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Triple-Negative Breast Cancer: Molecular Characteristics, Treatment Challenges and Solutions
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Triple-Negative Breast Cancer: Molecular Characteristics, Treatment Challenges and Solutions

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

Deadline for manuscript submissions: closed (30 November 2020) | Viewed by 82248

Special Issue Editors

Dr. Dayanidhi Raman

E-Mail Website
Guest Editor
Department of Cell and Cancer Biology, College of Medicine and Life Sciences, Health Science Campus, University of Toledo, Toledo, OH 43614, USA
Interests: chemokine receptors; chemotaxis; cap-dependent mRNA translation in cancer; eukaryotic translation initiation factors, eIF4A1, metastasis; breast cancer; pancreatic cancer; precision medicine/targeted therapy; small molecule inhibitors
Special Issues, Collections and Topics in MDPI journals
Dr. Anil Shanker

E-Mail Website
Guest Editor
Office for Research and Innovation, Meharry Medical College, Nashville, TN 37208, USA
Interests: regulation of lymphocyte crosstalk; tumor immunology; cancer immunotherapy; T cell and NK cell biology; neuroimmunology
Special Issues, Collections and Topics in MDPI journals
Dr. Venkataswarup Tiriveedhi

E-Mail Website
Guest Editor
1. Department of Biological Sciences, Tennessee State University, Nashville, TN 37209, USA
2. Department of Pharmacology, Vanderbilt University, Nashville, TN 37209, USA
Interests: biomarkers; solid-organ transplantation; inflammatory cytokines; cancer immunology; advanced drug delivery
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Triple-negative breast cancer (TNBC) remains a serious challenge to be tackled hopefully via a variety of approaches. TNBC lacks the expression of three markers: estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). Based on the gene expression profile, TNBC is classified into basal-like 1 (BL1) and 2 (BL2), mesenchymal (M), mesenchymal stem-like (MSL), immunomodulatory (IM), and luminal androgen receptor (LAR) types. The pathological complete response (pCR) rate with BL1, BL2, LAR, and MSL tumors is 52%, 0%, 10%, and 23%, respectively. Moreover, the intra- and inter-tumor heterogeneity (clonal diversity) and plasticity that are observed in TNBC lead to chemoresistance, tumor relapse, and poor patient outcome. TNBC is highly lethal (5-year mortality >75%) due to a lack of successful targeted therapies and it is characterized by aggressive growth, therapy failure, minimal residual disease, relapse, and mortality. These are the main clinically observed challenges that we currently face in metastatic breast cancer.

For this Special Issue of Cancers, we welcome articles of different types—mini-reviews, full reviews, and data articles (basic cancer biology, pre-clinical and clinical studies)—pertaining to the biological characteristics, molecular pathways, redox signaling, novel targets, resistance mechanisms, and plasticity of TNBC cells, including breast cancer stem cells. In terms of efforts toward finding effective solutions to TNBC, we welcome articles on the identification of novel and selective targets in cancer cells and tumor stroma, targeted chemotherapy, nanoformulation and targeted delivery of drugs, cellular immunotherapy with or without checkpoint antibodies, such as anti-PD-1, anti-PD-L1, and anti-CTLA-4, and vaccines and any potential combinatorial therapies against TNBC, including metastatic breast cancer.

Dr. Dayanidhi Raman
Dr. Anil Shanker
Dr. Venkataswarup Tiriveedhi
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. 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

  • Triple-negative breast cancer (TNBC)
  • estrogen receptor (ER)
  • progesterone receptor (PR)
  • human epidermal growth factor receptor 2 (HER2)
  • metastatic breast cancer

Published Papers (14 papers)

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Research

Jump to: Review

17 pages, 2199 KiB  
Article
Clinical Significance of Annexin A2 Expression in Breast Cancer Patients
by Lee D. Gibbs, Kelsey Mansheim, Sayantan Maji, Rajesh Nandy, Cheryl M. Lewis, Jamboor K. Vishwanatha and Pankaj Chaudhary
Cancers 2021, 13(1), 2; https://doi.org/10.3390/cancers13010002 - 22 Dec 2020
Cited by 19 | Viewed by 2997
Abstract
Increasing evidence suggests that AnxA2 contributes to invasion and metastasis of breast cancer. However, the clinical significance of AnxA2 expression in breast cancer has not been reported. The expression of AnxA2 in cell lines, tumor tissues, and serum samples of breast cancer patients [...] Read more.
Increasing evidence suggests that AnxA2 contributes to invasion and metastasis of breast cancer. However, the clinical significance of AnxA2 expression in breast cancer has not been reported. The expression of AnxA2 in cell lines, tumor tissues, and serum samples of breast cancer patients were analyzed by immunoblotting, immunohistochemistry, and enzyme-linked immunosorbent assay, respectively. We found that AnxA2 was significantly upregulated in tumor tissues and serum samples of breast cancer patients compared with normal controls. The high expression of serum AnxA2 was significantly associated with tumor grades and poor survival of the breast cancer patients. Based on molecular subtypes, AnxA2 expression was significantly elevated in tumor tissues and serum samples of triple-negative breast cancer (TNBC) patients compared with other breast cancer subtypes. Our analyses on breast cancer cell lines demonstrated that secretion of AnxA2 is associated with its tyrosine 23 (Tyr23) phosphorylation in cells. The expression of non-phosphomimetic mutant of AnxA2 in HCC1395 cells inhibits its secretion from cells compared to wild-type AnxA2, which further suggest that Tyr23 phosphorylation is a critical step for AnxA2 secretion from TNBC cells. Our analysis of AnxA2 phosphorylation in clinical samples further confirmed that the phosphorylation of AnxA2 at Tyr23 was high in tumor tissues of TNBC patients compared to matched adjacent non-tumorigenic breast tissues. Furthermore, we observed that the diagnostic value of serum AnxA2 was significantly high in TNBC compared with other breast cancer subtypes. These findings suggest that serum AnxA2 concentration could be a potential diagnostic biomarker for TNBC patients. Full article
(This article belongs to the Special Issue Triple-Negative Breast Cancer: Molecular Characteristics, Treatment Challenges and Solutions)
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23 pages, 3138 KiB  
Article
Multi-Omics Investigation of Innate Navitoclax Resistance in Triple-Negative Breast Cancer Cells
by Michal Marczyk, Gauri A. Patwardhan, Jun Zhao, Rihao Qu, Xiaotong Li, Vikram B. Wali, Abhishek K. Gupta, Manoj M. Pillai, Yuval Kluger, Qin Yan, Christos Hatzis, Lajos Pusztai and Vignesh Gunasekharan
Cancers 2020, 12(9), 2551; https://doi.org/10.3390/cancers12092551 - 8 Sep 2020
Cited by 13 | Viewed by 4647
Abstract
Cancer cells employ various defense mechanisms against drug-induced cell death. Investigating multi-omics landscapes of cancer cells before and after treatment can reveal resistance mechanisms and inform new therapeutic strategies. We assessed the effects of navitoclax, a BCL2 family inhibitor, on the transcriptome, methylome, [...] Read more.
Cancer cells employ various defense mechanisms against drug-induced cell death. Investigating multi-omics landscapes of cancer cells before and after treatment can reveal resistance mechanisms and inform new therapeutic strategies. We assessed the effects of navitoclax, a BCL2 family inhibitor, on the transcriptome, methylome, chromatin structure, and copy number variations of MDA-MB-231 triple-negative breast cancer (TNBC) cells. Cells were sampled before treatment, at 72 h of exposure, and after 10-day drug-free recovery from treatment. We observed transient alterations in the expression of stress response genes that were accompanied by corresponding changes in chromatin accessibility. Most of these changes returned to baseline after the recovery period. We also detected lasting alterations in methylation states and genome structure that suggest permanent changes in cell population composition. Using single-cell analyses, we identified 2350 genes significantly upregulated in navitoclax-resistant cells and derived an 18-gene navitoclax resistance signature. We assessed the navitoclax-response-predictive function of this signature in four additional TNBC cell lines in vitro and in silico in 619 cell lines treated with 251 different drugs. We observed a drug-specific predictive value in both experiments, suggesting that this signature could help guiding clinical biomarker studies involving navitoclax. Full article
(This article belongs to the Special Issue Triple-Negative Breast Cancer: Molecular Characteristics, Treatment Challenges and Solutions)
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23 pages, 5086 KiB  
Article
The CXCR4-Dependent LASP1-Ago2 Interaction in Triple-Negative Breast Cancer
by Augustus M. C. Tilley, Cory M. Howard, Sangita Sridharan, Boopathi Subramaniyan, Nicole R. Bearss, Sawsan Alkhalili and Dayanidhi Raman
Cancers 2020, 12(9), 2455; https://doi.org/10.3390/cancers12092455 - 29 Aug 2020
Cited by 12 | Viewed by 4137
Abstract
The CXCR4-LASP1 axis is an emerging target in the field of breast cancer metastasis. C-X-C chemokine receptor type 4 (CXCR4) mediates directed cell migration when activated by its cognate ligand CXCL12. LIM and SH3 Protein 1 (LASP1) is a critical node in the [...] Read more.
The CXCR4-LASP1 axis is an emerging target in the field of breast cancer metastasis. C-X-C chemokine receptor type 4 (CXCR4) mediates directed cell migration when activated by its cognate ligand CXCL12. LIM and SH3 Protein 1 (LASP1) is a critical node in the CXCR4 signaling pathway, as its deficiency blocks CXCR4-dependent Matrigel invasion. The mechanism by which LASP1 facilitates this invasive ability of tumor cells when CXCR4 is activated is unknown. Our previous proteomics work had revealed several components of the RNA interference (RNAi) machinery as being potential LASP1 interacting proteins. Here we report that argonaute 2 (Ago2), a protein with central involvement in RNAi, associates with LASP1 in triple-negative breast cancer (TNBC) cells. We demonstrate that LASP1 co-immunoprecipitates with Ago2 endogenously in a CXCL12-dependent manner, with further confirmation of this interaction by proximity ligation assay. Furthermore, this association is specific to CXCR4 as it can be abrogated by the CXCR4 antagonist, AMD3465. By GST-pulldown approach, we identify that LASP1 directly binds to Ago2 through its LIM and SH3 domains, and that this binding is dictated by the S146 and Y171 phosphorylation sites of LASP1. Additionally, the phosphorylation status of LASP1 affected tumor suppressor microRNA (miRNA) Let-7a-guided Ago2 activity. Levels of several endogenous targets of Let-7a were found to be altered including C-C chemokine receptor type 7 (CCR7), which is another critical chemokine receptor involved in metastasis to lymph nodes. Our results suggest a novel role for the LASP1-Ago2 module in shaping the RNAi landscape, functionally impacting the invasive ability of cancer cells. Full article
(This article belongs to the Special Issue Triple-Negative Breast Cancer: Molecular Characteristics, Treatment Challenges and Solutions)
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18 pages, 2921 KiB  
Article
Identification of Cardiac Glycosides as Novel Inhibitors of eIF4A1-Mediated Translation in Triple-Negative Breast Cancer Cells
by Cory M. Howard, Matthew Estrada, David Terrero, Amit K. Tiwari and Dayanidhi Raman
Cancers 2020, 12(8), 2169; https://doi.org/10.3390/cancers12082169 - 4 Aug 2020
Cited by 19 | Viewed by 3920
Abstract
The eukaryotic translation initiation factor 4F complex (eIF4F) is a potential chemotherapeutic target in triple-negative breast cancer (TNBC). This complex regulates cap-dependent translational initiation and consists of three core proteins: eIF4E, eIF4G, and eIF4A1. In this study, we focus on repositioning compounds as [...] Read more.
The eukaryotic translation initiation factor 4F complex (eIF4F) is a potential chemotherapeutic target in triple-negative breast cancer (TNBC). This complex regulates cap-dependent translational initiation and consists of three core proteins: eIF4E, eIF4G, and eIF4A1. In this study, we focus on repositioning compounds as novel inhibitors of eIF4A1-mediated translation. In order to accomplish this goal, a modified synthetic reporter assay was established. More specifically, a (CGG)4 motif, which confers eIF4A dependency, was incorporated into the 5’-leader region of a luciferase-tdTomato lentiviral reporter construct. The Prestwick Chemical Library was then screened in multiple TNBC cell lines by measuring the tdTomato fluorescent intensity. We identified several cardiac glycosides as potential inhibitors of eIF4A1-mediated translation. Based on our studies, we find that cardiac glycosides inhibit the expression of eIF4A1. To identify a potential mechanism by which this was occurring, we utilized the Integrative Library of Integrated Network-Based Cellular Signatures (iLINCS). Our pursuits led us to the discovery that cardiac glycosides also decrease levels of c-MYC. Quantitative PCR confirmed that decreases in c-MYC and eIF4A were occurring at the transcriptional level. As such, disruption of the eIF4A1-c-MYC axis may be a viable approach in the treatment of TNBC. The novel combination of rocaglamide A and digoxin exhibited synergistic anti-cancer activity against TNBC cells in vitro. The findings in this study and others are important for formulating potential combination chemotherapies against eIF4A1 in vivo. Thus, drug repositioning may be one classical approach to successfully target eIF4A1 in TNBC patients. Full article
(This article belongs to the Special Issue Triple-Negative Breast Cancer: Molecular Characteristics, Treatment Challenges and Solutions)
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13 pages, 3080 KiB  
Article
Hypoxanthine Phosphoribosyl Transferase 1 Is Upregulated, Predicts Clinical Outcome and Controls Gene Expression in Breast Cancer
by Melina J. Sedano, Enrique I. Ramos, Ramesh Choudhari, Alana L. Harrison, Ramadevi Subramani, Rajkumar Lakshmanaswamy, Mina Zilaie and Shrikanth S. Gadad
Cancers 2020, 12(6), 1522; https://doi.org/10.3390/cancers12061522 - 10 Jun 2020
Cited by 22 | Viewed by 3005
Abstract
Hypoxanthine phosphoribosyl transferase 1 (HPRT1) is traditionally believed to be a housekeeping gene; however, recent reports suggest that it is upregulated in several cancers and is associated with clinical outcomes. HPRT1 is located on chromosome X and encodes the HPRT enzyme, [...] Read more.
Hypoxanthine phosphoribosyl transferase 1 (HPRT1) is traditionally believed to be a housekeeping gene; however, recent reports suggest that it is upregulated in several cancers and is associated with clinical outcomes. HPRT1 is located on chromosome X and encodes the HPRT enzyme, which functions in recycling nucleotides to supply for DNA and RNA synthesis in actively dividing cells. Here, we used transcriptomic analyses to interrogate its expression across all known cancer types and elucidated its role in regulating gene expression in breast cancer. We observed elevated HPRT1 RNA levels in malignant tissues when compared to normal controls, indicating its potential as a diagnostic and prognostic marker. Further, in breast cancer, the subtype-specific analysis showed that its expression was highest in basal and triple-negative breast cancer, and HPRT1 knockdown in breast cancer cells suggested that HPRT1 positively regulates genes related to cancer pathways. Collectively, our results essentially highlight the importance of and change the way in which HPRT1’s function is studied in biology, warranting careful examination of its role in cancer. Full article
(This article belongs to the Special Issue Triple-Negative Breast Cancer: Molecular Characteristics, Treatment Challenges and Solutions)
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18 pages, 5438 KiB  
Article
A New Histone Deacetylase Inhibitor Enhances Radiation Sensitivity through the Induction of Misfolded Protein Aggregation and Autophagy in Triple-Negative Breast Cancer
by Hui-Wen Chiu, Ya-Ling Yeh, Sheng-Yow Ho, Yuan-Hua Wu, Bour-Jr Wang, Wei-Jan Huang, Yuan-Soon Ho, Ying-Jan Wang, Li-Ching Chen and Shih-Hsin Tu
Cancers 2019, 11(11), 1703; https://doi.org/10.3390/cancers11111703 - 1 Nov 2019
Cited by 14 | Viewed by 3560
Abstract
Radiation therapy (RT) is one of the main treatments for triple-negative breast cancer (TNBC). However, many patients experience RT failure due to the metastatic potential of RT and the radiation resistance of several cancers. Histone deacetylase inhibitors (HDACis) can serve as radiosensitizers. In [...] Read more.
Radiation therapy (RT) is one of the main treatments for triple-negative breast cancer (TNBC). However, many patients experience RT failure due to the metastatic potential of RT and the radiation resistance of several cancers. Histone deacetylase inhibitors (HDACis) can serve as radiosensitizers. In this study, we investigated whether a novel HDACi, TMU-35435, could reinforce radiosensitivity through the induction of misfolded protein aggregation and autophagy in TNBC. Significantly enhanced toxicity was found for the combination treatment compared with TMU-35435 or irradiation (IR) treatment alone in TNBC cells. The combination treatment induced misfolded protein aggregation and TMU-35435 inhibited the interaction of HDAC6 with dynein. Furthermore, the combined treatment induced endoplasmic reticulum (ER) stress but did not trigger apoptosis. In addition, the combination treatment caused autophagic cell death. Tumor growth in the mouse of model orthotopic breast cancer was suppressed by the combination treatment through the induction of ER stress and autophagy. These findings support the future evaluation of the novel HDACi TMU-35435, as a potent radiosensitizer in TNBC. Full article
(This article belongs to the Special Issue Triple-Negative Breast Cancer: Molecular Characteristics, Treatment Challenges and Solutions)
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Review

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19 pages, 1499 KiB  
Review
A High-Dimensional Window into the Micro-Environment of Triple Negative Breast Cancer
by Iris Nederlof, Hugo M. Horlings, Christina Curtis and Marleen Kok
Cancers 2021, 13(2), 316; https://doi.org/10.3390/cancers13020316 - 16 Jan 2021
Cited by 13 | Viewed by 5922
Abstract
Providing effective personalized immunotherapy for triple negative breast cancer (TNBC) patients requires a detailed understanding of the composition of the tumor microenvironment. Both the tumor cell and non-tumor components of TNBC can exhibit tremendous heterogeneity in individual patients and change over time. Delineating [...] Read more.
Providing effective personalized immunotherapy for triple negative breast cancer (TNBC) patients requires a detailed understanding of the composition of the tumor microenvironment. Both the tumor cell and non-tumor components of TNBC can exhibit tremendous heterogeneity in individual patients and change over time. Delineating cellular phenotypes and spatial topographies associated with distinct immunological states and the impact of chemotherapy will be necessary to optimally time immunotherapy. The clinical successes in immunotherapy have intensified research on the tumor microenvironment, aided by a plethora of high-dimensional technologies to define cellular phenotypes. These high-dimensional technologies include, but are not limited to, single cell RNA sequencing, spatial transcriptomics, T cell repertoire analyses, advanced flow cytometry, imaging mass cytometry, and their integration. In this review, we discuss the cellular phenotypes and spatial patterns of the lymphoid-, myeloid-, and stromal cells in the TNBC microenvironment and the potential value of mapping these features onto tumor cell genotypes. Full article
(This article belongs to the Special Issue Triple-Negative Breast Cancer: Molecular Characteristics, Treatment Challenges and Solutions)
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24 pages, 957 KiB  
Review
Effects of Cancer Stem Cells in Triple-Negative Breast Cancer and Brain Metastasis: Challenges and Solutions
by Kha-Liang Lee, Gao Chen, Tai-Yuan Chen, Yung-Che Kuo and Yu-Kai Su
Cancers 2020, 12(8), 2122; https://doi.org/10.3390/cancers12082122 - 31 Jul 2020
Cited by 19 | Viewed by 5880
Abstract
A higher propensity of developing brain metastasis exists in triple-negative breast cancer (TNBC). Upon comparing the metastatic patterns of all breast cancer subtypes, patients with TNBC exhibited increased risks of the brain being the initial metastatic site, early brain metastasis development, and shortest [...] Read more.
A higher propensity of developing brain metastasis exists in triple-negative breast cancer (TNBC). Upon comparing the metastatic patterns of all breast cancer subtypes, patients with TNBC exhibited increased risks of the brain being the initial metastatic site, early brain metastasis development, and shortest brain metastasis-related survival. Notably, the development of brain metastasis differs from that at other sites owing to the brain-unique microvasculature (blood brain barrier (BBB)) and intracerebral microenvironment. Studies of brain metastases from TNBC have revealed the poorest treatment response, mostly because of the relatively backward strategies to target vast disease heterogeneity and poor brain efficacy. Moreover, TNBC is highly associated with the existence of cancer stem cells (CSCs), which contribute to circulating cancer cell survival before BBB extravasation, evasion from immune surveillance, and plasticity in adaptation to the brain-specific microenvironment. We summarized recent literature regarding molecules and pathways and reviewed the effects of CSC biology during the formation of brain metastasis in TNBC. Along with the concept of individualized cancer therapy, certain strategies, namely the patient-derived xenograft model to overcome the lack of treatment-relevant TNBC classification and techniques in BBB disruption to enhance brain efficacy has been proposed in the hope of achieving treatment success. Full article
(This article belongs to the Special Issue Triple-Negative Breast Cancer: Molecular Characteristics, Treatment Challenges and Solutions)
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13 pages, 882 KiB  
Review
Molecular Features of Metaplastic Breast Carcinoma: An Infrequent Subtype of Triple Negative Breast Carcinoma
by Silvia González-Martínez, Belén Pérez-Mies, Irene Carretero-Barrio, María Luisa Palacios-Berraquero, José Perez-García, Javier Cortés and José Palacios
Cancers 2020, 12(7), 1832; https://doi.org/10.3390/cancers12071832 - 8 Jul 2020
Cited by 35 | Viewed by 4845
Abstract
Metaplastic breast carcinoma (MBC) is a heterogeneous group of infrequent invasive carcinomas that display differentiation of the neoplastic epithelium towards squamous cells and/or mesenchymal-type elements. Most MBC have a triple negative phenotype and poor prognosis. Thus, MBC have worse survival rates than other [...] Read more.
Metaplastic breast carcinoma (MBC) is a heterogeneous group of infrequent invasive carcinomas that display differentiation of the neoplastic epithelium towards squamous cells and/or mesenchymal-type elements. Most MBC have a triple negative phenotype and poor prognosis. Thus, MBC have worse survival rates than other invasive breast carcinomas, including other triple negative breast carcinomas (TNBC). In this study, we reviewed the molecular features of MBC, pointing out the differences among subtypes. The most frequently mutated genes in MBC were TP53 and PIK3CA. Additionally, mutations in the other genes of the PI3K/AKT pathway indicated its importance in the pathogenesis of MBC. Regarding copy number variations (CNVs), MYC was the most frequently amplified gene, and the most frequent gene loss affected the CDKN2A/CDKN2B locus. Furthermore, the pattern of mutations and CNVs of MBC differed from those reported in other TNBC. However, the molecular profile of MBC was not homogeneous among histological subtypes, being the alterations in the PI3K pathway most frequent in spindle cell carcinomas. Transcriptomic studies have demonstrated an epithelial to mesenchymal program activation and the enrichment of stemness genes in most MBC. In addition, current studies are attempting to define the immune microenvironment of these tumors. In conclusion, due to specific molecular features, MBC have a different clinical behavior from other types of TNBC, being more resistant to standard chemotherapy. For this reason, new therapeutic approaches based on tumor molecular characteristics are needed to treat MBC. Full article
(This article belongs to the Special Issue Triple-Negative Breast Cancer: Molecular Characteristics, Treatment Challenges and Solutions)
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28 pages, 2892 KiB  
Review
Insights into the Role of Estrogen Receptor β in Triple-Negative Breast Cancer
by Assunta Sellitto, Ylenia D’Agostino, Elena Alexandrova, Jessica Lamberti, Giovanni Pecoraro, Domenico Memoli, Domenico Rocco, Elena Coviello, Giorgio Giurato, Giovanni Nassa, Roberta Tarallo, Alessandro Weisz and Francesca Rizzo
Cancers 2020, 12(6), 1477; https://doi.org/10.3390/cancers12061477 - 5 Jun 2020
Cited by 33 | Viewed by 7676
Abstract
Estrogen receptors (ERα and ERβ) are ligand-activated transcription factors that play different roles in gene regulation and show both overlapping and specific tissue distribution patterns. ERβ, contrary to the oncogenic ERα, has been shown to act as an oncosuppressor in several instances. However, [...] Read more.
Estrogen receptors (ERα and ERβ) are ligand-activated transcription factors that play different roles in gene regulation and show both overlapping and specific tissue distribution patterns. ERβ, contrary to the oncogenic ERα, has been shown to act as an oncosuppressor in several instances. However, while the tumor-promoting actions of ERα are well-known, the exact role of ERβ in carcinogenesis and tumor progression is not yet fully understood. Indeed, to date, highly variable and even opposite effects have been ascribed to ERβ in cancer, including for example both proliferative and growth-inhibitory actions. Recently ERβ has been proposed as a potential target for cancer therapy, since it is expressed in a variety of breast cancers (BCs), including triple-negative ones (TNBCs). Because of the dependence of TNBCs on active cellular signaling, numerous studies have attempted to unravel the mechanism(s) behind ERβ-regulated gene expression programs but the scenario has not been fully revealed. We comprehensively reviewed the current state of knowledge concerning ERβ role in TNBC biology, focusing on the different signaling pathways and cellular processes regulated by this transcription factor, as they could be useful in identifying new diagnostic and therapeutic approaches for TNBC. Full article
(This article belongs to the Special Issue Triple-Negative Breast Cancer: Molecular Characteristics, Treatment Challenges and Solutions)
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21 pages, 622 KiB  
Review
Neoadjuvant Treatment for Triple Negative Breast Cancer: Recent Progresses and Challenges
by Jin Sun Lee, Susan E. Yost and Yuan Yuan
Cancers 2020, 12(6), 1404; https://doi.org/10.3390/cancers12061404 - 29 May 2020
Cited by 84 | Viewed by 8214
Abstract
Triple negative breast cancer (TNBC) is an aggressive breast cancer with historically poor outcomes, primarily due to the lack of effective targeted therapies. The tumor molecular heterogeneity of TNBC has been well recognized, yet molecular subtype driven therapy remains lacking. While neoadjuvant anthracycline [...] Read more.
Triple negative breast cancer (TNBC) is an aggressive breast cancer with historically poor outcomes, primarily due to the lack of effective targeted therapies. The tumor molecular heterogeneity of TNBC has been well recognized, yet molecular subtype driven therapy remains lacking. While neoadjuvant anthracycline and taxane-based chemotherapy remains the standard of care for early stage TNBC, the optimal chemotherapy regimen is debatable. The addition of carboplatin to anthracycline, cyclophosphamide, and taxane (ACT) regimen is associated with improved complete pathologic response (pCR). Immune checkpoint inhibitor (ICI) combinations significantly increase pCR in TNBC. Increased tumor infiltrating lymphocyte (TILs) or the presence of DNA repair deficiency (DRD) mutation is associated with increased pCR. Other targets, such as poly-ADP-ribosyl polymerase inhibitors (PARPi) and Phosphatidylinositol-3-kinase/Protein Kinase B/mammalian target of rapamycin (PI3K-AKT-mTOR) pathway inhibitors, are being evaluated in the neoadjuvant setting. This review examines recent progress in neoadjuvant therapy of TNBC, including platinum, ICI, PARPi, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) pathway targeted therapies, and novel tumor microenvironment (TME) targeted therapy, in addition to biomarkers for the prediction of pCR. Full article
(This article belongs to the Special Issue Triple-Negative Breast Cancer: Molecular Characteristics, Treatment Challenges and Solutions)
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25 pages, 1173 KiB  
Review
The Landscape of Targeted Therapies in TNBC
by Elena Vagia, Devalingam Mahalingam and Massimo Cristofanilli
Cancers 2020, 12(4), 916; https://doi.org/10.3390/cancers12040916 - 8 Apr 2020
Cited by 230 | Viewed by 13321
Abstract
Triple negative breast cancer (TNBC) constitutes the most aggressive molecular subtype among breast tumors. Despite progress on the underlying tumor biology, clinical outcomes for TNBC unfortunately remain poor. The median overall survival for patients with metastatic TNBC is approximately eighteen months. Chemotherapy is [...] Read more.
Triple negative breast cancer (TNBC) constitutes the most aggressive molecular subtype among breast tumors. Despite progress on the underlying tumor biology, clinical outcomes for TNBC unfortunately remain poor. The median overall survival for patients with metastatic TNBC is approximately eighteen months. Chemotherapy is the mainstay of treatment while there is a growing body of evidence that targeted therapies may be on the horizon with poly-ADP-ribose polymerase (PARP) and immune check-point inhibitors already established in the treatment paradigm of TNBC. A large number of novel therapeutic agents are being evaluated for their efficacy in TNBC. As novel therapeutics are now incorporated into clinical practice, it is clear that tumor heterogeneity and clonal evolution can result to de novo or acquired treatment resistance. As precision medicine and next generation sequencing is part of cancer diagnostics, tailored treatment approaches based on the expression of molecular markers are currently being implemented in clinical practice and clinical trial design. The scope of this review is to highlight the most relevant current knowledge regarding underlying molecular profile of TNBC and its potential application in clinical practice. Full article
(This article belongs to the Special Issue Triple-Negative Breast Cancer: Molecular Characteristics, Treatment Challenges and Solutions)
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25 pages, 358 KiB  
Review
Early Triple Negative Breast Cancer: Conventional Treatment and Emerging Therapeutic Landscapes
by Anna Diana, Francesca Carlino, Elisena Franzese, Olga Oikonomidou, Carmen Criscitiello, Ferdinando De Vita, Fortunato Ciardiello and Michele Orditura
Cancers 2020, 12(4), 819; https://doi.org/10.3390/cancers12040819 - 29 Mar 2020
Cited by 55 | Viewed by 7444
Abstract
Triple negative breast cancers (TNBCs) are characterized by worse prognosis, higher propensity to earlier metastases, and shorter survival after recurrence compared with other breast cancer subtypes. Anthracycline- and taxane-based chemotherapy is still the mainstay of treatment in early stages, although several escalation approaches [...] Read more.
Triple negative breast cancers (TNBCs) are characterized by worse prognosis, higher propensity to earlier metastases, and shorter survival after recurrence compared with other breast cancer subtypes. Anthracycline- and taxane-based chemotherapy is still the mainstay of treatment in early stages, although several escalation approaches have been evaluated to improve survival outcomes. The addition of platinum salts to standard neoadjuvant chemotherapy (NACT) remains controversial due to the lack of clear survival advantage, and the use of adjuvant capecitabine represents a valid treatment option in TNBC patients with residual disease after NACT. Recently, several clinical trials showed promising results through the use of poly ADP-ribose polymerase (PARP) inhibitors and by incorporating immunotherapy with chemotherapy, enriching treatment options beyond conventional cytotoxic agents. In this review, we provided an overview on the current standard of care and a comprehensive update of the recent advances in the management of early stage TNBC and focused on the latest emerging biomarkers and their clinical application to select the best therapeutic strategy in this hard-to-treat population. Full article
(This article belongs to the Special Issue Triple-Negative Breast Cancer: Molecular Characteristics, Treatment Challenges and Solutions)
15 pages, 916 KiB  
Review
Role of BET Inhibitors in Triple Negative Breast Cancers
by Durga Khandekar and Venkataswarup Tiriveedhi
Cancers 2020, 12(4), 784; https://doi.org/10.3390/cancers12040784 - 25 Mar 2020
Cited by 16 | Viewed by 5120
Abstract
Bromodomain and extraterminal domain (BET) proteins have evolved as key multifunctional super-regulators that control gene expression. These proteins have been shown to upregulate transcriptional machinery leading to over expression of genes involved in cell proliferation and carcinogenesis. Based on favorable preclinical evidence of [...] Read more.
Bromodomain and extraterminal domain (BET) proteins have evolved as key multifunctional super-regulators that control gene expression. These proteins have been shown to upregulate transcriptional machinery leading to over expression of genes involved in cell proliferation and carcinogenesis. Based on favorable preclinical evidence of BET inhibitors in various cancer models; currently, 26 clinical trials are underway in various stages of study on various hematological and solid organ cancers. Unfortunately, preliminary evidence for these clinical studies does not support the application of BET inhibitors as monotherapy in cancer treatment. Furthermore, the combinatorial efficiency of BET inhibitors with other chemo-and immunotherapeutic agents remain elusive. In this review, we will provide a concise summary of the molecular basis and preliminary clinical outcomes of BET inhibitors in cancer therapy, with special focus on triple negative breast cancer. Full article
(This article belongs to the Special Issue Triple-Negative Breast Cancer: Molecular Characteristics, Treatment Challenges and Solutions)
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