scholarly journals A Comprehensive Immunologic Portrait of Triple-Negative Breast Cancer

2017 ◽  
Author(s):  
Zhixian Liu ◽  
Mengyuan Li ◽  
Zehang Jiang ◽  
Xiaosheng Wang
Keyword(s):  
Breast Cancer ◽  
Triple Negative ◽  
Immune Cell ◽  
Survival Prognosis ◽  
Expression Levels ◽  
Immune Related Gene ◽  
Gene Sets ◽  
Immune Cell Infiltrate ◽  
Elevated Expression ◽  
Immune Related Genes

AbstractBackgroundTriple-negative breast cancer (TNBC) is a high-risk malignancy due to its high capacity for invasion and lack of targeted therapy. Immunotherapy continues to demonstrate efficacy in a variety of cancers, and thus may be a promising strategy for TNBC given the limited therapeutic options currently available for TNBC. In this study, we performed a comprehensive portrait of immunologic landscape of TNBC based on 2 large-scale breast cancer genomic data.MethodsWe compared expression levels of immune-related genes and gene-sets among TNBC, non-TNBC, and normal tissue, and within TNBCs of different genotypic or phenotypic features. Moreover, we explored the association of immune-related genes or gene-sets expression and survival prognosis in TNBC patients.ResultsWe found that almost all analyzed immune-related gene-sets had significantly higher expression levels in TNBC than non-TNBC. These highly expressed gene-sets in TNBC included 15 immune cell type and function, human leukocyte antigen (HLA), cancer testis (CT), tumor-infiltrating lymphocytes (TILs), immune cell infiltrate, regulatory T (Treg) cells, immune checkpoint, cytokine and cytokine receptor, metastasis-promoting, pro-inflammatory and parainflammation (PI) gene-sets. Moreover, TP53-mutated, TNBC had significantly higher expression levels of the immune checkpoint, Treg, PI, and CT gene-sets, and lower expression levels of the immune cell infiltrate gene-set than TP53-wildtype TNBC. Furthermore, we found that elevated expression of most of the immune-related genes in TNBC was associated with the ER-status, while some were associated with both ER-and HER2-status. Elevated expression of the immune-related genes in TNBC was also associated with the high tumor mutation burden (TMB) in TNBC. Finally, elevated expression of the immune-related gene-sets was likely to be associated with better survival prognosis in TNBC.ConclusionsOur findings suggest that TNBC is a breast cancer subtype with particularly strong immunogenicity, and therefore could be propitious to immunotherapeutic options.

scholarly journals The BIRC Family Genes Expression in Patients with Triple Negative Breast Cancer

2021 ◽  
Vol 22 (4) ◽  
pp. 1820
Author(s):  
Anna Makuch-Kocka ◽  
Janusz Kocki ◽  
Anna Brzozowska ◽  
Jacek Bogucki ◽  
Przemysław Kołodziej ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Clinical Data ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Lymphatic Vessels ◽  
The Cancer Genome Atlas ◽  
Expression Level ◽  
Cancer Tissue ◽  
Expression Levels

The BIRC (baculoviral IAP repeat-containing; BIRC) family genes encode for Inhibitor of Apoptosis (IAP) proteins. The dysregulation of the expression levels of the genes in question in cancer tissue as compared to normal tissue suggests that the apoptosis process in cancer cells was disturbed, which may be associated with the development and chemoresistance of triple negative breast cancer (TNBC). In our study, we determined the expression level of eight genes from the BIRC family using the Real-Time PCR method in patients with TNBC and compared the obtained results with clinical data. Additionally, using bioinformatics tools (Ualcan and The Breast Cancer Gene-Expression Miner v4.5 (bc-GenExMiner v4.5)), we compared our data with the data in the Cancer Genome Atlas (TCGA) database. We observed diverse expression pattern among the studied genes in breast cancer tissue. Comparing the expression level of the studied genes with the clinical data, we found that in patients diagnosed with breast cancer under the age of 50, the expression levels of all studied genes were higher compared to patients diagnosed after the age of 50. We observed that in patients with invasion of neoplastic cells into lymphatic vessels and fat tissue, the expression levels of BIRC family genes were lower compared to patients in whom these features were not noted. Statistically significant differences in gene expression were also noted in patients classified into three groups depending on the basis of the Scarff-Bloom and Richardson (SBR) Grading System.

scholarly journals Activated STAT3 Is a Novel Regulator of the XRCC1 Promoter and Selectively Increases XRCC1 Protein Levels in Triple Negative Breast Cancer

2021 ◽  
Vol 22 (11) ◽  
pp. 5475
Author(s):  
Griffin Wright ◽  
Manoj Sonavane ◽  
Natalie R. Gassman
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Excision Repair ◽  
Strand Break ◽  
Xrcc1 Gene ◽  
Single Strand Break ◽  
Expression Levels ◽  
Constitutive Activation ◽  
Gene And Protein Expression

Base Excision Repair (BER) addresses base lesions and abasic sites induced by exogenous and endogenous stressors. X-ray cross complementing group 1 (XRCC1) functions as a scaffold protein in BER and single-strand break repair (SSBR), facilitating and coordinating repair through its interaction with a host of critical repair proteins. Alterations of XRCC1 protein and gene expression levels are observed in many cancers, including colorectal, ovarian, and breast cancer. While increases in the expression level of XRCC1 are reported, the transcription factors responsible for this up-regulation are not known. In this study, we identify the signal transducer and activator of transcription 3 (STAT3) as a novel regulator of XRCC1 through chromatin immunoprecipitation. Activation of STAT3 through phosphorylation at Y705 by cytokine (IL-6) signaling increases the expression of XRCC1 and the occupancy of STAT3 within the XRCC1 promoter. In triple negative breast cancer, the constitutive activation of STAT3 upregulates XRCC1 gene and protein expression levels. Increased expression of XRCC1 is associated with aggressiveness and resistance to DNA damaging chemotherapeutics. Thus, we propose that activated STAT3 regulates XRCC1 under stress and growth conditions, but constitutive activation in cancers results in dysregulation of XRCC1 and subsequently BER and SSBR.

scholarly journals LncRNA DLX6-AS1 Contributes to Epithelial–Mesenchymal Transition and Cisplatin Resistance in Triple-negative Breast Cancer via Modulating Mir-199b-5p/Paxillin Axis

2020 ◽  
Vol 29 ◽  
pp. 096368972092998 ◽  
Author(s):  
Chuang Du ◽  
Yan Wang ◽  
Yingying Zhang ◽  
Jianhua Zhang ◽  
Linfeng Zhang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Proliferation ◽  
Drug Resistance ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Cisplatin Resistance ◽  
Epithelial Mesenchymal Transition ◽  
Mesenchymal Transition ◽  
Expression Levels

Triple-negative breast cancer (TNBC) is one of the most aggressive cancer types with high recurrence, metastasis, and drug resistance. Recent studies report that long noncoding RNAs (lncRNAs)-mediated competing endogenous RNAs (ceRNA) play an important role in tumorigenesis and drug resistance of TNBC. Although elevated lncRNA DLX6 antisense RNA 1 (DLX6-AS1) has been observed to promote carcinogenesis in various cancers, the role in TNBC remained unclear. In this study, expression levels of DLX6-AS1 were increased in TNBC tissues and cell lines when compared with normal tissues or breast fibroblast cells which were determined by quantitative real-time PCR (RT-qPCR). Then, CCK-8 assay, cell colony formation assay and western blot were performed in CAL-51 cells transfected with siRNAs of DLX6-AS1 or MDA-MB-231 cells transfected with DLX6-AS1 over expression plasmids. Knock down of DLX6-AS1 inhibited cell proliferation, epithelial-mesenchymal transition (EMT), decreased expression levels of BCL2 apoptosis regulator (Bcl-2), Snail family transcriptional repressor 1 (Snail) as well as N-cadherin and decreased expression levels of cleaved caspase-3, γ-catenin as well as E-cadherin, while up regulation of DLX6-AS1 had the opposite effect. Besides, knockdown of DLX6-AS1 in CAL-51 cells or up regulation of DLX6-AS1 in MDA-MB-231 cells also decreased or increased cisplatin resistance of those cells analyzed by MTT assay. Moreover, by using dual luciferase reporter assay, RNA immunoprecipitation and RNA pull down assay, a ceRNA which was consisted by lncRNA DLX6-AS1, microRNA-199b-5p (miR-199b-5p) and paxillin (PXN) was identified. And DLX6-AS1 function through miR-199b-5p/PXN in TNBC cells. Finally, results of xenograft experiments using nude mice showed that DLX6-AS1 regulated cell proliferation, EMT and cisplatin resistance by miR-199b-5p/PXN axis in vivo. In brief, DLX6-AS1 promoted cell proliferation, EMT, and cisplatin resistance through miR-199b-5p/PXN signaling in TNBC in vitro and in vivo.

scholarly journals 616 CD47 blockade modulates immunosuppressive checkpoint molecules and cellular metabolism to sensitize triple-negative breast cancer tumors to immune checkpoint blockade therapy

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A646-A646
Author(s):  
Elizabeth Stirling ◽  
Adam Wilson ◽  
Katherine Cook ◽  
Alexandra Thomas ◽  
Pierre Triozzi ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Fatty Acid ◽  
Triple Negative Breast Cancer ◽  
Immune Checkpoint ◽  
Triple Negative ◽  
Immune Cell ◽  
Tumor Burden ◽  
Metabolic Reprogramming ◽  
Acid Oxidation ◽  
Immunosuppressive Cell

BackgroundTriple-negative breast cancer(TNBC) lacks druggable targets and has high metastatic incidence. Immune checkpoint blockades (ICB) are FDA approved for TNBC treatment, but therapeutic response and biomarkers are limited. CD47 is an integral membrane protein overexpressed on cancer cells that alters anti-tumor immunosurveillance, resulting in tumor progression. CD47 is involved in metabolic reprogramming but whether CD47 is a marker of progression and its role in ICB response for TNBC remains unknown.MethodsHuman TNBC biopsies were subjected to immunohistochemical analysis to determine CD47 role in TNBC progression. To determine CD47 impact on tumor burden, a carcinogen-induced TNBC model was performed in female wild type(WT) and cd47 null(cd47-/-) C57Bl/6 mice. To evaluate immune infiltrate signaling, tumors underwent spatial tissue proteomics by multiplexing photo-cleavable antibodies in Formalin-Fixed Paraffin-Embedded samples. An orthotopic EMT-6 murine TNBC model was performed to investigate tumor burden for CD47 monotherapy or in combination with anti-PD-L1 therapy.ResultsHuman matched primary, and metastatic TNBC biopsies increased immunoreactivity to CD47, signifying a potential therapeutic target(n=24). CD47 deficiency in the carcinogen-induced DMBA model decreased tumor incidence, weight, and area compared to WT(n=8/group,*p<0.003). Since CD47 can regulate metabolism, tumors underwent metabolomic analysis. Principal component analysis displayed differentially regulated metabolites between WT and cd47-/- tumors. Decreased carnitine conjugated fatty acids and ketone bodies were observed in cd47-/- tumors compared to WT, suggesting decreased fatty acid availability and/or metabolism(n=9/group,*p<0.05). TNBC cell respiratory measurements validated that targeting CD47 shifted metabolic dependency from fatty acid oxidation to glycolysis(n=3,*p<0.05). Kynurenine/tryptophan pathway metabolites, which catabolize Indoleamine-2,3-dioxygenase(IDO1) and involved in anti-PD-1/PD-L1 resistance, were decreased in cd47-/- tumors compared to WT(n=9/group,*p<0.05). Spatial proteomic analysis determined that cd47-/- tumors had elevated immune cell infiltration(CD45+, CD3+), suggesting CD47 absence enhances tumor immunogenicity and immune-mediated tumor ablation. Multiplexing of photo-cleavable antibodies increased protein expression of immune checkpoint molecules(PD-L1,VISTA,B7-H3,BatF3) and immunosuppressive cell types(CD11b+,Ly6c+) in WT tumors compared to cd47-/-, suggesting CD47 absence limits immunosuppressive signaling(n=16/group,*p<0.05). Since anti-PD-L1 therapies are approved to treat TNBC and WT tumors have PD-L1 upregulation, we examined how targeting CD47 would impact tumor burden of mice receiving anti-PD-L1 therapy. Targeting CD47 or PD-L1 as monotherapy decreased tumor burden; however, in combination it further reduced tumor burden compared to anti-PD-L1 treatment due to increased intratumoral granzyme B secreting cytotoxic T cells(n=4–8/group,*p<0.05).ConclusionsOur data indicates that CD47 may serve as a marker of anti-PD-L1 response, and targeting CD47 enhances immunogenicity and decreases immunosuppressive molecules, sensitizing TNBC tumors to anti-PD-L1 therapy to reduce tumor burden.AcknowledgementsDSP is supported by the NCI R21 (CA249349) and the American Cancer Society Research Scholar Grant (133727-RSG-19-150-01-LIB). ERS is supported by the NIAID Immunology and Pathogenesis T32 Training Grant (T32AI007401).Ethics ApprovalAnimal studies were approved by the Institutional Care and Use Committee, Wake Forest Health Sciences.

scholarly journals TYROBP, TLR4 and ITGAM regulated macrophages polarization and immune checkpoints expression in osteosarcoma

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Tuo Liang ◽  
Jiarui Chen ◽  
GuoYong Xu ◽  
Zide Zhang ◽  
Jiang Xue ◽  
...  
Keyword(s):  
Risk Score ◽  
Immune Cell ◽  
Risk Model ◽  
Low Risk ◽  
Risk Scores ◽  
Immune Checkpoints ◽  
Kegg Pathways ◽  
Gene Sets ◽  
Macrophages Polarization ◽  
Immune Related Genes

AbstractWe established a relationship among the immune-related genes, tumor-infiltrating immune cells (TIICs), and immune checkpoints in patients with osteosarcoma. The gene expression data for osteosarcoma were downloaded from UCSC Xena and GEO database. Immune-related differentially expressed genes (DEGs) were detected to calculate the risk score. “Estimate” was used for immune infiltrating estimation and “xCell” was used to obtain 64 immune cell subtypes. Furthermore, the relationship among the risk scores, immune cell subtypes, and immune checkpoints was evaluated. The three immune-related genes (TYROBP, TLR4, and ITGAM) were selected to establish a risk scoring system based on their integrated prognostic relevance. The GSEA results for the Hallmark and KEGG pathways revealed that the low-risk score group exhibited the most gene sets that were related to immune-related pathways. The risk score significantly correlated with the xCell score of macrophages, M1 macrophages, and M2 macrophages, which significantly affected the prognosis of osteosarcoma. Thus, patients with low-risk scores showed better results with the immune checkpoints inhibitor therapy. A three immune-related, gene-based risk model can regulate macrophage activation and predict the treatment outcomes the survival rate in osteosarcoma.

scholarly journals Prognostic role of GPER/Ezrin in triple-negative breast cancer is associated with menopausal status

2019 ◽  
Vol 8 (6) ◽  
pp. 661-671 ◽  
Author(s):  
Shuang Ye ◽  
Yuanyuan Xu ◽  
Jiehao Li ◽  
Shuhui Zheng ◽  
Peng Sun ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Cox Regression ◽  
Menopausal Status ◽  
Prognostic Significance ◽  
Multivariable Analysis ◽  
Survival Prognosis ◽  
Kaplan Meier

The role of G protein-coupled estrogen receptor 1 (GPER) signaling, including promotion of Ezrin phosphorylation (which could be activated by estrogen), has not yet been clearly identified in triple-negative breast cancer (TNBC). This study aimed to evaluate the prognostic value of GPER and Ezrin in TNBC patients. Clinicopathologic features including age, menopausal status, tumor size, nuclear grade, lymph node metastasis, AJCC TNM stage, and ER, PR and HER-2 expression were evaluated from 249 TNBC cases. Immunohistochemical staining of GPER and Ezrin was performed on TNBC pathological sections. Kaplan–Meier analyses, as well as logistic regressive and Cox regression model tests were applied to evaluate the prognostic significance between different subgroups. Compared to the GPER-low group, the GPER-high group exhibited higher TNM staging (P = 0.021), more death (P < 0.001), relapse (P < 0.001) and distant events (P < 0.001). Kaplan–Meier analysis showed that GPER-high patients had a decreased OS (P < 0.001), PFS (P < 0.001), LRFS (P < 0.001) and DDFS (P < 0.001) than GPER-low patients. However, these differences in prognosis were not statistically significant in post-menopausal patients (OS, P = 0.8617; PFS, P = 0.1905; LRFS, P = 0.4378; DDFS, P = 0.2538). There was a significant positive correlation between GPER and Ezrin expression level (R = 0.508, P < 0.001) and the effect of Ezrin on survival prognosis corresponded with GPER. Moreover, a multivariable analysis confirmed that GPER and Ezrin level were both significantly associated with poor DDFS (HR: 0.346, 95% CI 0.182–0.658, P = 0.001; HR: 0.320, 95% CI 0.162–0.631, P = 0.001). Thus, overexpression of GPER and Ezrin may contribute to aggressive behavior and indicate unfavorable prognosis in TNBC; this may correspond to an individual’s estrogen levels.

scholarly journals The expression and clinical significance of GADD45A in breast cancer patients

PeerJ ◽  
2018 ◽  
Vol 6 ◽  
pp. e5344 ◽  
Author(s):  
Junnan Wang ◽  
Yiran Wang ◽  
Fei Long ◽  
Fengshang Yan ◽  
Ning Wang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Cancer Patients ◽  
Clinical Significance ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Breast Cancer Patients ◽  
Ki 67 ◽  
Expression Levels ◽  
Cancer Tissues

BackgroundGrowth arrest and DNA-damage-inducible protein 45 alpha (GADD45A) was previously found to be associated with risk of several kinds of human tumors. Here, we studied the expression and clinical significance of GADD45A in breast cancer.MethodsWe performed an immunohistochemical study of GADD45A protein from 419 breast cancer tissues and 116 adjacent non-neoplastic tissues.ResultsSignificantly high GADD45A expression were observed in breast cancer tissues compared with adjacent non-neoplastic tissues (P < 0.001) and were independently correlative with estrogen receptor negative (P = 0.028) and high Ki-67 index (P < 0.001). Kaplan–Meier survival analysis revealed that patients with high GADD45A expression levels had a worse long-term prognosis in triple negative breast cancer (P = 0.041), but it was not an independent prognostic factor in multivariate analysis (P = 0.058).ConclusionsGADD45A expression levels are significantly correlative with estrogen receptor status and Ki-67 index in human breast cancer. Patients with triple negative breast cancer might be stratified into high risk and low risk groups based on the GADD45A expression levels.

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