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Cancers
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Triple Negative Breast Cancer Therapy Resistance and Metastasis
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Triple Negative Breast Cancer Therapy Resistance and Metastasis

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Cancer Therapy".

Deadline for manuscript submissions: closed (5 November 2024) | Viewed by 9167

Special Issue Editor

Dr. Daniela Sousa

E-Mail Website
Guest Editor
Instituto de Investigação e Inovação em Saúde (I3S), Universidade do Porto, 4200-135 Porto, Portugal
Interests: breast cancer

Special Issue Information

Dear Colleagues,

Breast cancer (BC) is the most common type of cancer diagnosed in women worldwide. Around 10% of patients with BC are diagnosed with the Triple-Negative Breast Cancer (TNBC) subtype. Such subtype lacks the expression of the estrogen receptor, progesterone receptor and human epidermal growth factor receptor-2, thus limiting the therapeutic options for patients with TNBC.

TNBC is associated with a poor prognosis due to the high systemic recurrence and lack of response to conventional therapies, especially at an advanced stage of the disease. Moreover, patients with TNBC often develop therapy resistance and metastasis, negatively affecting patients’ survival rate.

As revealed by proteomics and transcriptomics, this specific clinical group of patients is highly heterogenous, comprising of distinct histological and molecular biomarkers. Therefore, identifying the most effective treatment/combination of therapeutic strategies that could effectively fight the disease and the occurrence of metastasis has been a major challenge in the clinics.

This Special Issue will focus on the current therapeutic approaches adopted to tackle TNBC and the progression of the disease, as well as the efforts made to uncover novel therapeutic targets and schemes, which ultimately will increase the survival rate of patients with TNBC. Here, we welcome both original or review articles in basic science, pre-clinical studies, clinical studies and translational medicine.

Dr. Daniela Sousa
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 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. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • TNBC
  • therapeutic resistance
  • immunotherapy
  • metastasis
  • personalized medicine
  • targeted therapies
  • adjuvant therapies
  • neoadjuvant therapies

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Published Papers (6 papers)

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Research

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17 pages, 4321 KiB  
Article
SLFN12 Expression Significantly Effects the Response to Chemotherapy Drugs in Triple-Negative Breast Cancer
by Savannah R. Brown, Emilie Erin Vomhof-DeKrey, Sarmad Al-Marsoummi, Trysten Beyer, Bo Lauckner, Mckenzie Samson, Sarah Sattar, Nicholas D. Brown and Marc D. Basson
Cancers 2024, 16(22), 3848; https://doi.org/10.3390/cancers16223848 - 16 Nov 2024
Viewed by 436
Abstract
Background/Objectives: Schlafen12 (SLFN12) is an intermediate human Schlafen protein shown to correlate with survivability in triple-negative breast cancer (TNBC). SLFN12 causes differential expressions of significant cancer genes, but how they change in response to chemotherapy remains unknown. Our aim is to identify the [...] Read more.
Background/Objectives: Schlafen12 (SLFN12) is an intermediate human Schlafen protein shown to correlate with survivability in triple-negative breast cancer (TNBC). SLFN12 causes differential expressions of significant cancer genes, but how they change in response to chemotherapy remains unknown. Our aim is to identify the effect of chemotherapy on genes that improve TNBC outcomes and other SLFN family members following SLFN12 knockout or overexpression. Methods: We overexpressed SLFN12 using a lentiviral vector and knocked out SLFN12 (AdvShSLFN12) using a hairpin adenovirus in MDA-MB-231 TNBC cells. Cells were treated with camptothecin, paclitaxel, zoledronic acid, or carboplatin to evaluate the SLFN12 signature cancer genes associated with improved TNBC outcomes using qPCR. Additionally, cells were treated alone and in combination with AdvShSLFN12, IFN-α2 (known SLFN12 stimulator), carboplatin, and paclitaxel. After treatment, the viable cell numbers were analyzed utilizing a colorimetric crystal violet assay for cell viability. Results: The SLFN family and SLFN12 cancer signature gene mRNA expressions were analyzed by RT-qPCR. Treating SLFN12-overexpressing TNBC cells with chemotherapy agents resulted in the differential expressions of eight cancer-related genes. Notably, GJB3 was downregulated following treatment with each chemotherapeutic drug. Inducing SLFN12 with IFN-α2 resulted in decreased cell viability and increased SLFN12 mRNA levels following treatment with paclitaxel or carboplatin. Conclusions: These results suggest that SLFN12 overexpression significantly affects the expressions of genes driving phenotypic changes in response to chemotherapy and influences additional SLFN family members following IFN-α2 treatment. This may contribute to improving the survival of patients with SLFN12 overexpression. Additionally, patient SLFN12 levels can be used as a factor when pursuing personalized chemotherapy treatments. Full article
(This article belongs to the Special Issue Triple Negative Breast Cancer Therapy Resistance and Metastasis)
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23 pages, 3729 KiB  
Article
The Engineered Drug 3′UTRMYC1-18 Degrades the c-MYC-STAT5A/B-PD-L1 Complex In Vivo to Inhibit Metastatic Triple-Negative Breast Cancer
by Chidiebere U. Awah, Joo Sun Mun, Aloka Paragodaarachchi, Baris Boylu, Chika Ochu, Hiroshi Matsui and Olorunseun O. Ogunwobi
Cancers 2024, 16(15), 2663; https://doi.org/10.3390/cancers16152663 - 26 Jul 2024
Viewed by 1094
Abstract
c-MYC is overexpressed in 70% of human cancers, including triple-negative breast cancer (TNBC), yet there is no clinically approved drug that directly targets it. Here, we engineered the mRNA-stabilizing poly U sequences within the 3′UTR of c-MYC to specifically destabilize and promote the [...] Read more.
c-MYC is overexpressed in 70% of human cancers, including triple-negative breast cancer (TNBC), yet there is no clinically approved drug that directly targets it. Here, we engineered the mRNA-stabilizing poly U sequences within the 3′UTR of c-MYC to specifically destabilize and promote the degradation of c-MYC transcripts. Interestingly, the engineered derivative outcompetes the endogenous overexpressed c-MYC mRNA, leading to reduced c-MYC mRNA and protein levels. The iron oxide nanocages (IO-nanocages) complexed with MYC-destabilizing constructs inhibited primary and metastatic tumors in mice bearing TNBC and significantly prolonged survival by degrading the c-MYC-STAT5A/B-PD-L1 complexes that drive c-MYC-positive TNBC. Taken together, we have described a novel therapy for c-MYC-driven TNBC and uncovered c-MYC-STAT5A/B-PD-L1 interaction as the target. Full article
(This article belongs to the Special Issue Triple Negative Breast Cancer Therapy Resistance and Metastasis)
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21 pages, 3711 KiB  
Article
Synergistic Action of Benzyl Isothiocyanate and Sorafenib in a Nanoparticle Delivery System for Enhanced Triple-Negative Breast Cancer Treatment
by Qi Wang, Nan Cheng, Wei Wang and Yongping Bao
Cancers 2024, 16(9), 1695; https://doi.org/10.3390/cancers16091695 - 26 Apr 2024
Viewed by 1327
Abstract
Triple-negative breast cancer (TNBC) presents a therapeutic challenge due to its complex pathology and limited treatment options. Addressing this challenge, our study focuses on the effectiveness of combination therapy, which has recently become a critical strategy in cancer treatment, improving therapeutic outcomes and [...] Read more.
Triple-negative breast cancer (TNBC) presents a therapeutic challenge due to its complex pathology and limited treatment options. Addressing this challenge, our study focuses on the effectiveness of combination therapy, which has recently become a critical strategy in cancer treatment, improving therapeutic outcomes and combating drug resistance and metastasis. We explored a novel combination therapy employing Benzyl isothiocyanate (BITC) and Sorafenib (SOR) and their nanoformulation, aiming to enhance therapeutic outcomes against TNBC. Through a series of in vitro assays, we assessed the cytotoxic effects of BITC and SOR, both free and encapsulated. The BITC–SOR-loaded nanoparticles (NPs) were synthesized using an amphiphilic copolymer, which demonstrated a uniform spherical morphology and favorable size distribution. The encapsulation efficiencies, as well as the sustained release profiles at varied pH levels, were quantified, revealing distinct kinetics that were well-modeled by the Korsmeyer–Peppas equation. The NP delivery system showed a marked dose-dependent cytotoxicity towards TNBC cells, with an IC50 of 7.8 μM for MDA-MB-231 cells, indicating improved efficacy over free drugs, while exhibiting minimal toxicity toward normal breast cells. Furthermore, the NPs significantly inhibited cell migration and invasion in TNBC models, surpassing the effects of free drugs. These findings underscore the potential of BITC–SOR-NPs as a promising therapeutic approach for TNBC, offering targeted delivery while minimizing systemic toxicity. Full article
(This article belongs to the Special Issue Triple Negative Breast Cancer Therapy Resistance and Metastasis)
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22 pages, 19263 KiB  
Article
Inhibition of TNBC Cell Growth by Paroxetine: Induction of Apoptosis and Blockage of Autophagy Flux
by Qianrui Huang, Mengling Wu, Yamin Pu, Junyou Zhou, Yiqian Zhang, Ru Li, Yong Xia, Yiwen Zhang and Yimei Ma
Cancers 2024, 16(5), 885; https://doi.org/10.3390/cancers16050885 - 22 Feb 2024
Cited by 1 | Viewed by 1655
Abstract
The strategy of drug repurposing has gained traction in the field of cancer therapy as a means of discovering novel therapeutic uses for established pharmaceuticals. Paroxetine (PX), a selective serotonin reuptake inhibitor typically utilized in the treatment of depression, has demonstrated promise as [...] Read more.
The strategy of drug repurposing has gained traction in the field of cancer therapy as a means of discovering novel therapeutic uses for established pharmaceuticals. Paroxetine (PX), a selective serotonin reuptake inhibitor typically utilized in the treatment of depression, has demonstrated promise as an agent for combating cancer. Nevertheless, the specific functions and mechanisms by which PX operates in the context of triple-negative breast cancer (TNBC) remain ambiguous. This study aimed to examine the impact of PX on TNBC cells in vitro as both a standalone treatment and in conjunction with other pharmaceutical agents. Cell viability was measured using the 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay, apoptosis was assessed through flow cytometry, and the effects on signaling pathways were analyzed using RNA sequencing and Western blot techniques. Furthermore, a subcutaneous tumor model was utilized to assess the in vivo efficacy of combination therapy on tumor growth. The results of our study suggest that PX may activate the Ca2+-dependent mitochondria-mediated intrinsic apoptosis pathway in TNBC by potentially influencing the PI3K/AKT/mTOR pathway as well as by inducing cytoprotective autophagy. Additionally, the combination of PX and chemotherapeutic agents demonstrated moderate inhibitory effects on 4T1 tumor growth in an in vivo model. These findings indicate that PX may exert its effects on TNBC through modulation of critical molecular pathways, offering important implications for improving chemosensitivity and identifying potential therapeutic combinations for clinical use. Full article
(This article belongs to the Special Issue Triple Negative Breast Cancer Therapy Resistance and Metastasis)
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14 pages, 5715 KiB  
Article
Head-to-Head Comparison of [18F]PSMA-1007 and [18F]FDG PET/CT in Patients with Triple-Negative Breast Cancer
by Natalia Andryszak, Daria Świniuch, Elżbieta Wójcik, Rodryg Ramlau, Marek Ruchała and Rafał Czepczyński
Cancers 2024, 16(3), 667; https://doi.org/10.3390/cancers16030667 - 4 Feb 2024
Cited by 7 | Viewed by 2345
Abstract
Background: Triple-negative breast cancer (TNBC) exhibits high aggressiveness and a notably poorer prognosis at advanced stages. Nuclear medicine offers new possibilities, not only for diagnosis but also potentially promising therapeutic strategies. This prospective study explores the potential of prostate-specific membrane antigen (PSMA) as [...] Read more.
Background: Triple-negative breast cancer (TNBC) exhibits high aggressiveness and a notably poorer prognosis at advanced stages. Nuclear medicine offers new possibilities, not only for diagnosis but also potentially promising therapeutic strategies. This prospective study explores the potential of prostate-specific membrane antigen (PSMA) as a diagnostic and therapeutic target in TNBC. Methods: the research investigates PSMA expression in vivo among TNBC patients using [18F]PSMA-1007 PET/CT and compares it head-to-head with the standard-of-care [18F]FDG PET/CT. Results: The study involves 10 TNBC patients, revealing comparable uptake of [18F]PSMA-1007 and [18F]FDG in primary and metastatic lesions. Nodal metastases were found in eight patients, showing similar SUVmax values in both modalities. Two patients had uncountable lung metastases positive in both [18F]FDG and [18F]PSMA-1007 scans. PET-positive bone metastases were identified by 18F-PSMA in four patients, while elevated [18F]FDG uptake was found only in three of them. Distant metastases displayed higher SUVmax values in the [18F]PSMA-1007 PET/CT, as compared to [18F]FDG. Additionally, brain metastases were exclusively detected using [18F]PSMA-1007. Conclusions: the findings provide valuable insights into the expression of PSMA in TNBC and underscore the potential clinical significance of [18F]PSMA-1007 PET/CT in enhancing both diagnostic and therapeutic approaches for this aggressive breast cancer subtype. Full article
(This article belongs to the Special Issue Triple Negative Breast Cancer Therapy Resistance and Metastasis)
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Review

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16 pages, 2011 KiB  
Review
Advanced Insights into Competitive Endogenous RNAs (ceRNAs) Regulated Pathogenic Mechanisms in Metastatic Triple-Negative Breast Cancer (mTNBC)
by Amal Qattan, Taher Al-Tweigeri, Kausar Suleman, Wafa Alkhayal and Asma Tulbah
Cancers 2024, 16(17), 3057; https://doi.org/10.3390/cancers16173057 - 1 Sep 2024
Viewed by 1540
Abstract
Triple-negative breast cancer is aggressive and challenging to treat because of a lack of targets and heterogeneity among tumors. A paramount factor in the mortality from breast cancer is metastasis, which is driven by genetic and phenotypic alterations that drive epithelial–mesenchymal transition, stemness, [...] Read more.
Triple-negative breast cancer is aggressive and challenging to treat because of a lack of targets and heterogeneity among tumors. A paramount factor in the mortality from breast cancer is metastasis, which is driven by genetic and phenotypic alterations that drive epithelial–mesenchymal transition, stemness, survival, migration and invasion. Many genetic and epigenetic mechanisms have been identified in triple-negative breast cancer that drive these metastatic phenotypes; however, this knowledge has not yet led to the development of effective drugs for metastatic triple-negative breast cancer (mTNBC). One that may not have received enough attention in the literature is post-translational regulation of broad sets of cancer-related genes through inhibitory microRNAs and the complex competitive endogenous RNA (ceRNA) regulatory networks they are influenced by. This field of study and the resulting knowledge regarding alterations in these networks is coming of age, enabling translation into clinical benefit for patients. Herein, we review metastatic triple-negative breast cancer (mTNBC), the role of ceRNA network regulation in metastasis (and therefore clinical outcomes), potential approaches for therapeutic exploitation of these alterations, knowledge gaps and future directions in the field. Full article
(This article belongs to the Special Issue Triple Negative Breast Cancer Therapy Resistance and Metastasis)
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