [...] Read more.
Dyslipidemias involving high concentrations of low-density lipoproteins (LDLs) increase the risk of developing triple-negative breast cancer (TNBC), wherein cholesterol metabolism and protein translation initiation mechanisms have been linked with chemoresistance. Doxorubicin (Dox) treatment, a member of the anthracycline family, represents a typical therapeutic strategy; however, chemoresistance remains a significant challenge. Exosomes (Exs) secreted by tumoral cells have been implicated in cell communication pathways and chemoresistance mechanisms; the content of exosomes is an outcome of cellular cholesterol metabolism. We previously induced Dox resistance in TNBC cell models, characterizing a variant denominated as variant B cells. Our results suggest that LDL internalization in parental and chemoresistant variant B cells is associated with increased cell proliferation, migration, invasion, and spheroid growth. We identified the role of eIF4F translation initiation factor and the down-regulation of tumor suppressor gene PDCD4, an inhibitor of eIF4A, in chemoresistant variant B cells. In addition, the exomes secreted by variant B cells were characterized by the protein content, electronic microscopy, and cell internalization assays. Critically, exosomes purified from LDL-treated variant B cell promoted cell proliferation, migration, and an increment in lactate concentration. Our results suggest that an autocrine phenomenon induced by exosomes in chemoresistant cells may induce modifications on signaling mechanisms of the p53/Mdm2 axis and activation of p70 ribosomal protein kinase S6. Moreover, the specific down-regulated profile of chaperones Hsp90 and Hsp70 secretion inside the exosomes of the chemoresistant variant could be associated with this phenomenon. Therefore, autocrine activation mediated by exosomes and the effect of LDL internalization may influence changes in exosome chaperone content and modulate proliferative signaling pathways, increasing the aggressiveness of MDA-MB-231 chemoresistant cells. Full article
(This article belongs to the Special Issue Molecular Research of Triple-Negative Breast Cancer)
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28 pages, 11881 KiB  
Article
Activation of MAP Kinase Pathway by Polyisoprenylated Cysteinyl Amide Inhibitors Causes Apoptosis and Disrupts Breast Cancer Cell Invasion
by Jassy Mary S. Lazarte and Nazarius S. Lamango
Biomedicines 2024, 12(3), 470; https://doi.org/10.3390/biomedicines12030470 - 20 Feb 2024
Viewed by 970
Abstract
Prognoses for TNBC remain poor due to its aggressive nature and the lack of therapies that target its “drivers”. RASA1, a RAS-GAP or GTPase-activating protein whose activity inhibits RAS signaling, is downregulated in up to 77% of TNBC cases. As such, RAS proteins [...] Read more.
Prognoses for TNBC remain poor due to its aggressive nature and the lack of therapies that target its “drivers”. RASA1, a RAS-GAP or GTPase-activating protein whose activity inhibits RAS signaling, is downregulated in up to 77% of TNBC cases. As such, RAS proteins become hyperactive and similar in effect to mutant hyperactive RAS proteins with impaired GTPase activities. PCAIs are a novel class of agents designed to target and disrupt the activities of KRAS and other G-proteins that are hyperactive in various cancers. This study shows the anticancer mechanisms of the PCAIs in two breast cancer cell lines, MDA-MB-468 and MDA-MB-231. PCAIs (NSL-YHJ-2-27) treatment increased BRAF phosphorylation, whereas CRAF phosphorylation significantly decreased in both cell lines. Moreover, the PCAIs also stimulated the phosphorylation of MEK, ERK, and p90RSK by 116, 340, and 240% in MDA-MB-468 cells, respectively. However, in MDA-MB-231 cells, a significant increase of 105% was observed only in p90RSK phosphorylation. Opposing effects were observed for AKT phosphorylation, whereby an increase was detected in MDA-MB-468 cells and a decrease in MDA-MB-231 cells. The PCAIs also induced apoptosis, as observed in the increased pro-apoptotic protein BAK1, by 51%, after treatment. The proportion of live cells in PCAIs-treated spheroids decreased by 42 and 34% in MDA-MB-468 and MDA-MB-231 cells, respectively, which further explains the PCAIs-induced apoptosis. The movement of the cells through the Matrigel was also inhibited by 74% after PCAIs exposure, which could have been due to the depleted levels of F-actin and vinculin punctate, resulting in the shrinkage of the cells by 76%, thereby impeding cell movement. These results show promise for PCAIs as potential therapies for TNBC as they significantly inhibit the hallmark processes and pathways that promote cell proliferation, migration, and invasion, which result in poor prognoses for breast cancer patients. Full article
(This article belongs to the Special Issue Molecular Research of Triple-Negative Breast Cancer)
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15 pages, 3879 KiB  
Article
Differential Expression of NOTCH-1 and Its Molecular Targets in Response to Metronomic Followed by Conventional Therapy in a Patient with Advanced Triple-Negative Breast Cancer
by Alice Ilari, Viola Cogliati, Noorhan Sherif, Emanuela Grassilli, Daniele Ramazzotti, Nicoletta Cordani, Giorgio Cazzaniga, Camillo Di Bella, Marialuisa Lavitrano, Marina Elena Cazzaniga and Maria Grazia Cerrito
Biomedicines 2024, 12(2), 272; https://doi.org/10.3390/biomedicines12020272 - 25 Jan 2024
Viewed by 964
Abstract
A group of 27 patients diagnosed with metastatic triple-negative breast cancer (mTNBC) was randomly distributed into two groups and underwent different lines of metronomic treatment (mCHT). The former group (N 14) received first-line mCHT and showed a higher overall survival rate than the [...] Read more.
A group of 27 patients diagnosed with metastatic triple-negative breast cancer (mTNBC) was randomly distributed into two groups and underwent different lines of metronomic treatment (mCHT). The former group (N 14) received first-line mCHT and showed a higher overall survival rate than the second group (N 13), which underwent second-line mCHT. Analysis of one patient still alive from the first group, diagnosed with mTNBC in 2019, showed a complete metabolic response (CMR) after a composite approach implicating first-line mCHT followed by second-line epirubicin and third-line nab-paclitaxel, and was chosen for subsequent molecular characterization. We found altered expression in the cancer stemness-associated gene NOTCH-1 and its corresponding protein. Additionally, we found changes in the expression of oncogenes, such as MYC and AKT, along with their respective proteins. Overall, our data suggest that a first-line treatment with mCHT followed by MTD might be effective by negatively regulating stemness traits usually associated with the emergence of drug resistance. Full article
(This article belongs to the Special Issue Molecular Research of Triple-Negative Breast Cancer)
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18 pages, 4909 KiB  
Article
Identification of a NACC1-Regulated Gene Signature Implicated in the Features of Triple-Negative Breast Cancer
by Chrispus M. Ngule, Hami Hemati, Xingcong Ren, Oluwafunminiyi Obaleye, Amos O. Akinyemi, Felix F. Oyelami, Xiaofang Xiong, Jianxun Song, Xia Liu and Jin-Ming Yang
Biomedicines 2023, 11(4), 1223; https://doi.org/10.3390/biomedicines11041223 - 20 Apr 2023
Cited by 1 | Viewed by 2678
Abstract
Triple-negative breast cancer (TNBC), characterized by a deficiency in estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor2 (HER2), is among the most lethal subtypes of breast cancer (BC). Nevertheless, the molecular determinants that contribute to its malignant phenotypes such [...] Read more.
Triple-negative breast cancer (TNBC), characterized by a deficiency in estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor2 (HER2), is among the most lethal subtypes of breast cancer (BC). Nevertheless, the molecular determinants that contribute to its malignant phenotypes such as tumor heterogeneity and therapy resistance, remain elusive. In this study, we sought to identify the stemness-associated genes involved in TNBC progression. Using bioinformatics approaches, we found 55 up- and 9 downregulated genes in TNBC. Out of the 55 upregulated genes, a 5 gene-signature (CDK1, EZH2, CCNB1, CCNA2, and AURKA) involved in cell regeneration was positively correlated with the status of tumor hypoxia and clustered with stemness-associated genes, as recognized by Parametric Gene Set Enrichment Analysis (PGSEA). Enhanced infiltration of immunosuppressive cells was also positively correlated with the expression of these five genes. Moreover, our experiments showed that depletion of the transcriptional co-factor nucleus accumbens-associated protein 1 (NAC1), which is highly expressed in TNBC, reduced the expression of these genes. Thus, the five genes signature identified by this study warrants further exploration as a potential new biomarker of TNBC heterogeneity/stemness characterized by high hypoxia, stemness enrichment, and immune-suppressive tumor microenvironment. Full article
(This article belongs to the Special Issue Molecular Research of Triple-Negative Breast Cancer)
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Review

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19 pages, 1300 KiB  
Review
MicroRNAs as Molecular Biomarkers for the Characterization of Basal-like Breast Tumor Subtype
by Muhammad Tariq, Vinitha Richard and Michael J. Kerin
Biomedicines 2023, 11(11), 3007; https://doi.org/10.3390/biomedicines11113007 - 9 Nov 2023
Viewed by 1116
Abstract
Breast cancer is a heterogeneous disease highlighted by the presence of multiple tumor variants and the basal-like breast cancer (BLBC) is considered to be the most aggressive variant with limited therapeutics and a poor prognosis. Though the absence of detectable protein and hormonal [...] Read more.
Breast cancer is a heterogeneous disease highlighted by the presence of multiple tumor variants and the basal-like breast cancer (BLBC) is considered to be the most aggressive variant with limited therapeutics and a poor prognosis. Though the absence of detectable protein and hormonal receptors as biomarkers hinders early detection, the integration of genomic and transcriptomic profiling led to the identification of additional variants in BLBC. The high-throughput analysis of tissue-specific micro-ribonucleic acids (microRNAs/miRNAs) that are deemed to have a significant role in the development of breast cancer also displayed distinct expression profiles in each subtype of breast cancer and thus emerged to be a robust approach for the precise characterization of the BLBC subtypes. The classification schematic of breast cancer is still a fluid entity that continues to evolve alongside technological advancement, and the transcriptomic profiling of tissue-specific microRNAs is projected to aid in the substratification and diagnosis of the BLBC tumor subtype. In this review, we summarize the current knowledge on breast tumor classification, aim to collect comprehensive evidence based on the microRNA expression profiles, and explore their potential as prospective biomarkers of BLBC. Full article
(This article belongs to the Special Issue Molecular Research of Triple-Negative Breast Cancer)
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17 pages, 2070 KiB  
Review
From Interaction to Intervention: How Mesenchymal Stem Cells Affect and Target Triple-Negative Breast Cancer
by Yong Wu, Hang Chee Erin Shum, Ke Wu and Jaydutt Vadgama
Biomedicines 2023, 11(4), 1182; https://doi.org/10.3390/biomedicines11041182 - 15 Apr 2023
Cited by 3 | Viewed by 2820
Abstract
Triple-negative breast cancer (TNBC) lacks estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 expressions, making targeted therapies ineffective. Mesenchymal stem cells (MSCs) have emerged as a promising approach for TNBC treatment by modulating the tumor microenvironment (TME) and interacting with [...] Read more.
Triple-negative breast cancer (TNBC) lacks estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 expressions, making targeted therapies ineffective. Mesenchymal stem cells (MSCs) have emerged as a promising approach for TNBC treatment by modulating the tumor microenvironment (TME) and interacting with cancer cells. This review aims to comprehensively overview the role of MSCs in TNBC treatment, including their mechanisms of action and application strategies. We analyze the interactions between MSC and TNBC cells, including the impact of MSCs on TNBC cell proliferation, migration, invasion, metastasis, angiogenesis, and drug resistance, along with the signaling pathways and molecular mechanisms involved. We also explore the impact of MSCs on other components of the TME, such as immune and stromal cells, and the underlying mechanisms. The review discusses the application strategies of MSCs in TNBC treatment, including their use as cell or drug carriers and the advantages and limitations of different types and sources of MSCs in terms of safety and efficacy. Finally, we discuss the challenges and prospects of MSCs in TNBC treatment and propose potential solutions or improvement methods. Overall, this review provides valuable insights into the potential of MSCs as a novel therapeutic approach for TNBC treatment. Full article
(This article belongs to the Special Issue Molecular Research of Triple-Negative Breast Cancer)
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Other

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10 pages, 1331 KiB  
Case Report
Tall Cell Carcinoma with Reversed Polarity: Case Report of a Rare Special Type of Breast Cancer and Review of the Literature
by Maiar Elghobashy, Stephanie Jenkins, Zachary Shulman, Anne O’Neil, Sofia Kouneli and Abeer M. Shaaban
Biomedicines 2023, 11(9), 2376; https://doi.org/10.3390/biomedicines11092376 - 24 Aug 2023
Cited by 2 | Viewed by 1486
Abstract
Background: Tall cell carcinoma of the breast with reversed polarity (TCCRP) is a rare type of invasive breast cancer with overlapping features with papillary thyroid carcinoma and a characteristic molecular profile. Few cases have been reported in the literature since the first case [...] Read more.
Background: Tall cell carcinoma of the breast with reversed polarity (TCCRP) is a rare type of invasive breast cancer with overlapping features with papillary thyroid carcinoma and a characteristic molecular profile. Few cases have been reported in the literature since the first case was described in 2003. Case presentation: We present the case of a 41-year-old female with a symptomatic left breast lump. Image-guided core biopsy was diagnosed as triple-negative apocrine carcinoma. Surgical excision revealed an invasive carcinoma with solid papillary pattern, nuclei arranged away from the basement membrane (reversed polarity) and luminal eosinophilic colloid-like material. The tumour was GATA3-, CK5-, CK14- and CK7-positive and TTF1-negative. Specialist opinion and the identification of hotspot mutations in the IDH2 p.Arg172 gene via PCR confirmed the diagnosis of TCCRP. Conclusions: TCCRP is a relatively recently recognised papillary epithelial neoplasm with characteristic morphological features and molecular profile. Due to its rarity, TCCRP can be diagnostically challenging, and features can be mistaken for benign and malignant lesions. Accurate diagnosis is important in effective treatment of this indolent malignant triple-negative breast cancer, which carries an excellent prognosis. Full article
(This article belongs to the Special Issue Molecular Research of Triple-Negative Breast Cancer)
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28 pages, 1633 KiB  
Systematic Review
Update on Classic and Novel Approaches in Metastatic Triple-Negative Breast Cancer Treatment: A Comprehensive Review
by Salvatore Greco, Nicolò Fabbri, Riccardo Spaggiari, Alfredo De Giorgi, Fabio Fabbian and Antonio Giovine
Biomedicines 2023, 11(6), 1772; https://doi.org/10.3390/biomedicines11061772 - 20 Jun 2023
Cited by 4 | Viewed by 2402
Abstract
Triple-negative breast cancer (TNBC) accounts for almost 15% of all diagnosed breast cancers and often presents high rates of relapses and metastases, with generally poor prognosis despite multiple lines of treatment. Immunotherapy has radically changed the approach of clinicians towards TNBC in the [...] Read more.
Triple-negative breast cancer (TNBC) accounts for almost 15% of all diagnosed breast cancers and often presents high rates of relapses and metastases, with generally poor prognosis despite multiple lines of treatment. Immunotherapy has radically changed the approach of clinicians towards TNBC in the last two to three years, even if targeted and specific therapeutic options are still missing; this unmet need is further justified by the extreme molecular and clinical heterogeneity of this subtype of breast cancer and by the weak response to both single-agent and combined therapies. In March 2023, the National Comprehensive Cancer Network (NCCN), the main association of cancer centers in the United States, released the last clinical practice guidelines, with an update on classic and novel approaches in the field of breast cancer. The purpose of this comprehensive review is to summarize the latest findings in the setting of metastatic TNBC treatment, focusing on each category of drugs approved by the Food and Drug Administration (FDA) and included in the NCCN guidelines. We also introduce part of the latest published studies, which have reported new and promising molecules able to specifically target some of the biomarkers involved in TNBC pathogenesis. We searched the PubMed and Scopus databases for free full texts reported in the literature of the last 5 years, using the words “triple-negative breast cancer” or “TNBC” or “basal-like”. The articles were analyzed by the authors independently and double-blindly, and a total of 114 articles were included in the review. Full article
(This article belongs to the Special Issue Molecular Research of Triple-Negative Breast Cancer)
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