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Potential Molecular Targets and Therapeutics in Triple-Negative Breast Cancer
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Potential Molecular Targets and Therapeutics in Triple-Negative Breast Cancer

A special issue of Pharmaceuticals (ISSN 1424-8247). This special issue belongs to the section "Pharmacology".

Deadline for manuscript submissions: closed (29 October 2021) | Viewed by 51388

Special Issue Editors

Dr. Maryam Nakhjavani

E-Mail Website
Guest Editor
School of Medicine, Faculty of Health, Deakin University, 75 Pigdons Road, Waurn Ponds, VIC 3216, Australia
Interests: novel therapeutics in cancer treatment; breast cancer; drug development
Special Issues, Collections and Topics in MDPI journals
Dr. Amanda R. Townsend

E-Mail Website1 Website2
Co-Guest Editor
Medical Oncology Unit, The Queen Elizabeth Hospital, Woodville South, SA 5011, Australia
Interests: breast cancer; colon cancer; targeted therapy
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Triple-negative breast cancer (TNBC) is a subtype breast cancer that lacks any targeted therapy, and despite current improvements in the treatment of breast cancer patients, fewer drugs have been approved and are available to these patients, especially those with metastatic TNBC. The first line treatment options for these patients are chemotherapies which, despite their toxicity, are not very successful treatments, because often patients’ compliance with these treatments is low, and moreover, chemotherapies cannot overcome tumour resistance.

This Special Issue aims to integrate recent improvements in finding molecular targets and innovative approaches in the treatment of metastatic TNBC with an effort to expand the knowledge on a wide range of topics in this field. I would like to sincerely invite you to contribute on this Special Issue with your research articles and reviews, which include but are not limited to the following topics: molecular targets, signalling pathways, miRs, gene expression and multigene predictors, role of epigenetics, stem cells, single or combination treatments, targeted treatments and novel targeted formulations, animal models, and clinical outcomes.

Dr. Maryam Nakhjavani
Dr. Amanda Townsend
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Pharmaceuticals is an international peer-reviewed open access monthly 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

  • triple-negative breast cancer
  • metastasis
  • relapse
  • molecular target
  • gene expression
  • treatment
  • animal model
  • clinical outcome

Published Papers (15 papers)

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24 pages, 1716 KiB  
Review
Reversing an Oncogenic Epithelial-to-Mesenchymal Transition Program in Breast Cancer Reveals Actionable Immune Suppressive Pathways
by Michelle M. Williams, Sabrina A. Hafeez, Jessica L. Christenson, Kathleen I. O’Neill, Nia G. Hammond and Jennifer K. Richer
Pharmaceuticals 2021, 14(11), 1122; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14111122 - 02 Nov 2021
Cited by 3 | Viewed by 2979
Abstract
Approval of checkpoint inhibitors for treatment of metastatic triple negative breast cancer (mTNBC) has opened the door for the use of immunotherapies against this disease. However, not all patients with mTNBC respond to current immunotherapy approaches such as checkpoint inhibitors. Recent evidence demonstrates [...] Read more.
Approval of checkpoint inhibitors for treatment of metastatic triple negative breast cancer (mTNBC) has opened the door for the use of immunotherapies against this disease. However, not all patients with mTNBC respond to current immunotherapy approaches such as checkpoint inhibitors. Recent evidence demonstrates that TNBC metastases are more immune suppressed than primary tumors, suggesting that combination or additional immunotherapy strategies may be required to activate an anti-tumor immune attack at metastatic sites. To identify other immune suppressive mechanisms utilized by mTNBC, our group and others manipulated oncogenic epithelial-to-mesenchymal transition (EMT) programs in TNBC models to reveal differences between this breast cancer subtype and its more epithelial counterpart. This review will discuss how EMT modulation revealed several mechanisms, including tumor cell metabolism, cytokine milieu and secretion of additional immune modulators, by which mTNBC cells may suppress both the innate and adaptive anti-tumor immune responses. Many of these pathways/proteins are under preclinical or clinical investigation as therapeutic targets in mTNBC and other advanced cancers to enhance their response to chemotherapy and/or checkpoint inhibitors. Full article
(This article belongs to the Special Issue Potential Molecular Targets and Therapeutics in Triple-Negative Breast Cancer)
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20 pages, 5573 KiB  
Article
Anti-Cancer Effects of an Optimised Combination of Ginsenoside Rg3 Epimers on Triple Negative Breast Cancer Models
by Maryam Nakhjavani, Eric Smith, Helen M. Palethorpe, Yoko Tomita, Kenny Yeo, Tim J. Price, Amanda R. Townsend and Jennifer E. Hardingham
Pharmaceuticals 2021, 14(7), 633; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14070633 - 30 Jun 2021
Cited by 8 | Viewed by 2922
Abstract
Key problems of chemotherapies, as the mainstay of treatment for triple-negative breast cancer (TNBC), are toxicity and development of tumour resistance. Using response surface methodology, we previously optimised the combination of epimers of ginsenoside Rg3 (Rg3) for anti-angiogenic action. Here, we show that [...] Read more.
Key problems of chemotherapies, as the mainstay of treatment for triple-negative breast cancer (TNBC), are toxicity and development of tumour resistance. Using response surface methodology, we previously optimised the combination of epimers of ginsenoside Rg3 (Rg3) for anti-angiogenic action. Here, we show that the optimised combination of 50 µM SRg3 and 25 µM RRg3 (C3), derived from an RSM model of migration of TNBC cell line MDA-MB-231, inhibited migration of MDA-MB-231 and HCC1143, in 2D and 3D migration assays (p < 0.0001). C3 inhibited mammosphere formation efficiency in both cell lines and decreased the CD44+ stem cell marker in the mammospheres. Molecular docking predicted that Rg3 epimers had a better binding score with IGF-1R than with EGFR, HER-2 or PDGFR, and predicted an mTOR inhibitory function of Rg3. C3 affected the signalling of AKT in MDA-MB-231 and HCC1143 mammospheres. In a mouse model of metastatic TNBC, an equivalent dose of C3 (23 mg/kg SRg3 + 11 mg/kg RRg3) or an escalated dose of 46 mg/kg SRg3 + 23 mg/kg RRg3 was administered to NSG mice bearing MDA-MB-231-Luc cells. Calliper and IVIS spectrum measurement of the primary and secondary tumour showed that the treatment shrunk the primary tumour and decreased the load of metastasis in mice. In conclusion, this combination of Rg3 epimers showed promising results as a potential treatment option for TNBC patients. Full article
(This article belongs to the Special Issue Potential Molecular Targets and Therapeutics in Triple-Negative Breast Cancer)
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16 pages, 3194 KiB  
Article
Comprehensive Transcriptome and Pathway Analyses Revealed Central Role for Fascin in Promoting Triple-Negative Breast Cancer Progression
by Rayanah Barnawi, Samiyah Al-Khaldi, Salma Majid, Amal Qattan, Tala Bakheet, Mohannad Fallatah, Hazem Ghebeh, Nehad M. Alajez and Monther Al-Alwan
Pharmaceuticals 2021, 14(12), 1228; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14121228 - 26 Nov 2021
Cited by 4 | Viewed by 1929
Abstract
Recent years have witnessed major progress in development of novel therapeutic agents such as chemotherapy, targeted therapy and immune checkpoint inhibitors for breast cancer. However, cancer-related death remains high especially in triple-negative breast cancer (TNBC) due limited therapeutic options. Development of targeted therapies [...] Read more.
Recent years have witnessed major progress in development of novel therapeutic agents such as chemotherapy, targeted therapy and immune checkpoint inhibitors for breast cancer. However, cancer-related death remains high especially in triple-negative breast cancer (TNBC) due limited therapeutic options. Development of targeted therapies for TNBC requires better understanding of biology and signaling networks that promote disease progression. Fascin, an actin bundling protein, was identified as a key regulator of many signaling pathways that contribute to breast cancer progression. Herein, fascin ShRNA was used to generate stable fascin knockdown (FSCN1KD) in the MDA-MB-231 TNBC cell line and then were subjected to comprehensive mRNA and miRNA transcriptome analysis. We identified 129 upregulated and 114 downregulated mRNA transcripts, while 14 miRNAs were differentially expressed in FSCN1KD. Ingenuity pathway analysis (IPA) was used to predict the impact of differentially expressed transcripts on signaling pathways and functional categories and to construct miRNA-mRNA regulatory networks in the context of FSCN1 knockdown. Compared to FSCN1KD, fascin-positive (FSCN1CON) breast cancer cells showed enrichment in genes promoting cellular proliferation, migration, survival, DNA replication and repair. Expression of FSCN1high (identified in BRCA dataset from TCGA) in conjunction with elevated expression of the top 10 upregulated or decreased expression of the top 10 downregulated genes (identified in our FSCN1CON vs. FSCN1KD) correlates with worst survival outcome. Taken together, these data confirmed fascin’s role in promoting TNBC progression, and identified a novel opportunity for therapeutic interventions via targeting those FSCN1-related transcripts. Full article
(This article belongs to the Special Issue Potential Molecular Targets and Therapeutics in Triple-Negative Breast Cancer)
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24 pages, 828 KiB  
Review
Expanding the Use of PARP Inhibitors as Monotherapy and in Combination in Triple-Negative Breast Cancer
by Mariya Yordanova, Audrey Hubert and Saima Hassan
Pharmaceuticals 2021, 14(12), 1270; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14121270 - 06 Dec 2021
Cited by 5 | Viewed by 3339
Abstract
Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer, and is known to be associated with a poor prognosis and limited therapeutic options. Poly (ADP-ribose) polymerase inhibitors (PARPi) are targeted therapeutics that have demonstrated efficacy as monotherapy in metastatic BRCA [...] Read more.
Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer, and is known to be associated with a poor prognosis and limited therapeutic options. Poly (ADP-ribose) polymerase inhibitors (PARPi) are targeted therapeutics that have demonstrated efficacy as monotherapy in metastatic BRCA-mutant (BRCAMUT) TNBC patients. Improved efficacy of PARPi has been demonstrated in BRCAMUT breast cancer patients who have either received fewer lines of chemotherapy or in chemotherapy-naïve patients in the metastatic, adjuvant, and neoadjuvant settings. Moreover, recent trials in smaller cohorts have identified anti-tumor activity of PARPi in TNBC patients, regardless of BRCA-mutation status. While there have been concerns regarding the efficacy and toxicity of the use of PARPi in combination with chemotherapy, these challenges can be mitigated with careful attention to PARPi dosing strategies. To better identify a patient subpopulation that will best respond to PARPi, several genomic biomarkers of homologous recombination deficiency have been tested. However, gene expression signatures associated with PARPi response can integrate different pathways in addition to homologous recombination deficiency and can be implemented in the clinic more readily. Taken together, PARPi have great potential for use in TNBC patients beyond BRCAMUT status, both as a single-agent and in combination. Full article
(This article belongs to the Special Issue Potential Molecular Targets and Therapeutics in Triple-Negative Breast Cancer)
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16 pages, 766 KiB  
Review
Molecular Targets and Promising Therapeutics of Triple-Negative Breast Cancer
by Won-Ji Ryu and Joo Hyuk Sohn
Pharmaceuticals 2021, 14(10), 1008; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14101008 - 30 Sep 2021
Cited by 11 | Viewed by 2893
Abstract
Triple-negative breast cancer (TNBC) is one of the most heterogeneous diseases in solid tumors and has limited therapeutic options. Due to the lack of appropriate targetable markers, the mainstay therapeutic strategy for patients with TNBC has been chemotherapy for the last several decades. [...] Read more.
Triple-negative breast cancer (TNBC) is one of the most heterogeneous diseases in solid tumors and has limited therapeutic options. Due to the lack of appropriate targetable markers, the mainstay therapeutic strategy for patients with TNBC has been chemotherapy for the last several decades. Indeed, TNBC tumors have no expression of estrogen receptor, progesterone receptor, or human epidermal growth factor receptor 2 (HER2); therefore, they do not respond to hormone therapy and HER2-targeted therapy. In this review paper, the molecular heterogeneities, possible therapeutic targets, and recently approved and upcoming drugs for TNBC will be summarized. Full article
(This article belongs to the Special Issue Potential Molecular Targets and Therapeutics in Triple-Negative Breast Cancer)
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21 pages, 3606 KiB  
Article
Regulation of Cellular and Cancer Stem Cell-Related Putative Gene Expression of Parental and CD44+CD24− Sorted MDA-MB-231 Cells by Cisplatin
by May Zie Koh, Wan Yong Ho, Swee Keong Yeap, Norlaily Mohd Ali, Lily Boo and Noorjahan Banu Alitheen
Pharmaceuticals 2021, 14(5), 391; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14050391 - 21 Apr 2021
Cited by 8 | Viewed by 3097
Abstract
Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype that promotes a higher risk of metastasis and cancer reoccurrence. Cisplatin is one of the potential anticancer drugs for treating TNBC. However, the occurrence of cisplatin resistance still remains one of the challenges [...] Read more.
Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype that promotes a higher risk of metastasis and cancer reoccurrence. Cisplatin is one of the potential anticancer drugs for treating TNBC. However, the occurrence of cisplatin resistance still remains one of the challenges in fully eradicating TNBC. The presence of cancer stem cells (CSCs) has been proposed as one of the factors contributing to the development of cisplatin resistance. In this study, we aimed to characterize the cellular properties and reveal the corresponding putative target genes involved in cisplatin resistance associated with CSCs using the TNBC cell line (MDA-MB-231). CSC-like cells were isolated from parental cells and the therapeutic effect of cisplatin on CSC-like cells was compared to that of the parental cells via cell characterization bioassays. A PCR array was then conducted to study the expression of cellular mRNA for each subpopulation. As compared to treated parental cells, treated CSCs displayed lower events of late apoptosis/necrosis and G2/M phase cell arrest, with higher mammosphere formation capacity. Furthermore, a distinct set of putative target genes correlated to the Hedgehog pathway and angiogenesis were dysregulated solely in CSC-like cells after cisplatin treatment, which were closely related to the regulation of chemoresistance and self-renewability in breast cancer. In summary, both cellular and gene expression studies suggest the attenuated cytotoxicity of cisplatin in CSC-like cells as compared to parental cells. Understanding the role of dysregulated putative target genes induced by cisplatin in CSCs may aid in the potential development of therapeutic targets for cisplatin-resistant breast cancer. Full article
(This article belongs to the Special Issue Potential Molecular Targets and Therapeutics in Triple-Negative Breast Cancer)
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76 pages, 2419 KiB  
Review
Potentiating Therapeutic Effects of Epidermal Growth Factor Receptor Inhibition in Triple-Negative Breast Cancer
by Kyu Sic You, Yong Weon Yi, Jeonghee Cho, Jeong-Soo Park and Yeon-Sun Seong
Pharmaceuticals 2021, 14(6), 589; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14060589 - 18 Jun 2021
Cited by 31 | Viewed by 6530
Abstract
Triple-negative breast cancer (TNBC) is a subset of breast cancer with aggressive characteristics and few therapeutic options. The lack of an appropriate therapeutic target is a challenging issue in treating TNBC. Although a high level expression of epidermal growth factor receptor (EGFR) has [...] Read more.
Triple-negative breast cancer (TNBC) is a subset of breast cancer with aggressive characteristics and few therapeutic options. The lack of an appropriate therapeutic target is a challenging issue in treating TNBC. Although a high level expression of epidermal growth factor receptor (EGFR) has been associated with a poor prognosis among patients with TNBC, targeted anti-EGFR therapies have demonstrated limited efficacy for TNBC treatment in both clinical and preclinical settings. However, with the advantage of a number of clinically approved EGFR inhibitors (EGFRis), combination strategies have been explored as a promising approach to overcome the intrinsic resistance of TNBC to EGFRis. In this review, we analyzed the literature on the combination of EGFRis with other molecularly targeted therapeutics or conventional chemotherapeutics to understand the current knowledge and to provide potential therapeutic options for TNBC treatment. Full article
(This article belongs to the Special Issue Potential Molecular Targets and Therapeutics in Triple-Negative Breast Cancer)
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18 pages, 12215 KiB  
Article
Inhibition of DOT1L by Half-Selenopsammaplin A Analogs Suppresses Tumor Growth and EMT-Mediated Metastasis in Triple-Negative Breast Cancer
by Woong Sub Byun, Gyu Ho Lee, Hyeung-geun Park and Sang Kook Lee
Pharmaceuticals 2021, 14(1), 18; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14010018 - 28 Dec 2020
Cited by 6 | Viewed by 2470
Abstract
Due to a lack of hormone receptors, current treatment strategies for triple-negative breast cancer (TNBC) are limited with frequent disease recurrence and metastasis. Recent findings have suggested that aberrant methylation of histone H3 lysine 79 residue (H3K79me) by the histone methyltransferase disruptor of [...] Read more.
Due to a lack of hormone receptors, current treatment strategies for triple-negative breast cancer (TNBC) are limited with frequent disease recurrence and metastasis. Recent findings have suggested that aberrant methylation of histone H3 lysine 79 residue (H3K79me) by the histone methyltransferase disruptor of telomeric silencing 1-like (DOT1L) is a potential therapeutic target for TNBC clinical management. Therefore, we developed DOT1L inhibitors as potential antitumor agents against TNBC cells. We reveal that a synthetic half-selenopsammaplin A analog 9l (subsequently known as 9l) exhibited inhibitory activity against DOT1L-mediated H3K79 methylation, and showed antitumor activity in TNBC cells. The analog 9l also significantly inhibited TNBC invasion and migration via the modulation of epithelial-mesenchymal transition (EMT) markers, including N-cadherin and vimentin downregulation and E-cadherin upregulation. In an MDA-MB-231/Luc-implanted orthotopic mouse metastasis model, treatment with 9l effectively inhibited tumor growth and lung metastasis via DOT1L regulatory activity and EMT processes. Taken together, these findings highlight the potential of 9l as a novel therapeutic candidate for treating metastatic TNBC via DOT1L modulation. Full article
(This article belongs to the Special Issue Potential Molecular Targets and Therapeutics in Triple-Negative Breast Cancer)
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18 pages, 2461 KiB  
Article
Atovaquone Suppresses the Growth of Metastatic Triple-Negative Breast Tumors in Lungs and Brain by Inhibiting Integrin/FAK Signaling Axis
by Nehal Gupta and Sanjay K. Srivastava
Pharmaceuticals 2021, 14(6), 521; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14060521 - 28 May 2021
Cited by 9 | Viewed by 3115
Abstract
Triple-negative breast cancer (TNBC) is considered to be the most aggressive and malignant neoplasm and is highly metastatic in nature. In the current study, we investigated the anti-metastatic potential of atovaquone, a protozoal drug prescribed for Pneumocystis pneumonia. We showed that atovaquone induced [...] Read more.
Triple-negative breast cancer (TNBC) is considered to be the most aggressive and malignant neoplasm and is highly metastatic in nature. In the current study, we investigated the anti-metastatic potential of atovaquone, a protozoal drug prescribed for Pneumocystis pneumonia. We showed that atovaquone induced apoptosis and reduced the survival of several aggressive metastatic TNBC cell lines including metastatic patient-derived cells by reducing the expression of integrin α6, integrin β4, FAK, Src, and Vimentin. In order to study the efficacy of atovaquone in suppressing metastasized breast tumor cells in brain and lungs, we performed three in vivo experiments. We demonstrated that oral administration of 50 mg/kg of atovaquone suppressed MDA-MB-231 breast tumor growth by 90% in lungs in an intravenous metastatic tumor model. Anti-metastatic effect of atovaquone was further determined by intracardiac injection of 4T1-luc breast tumor cells into the left ventricle of mouse heart. Our results showed that atovaquone treatment suppressed the growth of metastatic tumors in lungs, liver and brain by 70%, 50% and 30% respectively. In an intracranial model, the growth of HCC1806-luc brain tumors in atovaquone treated mice was about 55% less than that of control. Taken together, our results indicate the anti-metastatic effects of atovaquone in vitro and in vivo in various breast tumor metastasis models. Full article
(This article belongs to the Special Issue Potential Molecular Targets and Therapeutics in Triple-Negative Breast Cancer)
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14 pages, 3380 KiB  
Article
Gene Dosage Analysis on the Single-Cell Transcriptomes Linking Cotranslational Protein Targeting to Metastatic Triple-Negative Breast Cancer
by Yining Liu and Min Zhao
Pharmaceuticals 2021, 14(9), 918; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14090918 - 10 Sep 2021
Cited by 3 | Viewed by 2071
Abstract
Many recent efforts have been put into the association between expression heterogeneity and different cell types and states using single-cell RNA transcriptome analysis. There is only limited understanding of gene dosage effects for the genetic heterogeneity at the single-cell level. By focusing on [...] Read more.
Many recent efforts have been put into the association between expression heterogeneity and different cell types and states using single-cell RNA transcriptome analysis. There is only limited understanding of gene dosage effects for the genetic heterogeneity at the single-cell level. By focusing on concordant copy number variation (CNV) and expression, we presented a computational framework to explore dosage effect for aggressive metastatic triple-negative breast cancer (TNBC) at the single-cell level. In practice, we collected CNV and single-cell expression data from the same patients with independent technologies. By focusing on 47,198 consistent copy number gains (CNG) and gene up-regulation from 1145 single cells, ribosome proteins with important roles in protein targeting were enriched. Independent validation in another metastatic TNBC dataset further prioritized signal recognition particle-dependent protein targeting as the top functional module. More interesting, the increased ribosome gene copies in TNBC may associate with their enhanced stemness and metastatic potential. Indeed, the prioritization of a well-upregulated functional module confirmed by high copy numbers at the single-cell level and contributing to patient survival may indicate the possibility of targeted therapy based on ribosome proteins for TNBC. Full article
(This article belongs to the Special Issue Potential Molecular Targets and Therapeutics in Triple-Negative Breast Cancer)
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14 pages, 1034 KiB  
Review
Growth Inhibitory Efficacy of Chinese Herbs in a Cellular Model for Triple-Negative Breast Cancer
by Nitin T. Telang, Hareesh B. Nair and George Y. C. Wong
Pharmaceuticals 2021, 14(12), 1318; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14121318 - 17 Dec 2021
Cited by 6 | Viewed by 2990
Abstract
Triple-negative breast cancer (TNBC) is characterized by the absence of estrogen receptor-α progesterone receptor and human epidermal growth factor receptor-2. Treatment for this breast cancer subtype is restricted to multidrug chemotherapy and survival pathway-based molecularly targeted therapy. The long-term treatment options are associated [...] Read more.
Triple-negative breast cancer (TNBC) is characterized by the absence of estrogen receptor-α progesterone receptor and human epidermal growth factor receptor-2. Treatment for this breast cancer subtype is restricted to multidrug chemotherapy and survival pathway-based molecularly targeted therapy. The long-term treatment options are associated with systemic toxicity, spontaneous and/or acquired tumor resistance and the emergence a of drug-resistant stem cell population. These limitations lead to advanced stage metastatic cancer. Current emphasis is on research directions that identify efficacious, naturally occurring agents representing an unmet need for testable therapeutic alternatives for therapy resistant breast cancer. Chinese herbs are widely used in traditional Chinese medicine in women for estrogen related health issues and also for integrative support for cancer treatment. This review discusses published evidence on a TNBC model for growth inhibitory effects of several mechanistically distinct nontoxic Chinese herbs, most of them nutritional in nature, and identifies susceptible pathways and potential molecular targets for their efficacy. Documented anti-proliferative and pro-apoptotic effects of these herbs are associated with downregulation of RB, RAS, PI3K, and AKT signaling, modulation of Bcl-2/BAX protein expressions and increased caspase activity. This review provides a proof of concept for Chinese herbs as testable alternatives for prevention/therapy of TNBC. Full article
(This article belongs to the Special Issue Potential Molecular Targets and Therapeutics in Triple-Negative Breast Cancer)
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13 pages, 476 KiB  
Review
Immunotherapy Treatment for Triple Negative Breast Cancer
by Elizabeth R. Berger, Tristen Park, Angeleke Saridakis, Mehra Golshan, Rachel A. Greenup and Nita Ahuja
Pharmaceuticals 2021, 14(8), 763; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14080763 - 04 Aug 2021
Cited by 31 | Viewed by 6511
Abstract
Triple-negative breast cancer (TNBC) is considered one of the highest-risk subtypes of breast cancer and has dismal prognosis. Local recurrence rate after standard therapy in the early breast cancer setting can be upwards to 72% in 5 years, and in the metastatic setting, [...] Read more.
Triple-negative breast cancer (TNBC) is considered one of the highest-risk subtypes of breast cancer and has dismal prognosis. Local recurrence rate after standard therapy in the early breast cancer setting can be upwards to 72% in 5 years, and in the metastatic setting, the 5-year overall survival is 12%. Due to the lack of receptor expression, there has been a paucity of targeted therapeutics available, with chemotherapy being the primary option for systemic treatment in both the neoadjuvant and metastatic setting. More recently, immunotherapy has revolutionized the landscape of cancer treatment, particularly immune checkpoint inhibitor (ICI) therapy, with FDA approval in over 20 types of cancer since 2011. Compared to other cancer types, breast cancer has been traditionally thought of as being immunologically cold; however, TNBC has demonstrated the most promise with immunotherapy use, a timely discovery due to its lack of targeted therapy options. In this review, we summarize the trials using checkpoint therapy in early and metastatic TNBC, as well as the development of biomarkers and the importance of immune related adverse events (IRAEs), in this disease process. Full article
(This article belongs to the Special Issue Potential Molecular Targets and Therapeutics in Triple-Negative Breast Cancer)
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20 pages, 13804 KiB  
Article
Growth Inhibition of Triple-Negative Breast Cancer: The Role of Spatiotemporal Delivery of Neoadjuvant Doxorubicin and Cisplatin
by Dominick Salerno and Stavroula Sofou
Pharmaceuticals 2021, 14(10), 1035; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14101035 - 12 Oct 2021
Cited by 2 | Viewed by 2071
Abstract
Combinations of platinum-based compounds with doxorubicin in free and/or in liposomal form for improved safety are currently being evaluated in the neoadjuvant setting on patients with advanced triple-negative breast cancer (TNBC). However, TNBC may likely be driven by chemotherapy-resistant cells. Additionally, established TNBC [...] Read more.
Combinations of platinum-based compounds with doxorubicin in free and/or in liposomal form for improved safety are currently being evaluated in the neoadjuvant setting on patients with advanced triple-negative breast cancer (TNBC). However, TNBC may likely be driven by chemotherapy-resistant cells. Additionally, established TNBC tumors may also exhibit diffusion-limited transport, resulting in heterogeneous intratumoral delivery of the administered therapeutics; this limits therapeutic efficacy in vivo. We studied TNBC cells with variable chemosensitivities, in the absence (on monolayers) and presence (in 3D multicellular spheroids) of transport barriers; we compared the combined killing effect of free doxorubicin and free cisplatin to the killing effect (1) of conventional liposomal forms of the two chemotherapeutics, and (2) of tumor-responsive lipid nanoparticles (NP), specifically engineered to result in more uniform spatiotemporal microdistributions of the agents within solid tumors. This was enabled by the NP properties of interstitial release, cell binding/internalization, and/or adhesion to the tumors’ extracellular matrix. The synergistic cell kill by combinations of the agents (in all forms), compared to the killing effect of each agent alone, was validated on monolayers of cells. Especially for spheroids formed by cells exhibiting resistance to doxorubicin combination treatments with both agents in free and/or in tumor-responsive NP-forms were comparably effective; we not only observed greater inhibition of outgrowth compared to the single agent(s) but also compared to the conventional liposome forms of the combined agents. We correlated this finding to more uniform spatiotemporal microdistributions of agents by the tumor-responsive NP. Our study shows that combinations of NP with properties specifically optimized to improve the spatiotemporal uniformity of the delivery of their corresponding therapeutic cargo can improve treatment efficacy while keeping favorable safety profiles. Full article
(This article belongs to the Special Issue Potential Molecular Targets and Therapeutics in Triple-Negative Breast Cancer)
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14 pages, 915 KiB  
Review
The Roles of DNA Demethylases in Triple-Negative Breast Cancer
by Shoghag Panjarian and Jean-Pierre J. Issa
Pharmaceuticals 2021, 14(7), 628; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14070628 - 29 Jun 2021
Cited by 3 | Viewed by 2991
Abstract
Triple-negative breast cancers (TNBCs) are very heterogenous, molecularly diverse, and are characterized by a high propensity to relapse or metastasize. Clinically, TNBC remains a diagnosis of exclusion by the lack of hormone receptors (Estrogen Receptor (ER) and Progesterone Receptor (PR)) as well as [...] Read more.
Triple-negative breast cancers (TNBCs) are very heterogenous, molecularly diverse, and are characterized by a high propensity to relapse or metastasize. Clinically, TNBC remains a diagnosis of exclusion by the lack of hormone receptors (Estrogen Receptor (ER) and Progesterone Receptor (PR)) as well as the absence of overexpression and/or amplification of HER2. DNA methylation plays an important role in breast cancer carcinogenesis and TNBCs have a distinct DNA methylation profile characterized by marked hypomethylation and lower gains of methylations compared to all other subtypes. DNA methylation is regulated by the balance of DNA methylases (DNMTs) and DNA demethylases (TETs). Here, we review the roles of TETs as context-dependent tumor-suppressor genes and/or oncogenes in solid tumors, and we discuss the current understandings of the oncogenic role of TET1 and its therapeutic implications in TNBCs. Full article
(This article belongs to the Special Issue Potential Molecular Targets and Therapeutics in Triple-Negative Breast Cancer)
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18 pages, 1202 KiB  
Review
Therapeutic Strategies for Metastatic Triple-Negative Breast Cancers: From Negative to Positive
by Dey Nandini, Aske Jennifer and De Pradip
Pharmaceuticals 2021, 14(5), 455; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14050455 - 12 May 2021
Cited by 19 | Viewed by 3469
Abstract
Metastatic triple-negative breast cancer (TNBC) is a distinct and immensely complex form of breast cancer. Among all subtypes of breast cancers, TNBC has a comparatively high rate of relapse, a high rate of distant metastasis, and poor overall survival after standard chemotherapy. Chemotherapy [...] Read more.
Metastatic triple-negative breast cancer (TNBC) is a distinct and immensely complex form of breast cancer. Among all subtypes of breast cancers, TNBC has a comparatively high rate of relapse, a high rate of distant metastasis, and poor overall survival after standard chemotherapy. Chemotherapy regimens are an essential component of the management of this estrogen receptor-negative, progesterone receptor-negative, and epidermal growth factor receptor2 negative subtype of breast cancers. Chemotherapy is critical for preventing the recurrence of the disease and for achieving long-term survival. Currently, a couple of agents are approved for the management of this disease, including chemotherapy like eribulin, targeted therapy like PARP inhibitor, as well as an antibody-drug conjugate (ADC) to target TROP2. Like many other metastatic cancers, immune checkpoint inhibitors (ICIs) have also been approved for TNBC patients with PD-L1 positive tumors and high tumor mutational burden. In this review article, we discuss these newly approved and promising novel agents that may change the therapeutic landscape for advanced/metastatic TNBC patients. Full article
(This article belongs to the Special Issue Potential Molecular Targets and Therapeutics in Triple-Negative Breast Cancer)
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