scholarly journals Bioinformatics identification of CCL8/21 as potential prognostic biomarkers in breast cancer microenvironment

2020 ◽  
Vol 40 (11) ◽  
Author(s):  
Bowen Chen ◽  
Shuyuan Zhang ◽  
Qiuyu Li ◽  
Shiting Wu ◽  
Han He ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Survival Data ◽  
Triple Negative ◽  
Immune Escape ◽  
Lymphocyte Activation ◽  
Prognostic Biomarkers ◽  
Bioinformatics Analyses ◽  
Tumor Immune Escape ◽  
Normal Tissues ◽  
Cc Chemokines

Abstract Background: Breast cancer (BC) is the most common malignancy among females worldwide. The tumor microenvironment usually prevents effective lymphocyte activation and infiltration, and suppresses infiltrating effector cells, leading to a failure of the host to reject the tumor. CC chemokines play a significant role in inflammation and infection. Methods: In our study, we analyzed the expression and survival data of CC chemokines in patients with BC using several bioinformatics analyses tools. Results: The mRNA expression of CCL2/3/4/5/7/8/11/17/19/20/22 was remarkably increased while CCL14/21/23/28 was significantly down-regulated in BC tissues compared with normal tissues. Methylation could down-regulate expression of CCL2/5/15/17/19/20/22/23/24/25/26/27 in BC. Low expression of CCL3/4/23 was found to be associated with drug resistance in BC. Results from Kaplan–Meier plotter and BC Gene-Expression Miner v4.2 (bcGenExMiner) v4.2 demonstrated that BC patients with high CCL8 and low CCL19/21/22 expression were more likely to have a worse prognosis. CCL8 expression was significantly up-regulated in BC tissues compared with normal tissues. High CCL8 expression was significantly correlated with negative PR, negative ER, positive nodal status, triple-negative BC subtype, basal-like BC subtype, triple-negative and basal-like BC subtype and high grades. CCL21 was down-regulated in BC, while high levels of CCL21 was associated with negative PR, triple-negative subtype, basal-like subtype and low tumor grade. Functional analysis demonstrated that CCL8 and CCL21 were involved in carcinogenesis, tumor immune escape and chemoresistance in BC. Conclusion: Integrative bioinformatics analysis demonstrated CCL8/21 as potential prognostic biomarkers in BC microenvironment.

scholarly journals Identification of death-associated protein-like 1 (DAPL1) as a novel prognostic biomarker of breast cancer

2020 ◽  
Author(s):  
Haichao Zhang ◽  
Xin Qu ◽  
Lu Han
Keyword(s):  
Breast Cancer ◽  
Dna Repair ◽  
Survival Data ◽  
Immune Cell ◽  
Excision Repair ◽  
Analysis Data ◽  
Clinical Prognosis ◽  
Free Survival ◽  
Normal Tissues ◽  
M1 Macrophage

Abstract Background: It is meaningful to identify the potential clinical prognosis-associated oncogenes for cases with breast cancer, considering the complicated pathogenesis of breast cancer.Methods: We first utilized the bioinformatics approach to investigate the role of the DAPL1 (death-associated protein-like 1) in breast cancer, based on the available datasets of TCGA and GEO.Results: DAPL1 is lowly expressed in breast cancer tissues compared with the normal tissues. For the breast cancer cases of the TCGA-BRCA cohort, we observed a correlation between lowly expressed DAPL1 gene and poor clinical prognosis of overall survival ( P =0.0028). Based on the survival data of GEO, the low DAPL1 expression was associated with a poor prognosis of distant metastasis free survival ( P =0.0023), and relapse free survival ( P =0.0065). DAPL1 expression was linked to the mutation status or copy number variation o f several genes, such as MAP3K1 , NUP98 , and CCDC59. The infiltration level of immune cells (e.g., M1 macrophage, Follicular B helper T cells, etc.) may be involved in the etiology of breast cancer. Based on the DAPL1 -correlated genes, GSEA, GO, and KEGG analysis data indicated the association between DAPL1 expression and a series of biological issues, such as DNA packaging complex, DNA repair complex, nucleotide excision repair, ubiquitin-like protein binding, and ubiquitin proteasome pathway. We also identified several DAPL1 -associated phosphorylation kinases, such as MAPK, PRKACA, and GSK3B.Conclusions: DAPL1 gene is first identified as a prognosis biomarker of breast cancer, and the underlying molecular mechanism involves protein phosphorylation, immune cell infiltration, and DNA repair or protein ubiquitin-associated cellular pathways.

scholarly journals Epigenetic Regulation of Immunotherapy Response in Triple-Negative Breast Cancer

Cancers ◽  
2021 ◽  
Vol 13 (16) ◽  
pp. 4139
Author(s):  
Pere Llinàs-Arias ◽  
Sandra Íñiguez-Muñoz ◽  
Kelly McCann ◽  
Leonie Voorwerk ◽  
Javier I. J. Orozco ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Immune Escape ◽  
Checkpoint Inhibitors ◽  
Early Stage ◽  
Regulatory Elements ◽  
Her2 Overexpression ◽  
Breast Cancers ◽  
Cancer Subtypes

Triple-negative breast cancer (TNBC) is defined by the absence of estrogen receptor and progesterone receptor and human epidermal growth factor receptor 2 (HER2) overexpression. This malignancy, representing 15–20% of breast cancers, is a clinical challenge due to the lack of targeted treatments, higher intrinsic aggressiveness, and worse outcomes than other breast cancer subtypes. Immune checkpoint inhibitors have shown promising efficacy for early-stage and advanced TNBC, but this seems limited to a subgroup of patients. Understanding the underlying mechanisms that determine immunotherapy efficiency is essential to identifying which TNBC patients will respond to immunotherapy-based treatments and help to develop new therapeutic strategies. Emerging evidence supports that epigenetic alterations, including aberrant chromatin architecture conformation and the modulation of gene regulatory elements, are critical mechanisms for immune escape. These alterations are particularly interesting since they can be reverted through the inhibition of epigenetic regulators. For that reason, several recent studies suggest that the combination of epigenetic drugs and immunotherapeutic agents can boost anticancer immune responses. In this review, we focused on the contribution of epigenetics to the crosstalk between immune and cancer cells, its relevance on immunotherapy response in TNBC, and the potential benefits of combined treatments.

scholarly journals Differential expression of histone cluster 1, H2bh in triple negative breast cancer.

2021 ◽  
Author(s):  
Shahan Mamoor
Keyword(s):  
Breast Cancer ◽  
Differential Expression ◽  
Tumor Cells ◽  
Triple Negative Breast Cancer ◽  
Survival Data ◽  
Triple Negative ◽  
Differentially Expressed ◽  
Significant Differential Expression ◽  
Primary Tumors ◽  
Ductal Cells

Women diagnosed with triple negative breast cancer can benefit neither from endocrine therapy nor from HER2-targeted therapies (1). We mined published microarray datasets (2, 3) to determine in an unbiased fashion and at the systems level genes most differentially expressed in the primary tumors of patients with breast cancer. We report here significant differential expression of the gene encoding histone cluster 1, H2bh, HIST1H2BH, when comparing the tumor cells of patients with triple negative breast cancer to normal mammary ductal cells (2). HIST1H2BH was also differentially expressed in the brain metastases of patients with metastastic breast cancer (3). HIST1H2BH mRNA was present at significantly increased quantities in TNBC tumor cells relative to normal mammary ductal cells. Analysis of human survival data revealed that expression of HIST1H2BH in primary tumors of the breast was correlated with overall survival in patients with luminal A type cancer, while within triple negative breast cancer, primary tumor expression of HIST1H2BH was correlated with distant metastasis-free survival in patients with immunomodulatory subtype disease. HIST1H2BH may be of relevance to initiation, maintenance or progression of triple negative breast cancers.

scholarly journals Platinum-Based Chemotherapy and Immunotherapy in Early Triple-Negative Breast Cancer: A Meta-Analysis and Indirect Treatment Comparison

2021 ◽  
Vol 11 ◽  
Author(s):  
Qin He ◽  
Yicheng Peng ◽  
Jie Sun ◽  
Jianxia Liu
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Survival Data ◽  
Triple Negative ◽  
Meta Analysis ◽  
Indirect Comparison ◽  
Controlled Trials ◽  
Platinum Drugs ◽  
Treatment Comparison ◽  
Platinum Based Chemotherapy

BackgroundTriple-negative breast cancer (TNBC) comprises 15% of invasive breast cancers. Platinum-based chemotherapy and immune checkpoint inhibitors (ICIs) have been extensively researched in recent years as promising treatments in the neoadjuvant setting. However, clinical data is lacking in direct comparisons of these two treating regimens.MethodsWe conducted an online search on PubMed, Embase, Cochrane Online Library and key oncological meetings for available randomized controlled trials (RCTs) investigating ICIs or platinum drugs versus anthracyclines and taxane-based neoadjuvant chemotherapy (AT-based NACT). Conventional meta-analyses were conducted separately, and then indirect comparisons for clinical efficacy and safety profile were performed between ICIs and platinum drugs using AT-based NACT as a common comparator.ResultsSeven random controlled trials (RCTs) with 1,647 patients were included in the meta-analysis. The indirect comparison demonstrated that ICIs plus chemotherapy significantly improved pathological complete response (pCR) rate (p = 0.00445, OR, 1.78; 95%CI, 0.70–4.53), and decreased the adverse effect (AE) related discontinuance versus platinum-based chemotherapy (P = 0.00015; OR 0.46; 95%CI, 0.26–0.82).ConclusionICIs plus chemotherapy showed increased pCR rate and decreased adverse effects compared with platinum-based chemotherapy in early TNBC. However, subgroup analysis and survival data to explore the proper patients for each treatment remains scarce. Therefore, further studies with powered direct comparisons of these two treating regimens are required.

scholarly journals Tumor-B-Cell Interactions Promote Isotype Switching to an Immunosuppressive IgG4 Antibody Response Through Upregulation of IL-10 in Triple Negative Breast Cancers

2021 ◽  
Author(s):  
Nicole J. Toney ◽  
Lynn M. Opdenaker ◽  
Kader Cicek ◽  
Holly Archinal ◽  
Lisa Frerichs ◽  
...  
Keyword(s):  
Breast Cancer ◽  
B Cells ◽  
Triple Negative ◽  
Immune Escape ◽  
Inflammatory Responses ◽  
Dependent Manner ◽  
Th2 Cytokines ◽  
Class Switching ◽  
Isotype Switching

Abstract Background: Triple negative breast cancer (TNBC) is an aggressive breast cancer for which there is currently no targeted therapy. Tumor-infiltrating B-cells (TIB) have been observed in tumor tissues of TNBC patients, but their functional role is unclear. IgG4 is one of four antibody subclasses of IgG expressed and secreted by B cells. Unlike other IgG isotypes, IgG4 has an immunosuppressive function and is induced by Th2-type cytokines. In cancers such as melanoma, IgG4 has been linked with advanced disease and poor patient survival. Therefore, we sought to determine the role of IgG4 in TNBC. Methods: We performed co-culture assays to examine expression of Th2 cytokines by TNBC cells with and without the presence of B cells. We also performed in vitro class switching experiments with peripheral B cells with and without co-culture with TNBC cells in the presence or absence of an IL-10 blocking antibody. We examined expression of CD20 + TIB, IgG4 and Th2 cytokines by immunohistochemistry in 152 TNBC samples. Statistical analysis was done using Log-Rank and Cox-proportional hazards tests. Results: Our findings indicate that B cells interact with TNBC to drive chronic inflammatory responses through increased expression of inflammatory cytokines including the TH2 cytokines IL-4 and IL-10. In vitro class switching studies show that interactions between TNBC cell lines and B cells drive isotype switching to the IgG4 isotype in an IL-10 dependent manner. In patient tissues, expression of IgG4 correlates with CD20 and tumor expression of IL-10. Both IgG4 and tumor IL-10 are associated to shorter recurrence free survival (RFS) and overall survival (OS) in TNBC. In a multi-variant analysis, IL-10 was associated with poor outcomes indicating that tumor IL-10 may drive immune escape. Conclusions: These findings indicate that interactions between TIB and TNBC results in activation of chronic inflammatory signals that suppress antibody driven immune responses

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