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Unraveling the Etiology, Therapeutics, and Molecular Signatures of Triple-Negative Breast Cancer

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Special Issue Information
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A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Molecular Cancer Biology".

Deadline for manuscript submissions: closed (30 November 2021) | Viewed by 25136

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Special Issue Editors

Prof. Dr. Gustavo A. Miranda-Carboni

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Guest Editor

College of Medicine, Department of Medicine, Division of Hematology-Oncology, Center for Cancer Research, The University of Tennessee Health Science Center, TN 38163, USA
Interests: mammary gland development; bone development; molecular immunology; triple negative breast cancer; breast cancer therapeutics; Wnt signaling; cancer health disparities

Dr. Susan A. Krum

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Guest Editor

Department of Orthopaedic Surgery and Biomedical Engineering, Center for Cancer Research, The University of Tennessee Health Science Center, Memphis, TN 38163, USA
Interests: nuclear receptors; estrogen biology; bone development; mammary gland development; ER-positive breast Cancer; GATA4; TNBC; osteosarcoma; cancer therapeutics

Dr. Tiffany N. Seagroves

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Guest Editor

Center for Cancer Research, The University of Tennessee Health Science Center, TN 38163, USA
Interests: breast cancer therapeutics; mammary gland biology; TNBC; HIF1/2 signaling; genetically modified mouse models

Special Issue Information

Dear Colleagues,

Triple-negative breast cancer (TNBC, estrogen receptor-negative (ER^-), progesterone receptor-negative (PR^-), and HER2 not amplified) is an aggressive subtype of breast cancer that frequently occurs in BRCA1 mutation carriers and young women of African descent. TNBC is highly metastatic and carries a poor prognosis. This type of tumor is treated with a combination of therapies, i.e., surgery, radiation therapy, and chemotherapy. Unlike other breast cancer subtypes, there are no FDA-approved targeted agents. The etiology of TNBC is controversial and is very heterogenous with at least four to six subtypes. The immune heterogeneity of TNBC has provided some hope as checkpoint inhibitors work in a minority of TNBCs but not in most subtypes. Moreover, the tumor microenvironment in TNBC patients is not well understood and its role in chemoresistance is not yet clear. Wnt and TGFβ signaling, amongst other signaling pathways, have been associated with metastasis and chemoresistance, providing venues to combine inhibitors for these pathways in combination with FDA-approved therapies to combat chemoresistance and metastasis.

This Special Issue aims to provide a comprehensive overview of the state-of-the-art in, and future perspectives of, “Unraveling the Etiology, Therapeutics, and Molecular Signatures of Triple-Negative Breast Cancer”.

Prof. Dr. Gustavo A. Miranda-Carboni
Dr. Susan A. Krum
Dr. Tiffany N. Seagroves
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.

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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

decoding of the etiology of TNBC
novel therapeutics for metastatic chemoresistant TNBC
unraveling the tumor microenvironment and the heterogenicity of the immune response of TNBC
characterization of molecular signaling of TNBC

Published Papers (7 papers)

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Research

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28 pages, 3890 KiB

Open AccessArticle

HIF-Dependent CKB Expression Promotes Breast Cancer Metastasis, Whereas Cyclocreatine Therapy Impairs Cellular Invasion and Improves Chemotherapy Efficacy

by Raisa I. Krutilina, Hilaire Playa, Danielle L. Brooks, Luciana P. Schwab, Deanna N. Parke, Damilola Oluwalana, Douglas R. Layman, Meiyun Fan, Daniel L. Johnson, Junming Yue, Heather Smallwood and Tiffany N. Seagroves

Cancers 2022, 14(1), 27; https://doi.org/10.3390/cancers14010027 - 22 Dec 2021

Cited by 9 | Viewed by 3589

Abstract

The oxygen-responsive hypoxia inducible factor (HIF)-1 promotes several steps of the metastatic cascade. A hypoxic gene signature is enriched in triple-negative breast cancers (TNBCs) and is correlated with poor patient survival. Inhibiting the HIF transcription factors with small molecules is challenging; therefore, we sought to identify genes downstream of HIF-1 that could be targeted to block invasion and metastasis. Creatine kinase brain isoform (CKB) was identified as a highly differentially expressed gene in a screen of HIF-1 wild type and knockout mammary tumor cells derived from a transgenic model of metastatic breast cancer. CKB is a cytosolic enzyme that reversibly catalyzes the phosphorylation of creatine, generating phosphocreatine (PCr) in the forward reaction, and regenerating ATP in the reverse reaction. Creatine kinase activity is inhibited by the creatine analog cyclocreatine (cCr). Loss- and gain-of-function genetic approaches were used in combination with cCr therapy to define the contribution of CKB expression or creatine kinase activity to cell proliferation, migration, invasion, and metastasis in ER-negative breast cancers. CKB was necessary for cell invasion in vitro and strongly promoted tumor growth and lung metastasis in vivo. Similarly, cyclocreatine therapy repressed cell migration, cell invasion, the formation of invadopodia and lung metastasis. Moreover, in common TNBC cell line models, the addition of cCr to conventional cytotoxic chemotherapy agents was either additive or synergistic to repress tumor cell growth. Full article

(This article belongs to the Special Issue Unraveling the Etiology, Therapeutics, and Molecular Signatures of Triple-Negative Breast Cancer)

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21 pages, 3818 KiB

Open AccessArticle

Immune Milieu and Genomic Alterations Set the Triple-Negative Breast Cancer Immunomodulatory Subtype Tumor Behavior

by Rubén Rodríguez-Bautista, Claudia H. Caro-Sánchez, Paula Cabrera-Galeana, Gerardo J. Alanis-Funes, Everardo Gutierrez-Millán, Santiago Ávila-Ríos, Margarita Matías-Florentino, Gustavo Reyes-Terán, José Díaz-Chávez, Cynthia Villarreal-Garza, Norma Y. Hernández-Pedro, Alette Ortega-Gómez, Luis Lara-Mejía, Claudia Rangel-Escareño and Oscar Arrieta

Cancers 2021, 13(24), 6256; https://doi.org/10.3390/cancers13246256 - 13 Dec 2021

Cited by 5 | Viewed by 3021

Abstract

Triple-negative breast cancer (TNBC) is an aggressive and heterogeneous disease. Seven subtypes have been described based on gene expression patterns. Herein, we characterized the tumor biology and clinical behavior of the immunomodulatory (IM) subtype. Methods: Formalin-fixed paraffin-embedded tumor samples from 68 high-risk (stage III-IV) TNBC patients were analyzed through microarrays, immunohistochemistry, and DNA sequencing. Results: The IM subtype was identified in 24% of TNBC tumor samples and characterized by a higher intratumoral (intT) and stromal (strml) infiltration of FOXP3+ TILs (Treg) compared with non-IM subtypes. Further, PD-L1+ (>1%) expression was significantly higher, as well as CTLA-4+ intT and strml expression in the IM subtype. Differential expression and gene set enrichment analysis identified biological processes associated with the immune system. Pathway analysis revealed enrichment of the β-catenin signaling pathway. The non-coding analysis led to seven Long Intergenic Non-Protein Coding RNAs (lincRNAs) (6 up-regulated and 1 down-regulated) that were associated with a favorable prognosis in the TNBC-IM subtype. The DNA sequencing highlighted two genes relevant to immune system responses: CTNNB1 (Catenin β-1) and IDH1. Conclusion: the IM subtype showed a distinct immune microenvironment, as well as subtype-specific genomic alterations. Characterizing TNBC at a molecular and transcriptomic level might guide immune-based therapy in this subgroup of patients. Full article

(This article belongs to the Special Issue Unraveling the Etiology, Therapeutics, and Molecular Signatures of Triple-Negative Breast Cancer)

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27 pages, 3779 KiB

Open AccessArticle

Epigenetic Dysregulation of KCNK9 Imprinting and Triple-Negative Breast Cancer

by David A. Skaar, Eric C. Dietze, Jackelyn A. Alva-Ornelas, David Ann, Dustin E. Schones, Terry Hyslop, Christopher Sistrunk, Carola Zalles, Adrian Ambrose, Kendall Kennedy, Ombeni Idassi, Gustavo Miranda Carboni, Michael N. Gould, Randy L. Jirtle and Victoria L. Seewaldt

Cancers 2021, 13(23), 6031; https://doi.org/10.3390/cancers13236031 - 30 Nov 2021

Cited by 1 | Viewed by 2220

Abstract

Genomic imprinting is an inherited form of parent-of-origin specific epigenetic gene regulation that is dysregulated by poor prenatal nutrition and environmental toxins. KCNK9 encodes for TASK3, a pH-regulated potassium channel membrane protein that is overexpressed in 40% of breast cancer. However, KCNK9 gene amplification accounts for increased expression in <10% of these breast cancers. Here, we showed that KCNK9 is imprinted in breast tissue and identified a differentially methylated region (DMR) controlling its imprint status. Hypomethylation at the DMR, coupled with biallelic expression of KCNK9, occurred in 63% of triple-negative breast cancers (TNBC). The association between hypomethylation and TNBC status was highly significant in African-Americans (p = 0.006), but not in Caucasians (p = 0.70). KCNK9 hypomethylation was also found in non-cancerous tissue from 77% of women at high-risk of developing breast cancer. Functional studies demonstrated that the KCNK9 gene product, TASK3, regulates mitochondrial membrane potential and apoptosis-sensitivity. In TNBC cells and non-cancerous mammary epithelial cells from high-risk women, hypomethylation of the KCNK9 DMR predicts for increased TASK3 expression and mitochondrial membrane potential (p < 0.001). This is the first identification of the KCNK9 DMR in mammary epithelial cells and demonstration that its hypomethylation in breast cancer is associated with increases in both mitochondrial membrane potential and apoptosis resistance. The high frequency of hypomethylation of the KCNK9 DMR in TNBC and non-cancerous breast tissue from high-risk women provides evidence that hypomethylation of the KNCK9 DMR/TASK3 overexpression may serve as a marker of risk and a target for prevention of TNBC, particularly in African American women. Full article

(This article belongs to the Special Issue Unraveling the Etiology, Therapeutics, and Molecular Signatures of Triple-Negative Breast Cancer)

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Graphical abstract

19 pages, 4533 KiB

Open AccessArticle

Kinome-Wide siRNA Screening Identifies DYRK1B as a Potential Therapeutic Target for Triple-Negative Breast Cancer Cells

by Chia-Che Chang, Chien-Chih Chiu, Pei-Feng Liu, Chih-Hsuan Wu, Yen-Chiang Tseng, Cheng-Hsin Lee and Chih-Wen Shu

Cancers 2021, 13(22), 5779; https://doi.org/10.3390/cancers13225779 - 18 Nov 2021

Cited by 6 | Viewed by 2205

Abstract

Aims: The selective molecules for targeted therapy of triple-negative breast cancer (TNBC) are limited. Several kinases play pivotal roles in cancer development and malignancy. The study aims to determine if any kinases confer to malignancy of TNBC cells, which could serve as a theranostic target for TNBC. Methods: Kinome siRNA library was used to screen selective genes required for the proliferation of TNBC cells. The involvement of DYRK1B in cancer malignancy was evaluated with migration, invasion assays, and spheroid culture. The expression of DYRK1B was confirmed with quantitative PCR and immunoblotting. The clinical correlation of DYRK1B in TNBC patients was examined with tissue microarray and The Cancer Genome Atlas (TCGA) database. Results: Our results showed that silencing DYRK1B significantly suppressed cell viability in DYRK1B-high expressed TNBC cells, likely by arresting the cell cycle at the G₁ phase. Nevertheless, silencing DYRK1B had marginal effects on DYRK1B-low expressed TNBC cells. Similarly, the knockdown of DYRK1B decreased tumorsphere formation and increased cell death of the tumorsphere. Moreover, inactivation of DYRK1B by either specific inhibitor or ectopic expressing catalytic mutant of DYRK1B inhibited cell viability and metastatic characteristics, including migration and invasion. In addition, DYRK1B protein expression was elevated in tumor tissues compared to that in adjacent normal tissues of TNBC patients. Further, DYRK1B gene expression was highly correlated with CCDC97 or ZNF581 genes in TNBC cells and patients. High co-expression of DYRK1B with CCDC97 or ZNF581 was significantly associated with unfavorable overall survival and disease-free survival of TNBC patients. Conclusions: our results suggest DYRK1B might be essential for promoting tumor progression and could be a theranostic target for TNBC. Silencing or inactivation of DYRK1B might be a potential targeted therapy for TNBC. Full article

(This article belongs to the Special Issue Unraveling the Etiology, Therapeutics, and Molecular Signatures of Triple-Negative Breast Cancer)

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Review

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18 pages, 783 KiB

Open AccessReview

Stromal Characteristics and Impact on New Therapies for Metastatic Triple-Negative Breast Cancer

by Shelby A. Fertal, Johanna E. Poterala, Suzanne M. Ponik and Kari B. Wisinski

Cancers 2022, 14(5), 1238; https://doi.org/10.3390/cancers14051238 - 27 Feb 2022

Cited by 7 | Viewed by 3107

Abstract

The heterogenous nature of triple-negative breast cancer (TNBC) is an underlying factor in therapy resistance, metastasis, and overall poor patient outcome. The lack of hormone and growth factor receptors lends to the use of chemotherapy as the first-line treatment for TNBC. However, the failure of chemotherapy demonstrates the need to develop novel immunotherapies, antibody–drug conjugates (ADCs), and other tumor- and stromal-targeted therapeutics for TNBC patients. The potential for stromal-targeted therapy is driven by studies indicating that the interactions between tumor cells and the stromal extracellular matrix (ECM) activate mechanisms of therapy resistance. Here, we will review recent outcomes from clinical trials targeting metastatic TNBC with immunotherapies aimed at programed death ligand–receptor interactions, and ADCs specifically linked to trophoblast cell surface antigen 2 (Trop-2). We will discuss how biophysical and biochemical cues from the ECM regulate the pathophysiology of tumor and stromal cells toward a pro-tumor immune environment, therapy resistance, and poor TNBC patient outcome. Moreover, we will highlight how ECM-mediated resistance is motivating the development of new stromal-targeted therapeutics with potential to improve therapy for this disease. Full article

(This article belongs to the Special Issue Unraveling the Etiology, Therapeutics, and Molecular Signatures of Triple-Negative Breast Cancer)

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15 pages, 701 KiB

Open AccessEditor’s ChoiceReview

Molecular Targets of Triple-Negative Breast Cancer: Where Do We Stand?

by Emma E. Newton, Lauren E. Mueller, Scout M. Treadwell, Cindy A. Morris and Heather L. Machado

Cancers 2022, 14(3), 482; https://doi.org/10.3390/cancers14030482 - 18 Jan 2022

Cited by 22 | Viewed by 4523

Abstract

Triple-negative breast cancer (TNBC) is a highly aggressive form of breast cancer. Due to its heterogeneity and lack of hormone receptor expression, this subtype is more likely to metastasize and resist treatment attempts than are other forms of breast cancer. Due to the absence of targetable receptors, chemotherapy and breast conserving surgery have been the predominant treatment options for patients. However, resistance to chemotherapy and local recurrence of the tumors is frequent. Emerging immunotherapies have begun to change treatment plans for patients diagnosed with TNBC. In this review, we discuss the various immune pathways identified in TNBC and the role they play as targets for new potential treatment choices. Various therapeutic options that inhibit key pathways in cellular growth cycles, DNA repair mechanisms, epithelial mesenchymal transition, and immunosuppression have been shown to improve survival in patients with this disease. With promising results thus far, continued studies of immunotherapy and neoadjuvant therapy options for TNBC are likely to alter the treatment course for these diagnoses in the future. Full article

(This article belongs to the Special Issue Unraveling the Etiology, Therapeutics, and Molecular Signatures of Triple-Negative Breast Cancer)

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29 pages, 920 KiB

Open AccessReview

Triple Negative Breast Cancer: A Mountain Yet to Be Scaled Despite the Triumphs

by Qitong Wu, Sumit Siddharth and Dipali Sharma

Cancers 2021, 13(15), 3697; https://doi.org/10.3390/cancers13153697 - 23 Jul 2021

Cited by 40 | Viewed by 5521

Abstract

Metastatic progression and tumor recurrence pertaining to TNBC are certainly the leading cause of breast cancer-related mortality; however, the mechanisms underlying TNBC chemoresistance, metastasis, and tumor relapse remain somewhat ambiguous. TNBCs show 77% of the overall 4-year survival rate compared to other breast cancer subtypes (82.7 to 92.5%). TNBC is the most aggressive subtype of breast cancer, with chemotherapy being the major approved treatment strategy. Activation of ABC transporters and DNA damage response genes alongside an enrichment of cancer stem cells and metabolic reprogramming upon chemotherapy contribute to the selection of chemoresistant cells, majorly responsible for the failure of anti-chemotherapeutic regime. These selected chemoresistant cells further lead to distant metastasis and tumor relapse. The present review discusses the approved standard of care and targetable molecular mechanisms in chemoresistance and provides a comprehensive update regarding the recent advances in TNBC management. Full article

(This article belongs to the Special Issue Unraveling the Etiology, Therapeutics, and Molecular Signatures of Triple-Negative Breast Cancer)

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