Secreted Non-Coding RNAs: Functional Impact on the Tumor Microenvironment and Clinical Relevance in Triple-Negative Breast Cancer

Triple-negative breast cancer (TNBC) is a subtype of breast carcinoma characterized by poor prognosis and high rate of metastasis. Current treatment is based on chemo- and/or radiotherapy and surgery. TNBC is devoid of estrogen, progesterone and HER2 receptors. Although precision medicine has come a long way to ameliorate breast cancer disease management, targeted therapies for the treatment of TNBC patients are still limited. Mounting evidence has shown that non-coding RNAs (ncRNAs) drive many oncogenic processes at the basis of increased proliferation, invasion and angiogenesis in TNBC, strongly contributing to tumor progression and resistance to treatments. Many of these ncRNAs are secreted in the tumor microenvironment (TME) and impinge on the activity of the diverse immune and stromal cell types infiltrating the TME. Importantly, secreted ncRNAs may be detected as circulating molecules in serum/plasma from cancer patients and are emerging a promising diagnostic/therapeutic tools in TNBC. This review aims to discuss novel insights about the role of secreted circulating ncRNAs in the intercellular communication in the tumor microenvironment and their potential clinical use as diagnostic and prognostic non-invasive biomarkers in TNBC.

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Mechanistic Involvement of Long Non-Coding RNAs in Oncotherapeutics Resistance in Triple-Negative Breast Cancer

Cells ◽

10.3390/cells9061511 ◽

2020 ◽

Vol 9 (6) ◽

pp. 1511 ◽

Cited By ~ 12

Author(s):

Samarth Kansara ◽

Vijay Pandey ◽

Peter E. Lobie ◽

Gautam Sethi ◽

Manoj Garg ◽

...

Keyword(s):

Breast Cancer ◽

Triple Negative Breast Cancer ◽

Disease Burden ◽

Triple Negative ◽

Functional Expression ◽

High Rate ◽

Cellular Functions ◽

Non Coding Rnas ◽

Significant Disease ◽

Worse Prognosis

Triple-negative breast cancer (TNBC) is one of the most lethal forms of breast cancer (BC), with a significant disease burden worldwide. Chemoresistance and lack of targeted therapeutics are major hindrances to effective treatments in the clinic and are crucial causes of a worse prognosis and high rate of relapse/recurrence in patients diagnosed with TNBC. In the last decade, long non-coding RNAs (lncRNAs) have been found to perform a pivotal role in most cellular functions. The aberrant functional expression of lncRNAs plays an ever-increasing role in the progression of diverse malignancies, including TNBC. Therefore, lncRNAs have been recently studied as predictors and modifiers of chemoresistance. Our review discusses the potential involvement of lncRNAs in drug-resistant mechanisms commonly found in TNBC and highlights various therapeutic strategies to target lncRNAs in this malignancy.

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Tumor microenvironment in triple-negative breast cancer: the correlation of tumor-associated macrophages and tumor-infiltrating lymphocytes

Clinical & Translational Oncology ◽

10.1007/s12094-021-02652-3 ◽

2021 ◽

Author(s):

H. Kuroda ◽

T. Jamiyan ◽

R. Yamaguchi ◽

A. Kakumoto ◽

A. Abe ◽

...

Keyword(s):

Breast Cancer ◽

T Cells ◽

Tumor Microenvironment ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Cytotoxic T Cells ◽

Tumor Infiltrating Lymphocytes ◽

Tumor Associated Macrophages ◽

Free Survival ◽

Infiltrating Lymphocytes

Abstract Purpose Immune cells such as cytotoxic T cells, helper T cells, B cells or tumor-associated macrophages (TAMs) contribute to the anti-tumor response or pro-tumorigenic effect in triple negative breast cancer (TNBC). The interrelation of TAMs, T and B tumor-infiltrating lymphocytes (TILs) in TNBC has not been fully elucidated. Methods We evaluated the association of tumor-associated macrophages, T and B TILs in TNBC. Results TNBCs with a high CD68+, CD163+ TAMs and low CD4+, CD8+, CD20+ TILs had a significantly shorter relapse-free survival (RFS) and overall survival (OS) than those with low CD68+, CD163+ TAMs and high CD4+, CD8+, CD20+ TILs. TNBCs with high CD68+ TAMs/low CD8+ TILs showed a significantly shorter RFS and OS and a significantly poorer prognosis than those with high CD68+ TAMs/high CD8+ TILs, low CD68+ TAMs/high CD8+ TILs, and low CD68+/low CD8+. TNBCs with high CD163+ TAMs/low CD8+, low CD20 + TILs showed a significantly shorter RFS and OS and a significantly poorer prognosis than those with high CD163+ TAMs/high CD8+ TILs and high CD163+ TAMs /high CD20+ TILs. Conclusions Our study suggests that TAMs further create an optimal tumor microenvironment (TME) for growth and invasion of cancer cells when evasion of immunoreactions due to T and B TILs occurs. In TNBCs, all these events combine to affect prognosis. The process of TME is highly complex in TNBCs and for an improved understanding, larger validation studies are necessary to confirm these findings.

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Tumor Microenvironment: Key Players in Triple Negative Breast Cancer Immunomodulation

Cancers ◽

10.3390/cancers13133357 ◽

2021 ◽

Vol 13 (13) ◽

pp. 3357

Author(s):

Hongmei Zheng ◽

Sumit Siddharth ◽

Sheetal Parida ◽

Xinhong Wu ◽

Dipali Sharma

Keyword(s):

Breast Cancer ◽

Tumor Microenvironment ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Treatment Options ◽

Combined Treatment ◽

High Mobility ◽

Sphingosine 1 Phosphate ◽

Molecular Patterns

Triple negative breast cancer (TNBC) is a heterogeneous disease and is highly related to immunomodulation. As we know, the most effective approach to treat TNBC so far is still chemotherapy. Chemotherapy can induce immunogenic cell death, release of damage-associated molecular patterns (DAMPs), and tumor microenvironment (TME) remodeling; therefore, it will be interesting to investigate the relationship between chemotherapy-induced TME changes and TNBC immunomodulation. In this review, we focus on the immunosuppressive and immunoreactive role of TME in TNBC immunomodulation and the contribution of TME constituents to TNBC subtype classification. Further, we also discuss the role of chemotherapy-induced TME remodeling in modulating TNBC immune response and tumor progression with emphasis on DAMPs-associated molecules including high mobility group box1 (HMGB1), exosomes, and sphingosine-1-phosphate receptor 1 (S1PR1), which may provide us with new clues to explore effective combined treatment options for TNBC.

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The Characteristics of Tumor Microenvironment in Triple Negative Breast Cancer

Cancer Management and Research ◽

10.2147/cmar.s316700 ◽

2022 ◽

Vol Volume 14 ◽

pp. 1-17

Author(s):

Yiqi Fan ◽

Shuai He

Keyword(s):

Breast Cancer ◽

Tumor Microenvironment ◽

Triple Negative Breast Cancer ◽

Triple Negative

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Novel miRNA Targets and Therapies in the Triple-Negative Breast Cancer Microenvironment: An Emerging Hope for a Challenging Disease

International Journal of Molecular Sciences ◽

10.3390/ijms21238905 ◽

2020 ◽

Vol 21 (23) ◽

pp. 8905

Author(s):

Amal Qattan

Keyword(s):

Breast Cancer ◽

Tumor Microenvironment ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Epidermal Growth Factor Receptors ◽

Mirna Regulation ◽

Novel Mirna ◽

Epidermal Growth ◽

Cell Subpopulations ◽

Insight Into

Treatment of triple-negative breast cancer (TNBC) remains challenging because of the heterogeneity of the disease and lack of single targetable driving mutations. TNBC does not rely on estrogen, progesterone or epidermal growth factor receptors and is associated with aggressive disease progression and poor prognosis. TNBC is also characterized by resistance to chemotherapeutics, and response to immunotherapies is limited despite promising results in a subset of TNBC patients. MicroRNAs (miRNAs) have emerged as significant drivers of tumorigenesis and tumor progression in triple-negative breast cancer (TNBC) and present unique opportunities to target various components of the TNBC microenvironment for improved efficacy against this difficult to treat cancer. Effects of miRNAs on multiple targets may improve response rates in the context of this genetically and biologically heterogeneous disease. In this review, we offer a comprehensive view of miRNA regulation in TNBC, treatment challenges presented by TNBC in the context of the tumor microenvironment and stem cell subpopulations, and current and emerging miRNA-based therapeutic strategies targeting various components of the TNBC microenvironment. In addition, we offer insight into novel targets that have potential for treating TNBC through multiple mechanisms in the tumor microenvironment simultaneously and those that may be synergistic with standard chemotherapies.

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Expression of Transgelin in Triple Negative and Non Triple Negative Breast Cancer: A Differential Study

Tumori Journal ◽

10.1177/0300891620914150 ◽

2020 ◽

Vol 106 (1_suppl) ◽

pp. 20-20

Author(s):

NS Tolba ◽

AS Alsedfy ◽

SW Skandar ◽

YM El-Kerm

Keyword(s):

Breast Cancer ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Molecular Subtypes ◽

High Rate ◽

Targeted Treatment ◽

Her2 Status ◽

Altered Expression ◽

Wide Range ◽

Significant Difference

Introduction: Triple negative breast cancer (TNBC) is defined by the absence of ER expression, PR expression and HER2 amplification. No targeted treatment is available for TNBC and chemotherapy remains the best therapeutic option. However, in the case of recurrence or chemo-resistance, therapeutic options are very limited. TNBC presents a high rate of proliferation and is highly aggressive having low survival rate. As the complexity of this disease is being simplified over time, new targets are also being discovered for the treatment of this disease. Therefore, there is still need for new biomarkers, which would serve for targeted treatment. Transgelin was proposed as a new potential cancer biomarker. Altered expression of Transgelin has been described in a wide range of cancers, often with contradictory results. The aim of the study was to compare Transgelin expression across molecular subtypes of breast cancer, to identify if it can be used as a future molecular targeted protein for TNBC. Material and Methods: Transgelin immunohistochemistry was applied on 60 retrospectively collected paraffin blocks of patients presenting with invasive breast carcinoma (NST) having different molecular subtypes. Blocks were collected between 2015 and 2016 from Pathology department, Medical Research Institute, Egypt. Her2 equivocal cases were excluded from the study. Results: Transgelin expression was positive in 23 cases and negative in 37 cases. There was a statistically significant difference between (Transgelin +) and (Transgelin -) cases being highly expressed in TNBC in comparison to other molecular subtypes. It was also highly expressed in tumors with large size, high grade, positive lymph-vascular invasion status & lymph node metastasis. There was no statistically significant difference between (Transgelin+) and (Transgelin-) as regards age and Her2 status. Conclusions: Transgelin is an aggressive biomarker differentially expressed among the molecular breast cancer subtypes with high expression in TNBC. Transgelin may provide a potential target for future treatment of TNBC.

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