scholarly journals Identification of Five Cytotoxicity-Related Genes Involved in the Progression of Triple-Negative Breast Cancer

2022 ◽  
Vol 12 ◽  
Author(s):  
Yan Zhang ◽  
Gui-hui Tong ◽  
Xu-Xuan Wei ◽  
Hai-yang Chen ◽  
Tian Liang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
T Cell ◽  
Signaling Pathway ◽  
Therapeutic Efficacy ◽  
Normal Tissue ◽  
R Package ◽  
Rna Seq ◽  
Matched Normal Tissue ◽  
M1 Macrophage ◽  
Key Genes

Background: Breast cancer is one of the deadly tumors in women, and its incidence continues to increase. This study aimed to identify novel therapeutic molecules using RNA sequencing (RNA-seq) data of breast cancer from our hospital.Methods: 30 pairs of human breast cancer tissue and matched normal tissue were collected and RNA sequenced in our hospital. Differentially expressed genes (DEGs) were calculated with raw data by the R package “edgeR”, and functionally annotated using R package “clusterProfiler”. Tumor-infiltrating immune cells (TIICs) were estimated using a website tool TIMER 2.0. Effects of key genes on therapeutic efficacy were analyzed using RNA-seq data and drug sensitivity data from two databases: the Cancer Cell Line Encyclopedia (CCLE) and the Cancer Therapeutics Response Portal (CTRP).Results: There were 2,953 DEGs between cancerous and matched normal tissue, as well as 975 DEGs between primary breast cancer and metastatic breast cancer. These genes were primarily enriched in PI3K-Akt signaling pathway, calcium signaling pathway, cAMP signaling pathway, and cell cycle. Notably, CD8+ T cell, M0 macrophage, M1 macrophage, regulatory T cell and follicular helper T cell were significantly elevated in cancerous tissue as compared with matched normal tissue. Eventually, we found five genes (GALNTL5, MLIP, HMCN2, LRRN4CL, and DUOX2) were markedly corelated with CD8+ T cell infiltration and cytotoxicity, and associated with therapeutic response.Conclusion: We found five key genes associated with tumor progression, CD8+ T cell and therapeutic efficacy. The findings would provide potential molecular targets for the treatment of breast cancer.

scholarly journals The role of ferroptosis in breast cancer patients: a comprehensive analysis

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Zeng-Hong Wu ◽  
Yun Tang ◽  
Hong Yu ◽  
Hua-Dong Li
Keyword(s):  
Breast Cancer ◽  
T Cell ◽  
Signaling Pathway ◽  
Differentially Expressed Genes ◽  
Function Analysis ◽  
Cancer Prognosis ◽  
Differentially Expressed ◽  
Immune Checkpoints ◽  
Cell Functions

AbstractBreast cancer (BC) affects the breast tissue and is the second most common cause of mortalities among women. Ferroptosis is an iron-dependent cell death mode that is characterized by intracellular accumulation of reactive oxygen species (ROS). We constructed a prognostic multigene signature based on ferroptosis-associated differentially expressed genes (DEGs). Moreover, we comprehensively analyzed the role of ferroptosis-associated miRNAs, lncRNAs, and immune responses. A total of 259 ferroptosis-related genes were extracted. KEGG function analysis of these genes revealed that they were mainly enriched in the HIF-1 signaling pathway, NOD-like receptor signaling pathway, central carbon metabolism in cancer, and PPAR signaling pathway. Fifteen differentially expressed genes (ALOX15, ALOX15B, ANO6, BRD4, CISD1, DRD5, FLT3, G6PD, IFNG, NGB, NOS2, PROM2, SLC1A4, SLC38A1, and TP63) were selected as independent prognostic factors for BC patients. Moreover, T cell functions, including the CCR score, immune checkpoint, cytolytic activity, HLA, inflammation promotion, para-inflammation, T cell co-stimulation, T cell co-inhibition, and type II INF responses were significantly different between the low-risk and high-risk groups of the TCGA cohort. Immune checkpoints between the two groups revealed that the expressions of PDCD-1 (PD-1), CTLA4, LAG3, TNFSF4/14, TNFRSF4/8/9/14/18/25, and IDO1/2 among others were significantly different. A total of 1185 ferroptosis-related lncRNAs and 219 ferroptosis-related miRNAs were also included in this study. From the online database, we identified novel ferroptosis-related biomarkers for breast cancer prognosis. The findings of this study provide new insights into the development of new reliable and accurate cancer treatment options.

Discussion On The Mechanism of Que In The Treatment of Breast Neoplasms And Immune Prevention And Treatment

2021 ◽  
Author(s):  
Dan Qiu ◽  
Xianxin Yan ◽  
Xinqin Xiao ◽  
Guijuan Zhang ◽  
Yanqiu Wang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
T Cells ◽  
T Cell ◽  
Breast Neoplasms ◽  
Signaling Pathway ◽  
Immune Regulation ◽  
Γδ T Cells ◽  
Protein Levels ◽  
Stat1 Signaling ◽  
Mcf 7

Abstract Background: The precancerous disease of breast cancer is an inevitable stage in the emergence and development of breast neoplasms. Breast cancer (BC) is a common malignant tumor in female worldwide. A large number of literatures have proved that, as antitumor drugs, flavonoid compounds can promote proliferation and immune regulation of T cell. Many researchers believe that Quercetin (Que) has great potential in the field of anti-breast cancer. Besides that, γδ T cells are a class of non-traditional T cells, which have long attracted attention due to their potential in immunotherapy. Above all, JAK/STAT1 signaling pathway is closely related to the immunity.MethodsIn the experiment designed in this paper, we first used Que, one of the flavonoids, to screen the target gene. Then, MCF-10A, MCF-10AT, MCF-7 and MDA-MB231 BC cells were co-cultured with Que for 24h and 48h, apoptosis was found in some the cells. We then cultured Que with γδ T cells and found that Que can promote the proliferation of Vδ2 T cell subsets of γδ T cells, thus enhancing the killing effect of γδ T cells. Western blot was use to showed the change of JAK/STAT1 signaling pathway related proteins after the Que was co-cultured with MCF-10AT and MCF-7 for 48h.ResultsNetwork pharmacology has shown that Que related pathways include the JAK/STAT1 signaling pathway and are associated with precancerous breast cancers. Que induced apoptosis of MCF-10AT, MCF-7 and MDA-MB-231 in a time and concentration-dependent manner. Most importantly, Que can promote the differentiation of γδ T cells into the Vδ2 T cell subpopulation, this means that Que and γδ T cells may play a synergistic role in killing tumor cells and cellular immune regulation. In addition, our results showed that Que can increase in protein levels of IFNγ-R, p-JAK2 and p-STAT1, while the concomitant decrease protein levels of PD-L1.ConclusionsIn conclusion, Que plays a synergistic role in killing BC cells and promoting apoptosis by regulating the expression of IFNγ-R, p-JAK2, p-STAT1, and PD-L1 in the JAK/STAT1 signaling pathway and promoting the regulation of γδ T cells. Que may be a potential drug for the prevention of precancerous breast cancer and adjuvant treatment of BC.

scholarly journals 754 TIGIT-PVR is a key immune checkpoint and therapeutic target in HPV-positive head and neck squamous cell carcinomas

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A788-A788
Author(s):  
Xiuning Le ◽  
Minghao Dang ◽  
Venkatesh Hegde ◽  
Bo Jiang ◽  
Ravaen Slay ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Murine Model ◽  
Immune Checkpoint ◽  
Therapeutic Target ◽  
Therapeutic Efficacy ◽  
Cd8 T Cell ◽  
Immune Checkpoints ◽  
Rna Seq

BackgroundHuman papillomavirus (HPV)-positive head and neck squamous cell carcinoma (HPV+ HNSCC) is a disease that has moderate response to anti-PD-1/L1 immune checkpoint blockade, with the response rates less than 20% and median progression-free survival less than 3 months. A greater understanding of tumor intrinsic and extrinsic factors that restrict anti-tumor immunity in the tumor immune microenvironment (TIME) is needed to identify other immune checkpoints to enhance therapeutic efficacy.MethodsTwo cohorts (TCGA n=72 and a separate cohort n=84) of surgically resected, treatment-naïve HPV+ HNSCC with RNA-seq were analyzed to understand the immune features. In addition, single-cell RNA-seq and TCR-seq were performed on 18 cases to further delineate the immune molecules' interactions. An immune-competent murine HPV+ HNSCC model was used to preliminarily evaluate the therapeutic efficacy.ResultsIn two bulk-sequenced HPV+ HNSCC cohorts, TIGIT ligands PVR and NECTIN2 were found to associate with an epithelial-to-mesenchymal gene expression signature, suppression of IFNα and IFNγ signaling, a stromal-enriched or immune-excluded TIME, and poor survival. Single-cell RNA-seq of over 72,000 cells of HPV+ HNSCC revealed that the PVR/NECTIN ligand TIGIT was highly prevalent in T-cells (34%), significantly higher than PD1- (20%, p<0.01). There is an enrichment of cell-cell interactions mediated by TIGIT-PVR/NECTIN2 in the TIME of HPV+HNSCC versus normal tonsil. TIGIT was the most differentially upregulated immune checkpoint on clonally expanded CD8+T-cells and was abundant on antigen-experienced, tissue-resident memory CD8+T-cell and T-regulatory subsets. TIGIT ligands PVR, NECTIN1, and NECTIN2 were abundant on mature regulatory dendritic cells (DCs), immunosuppressive plasmacytoid (p)DCs, and macrophages, respectively. TIGIT and PD-1 co-blockade in the mEER syngeneic murine model significantly reduced tumor growth, improved survival, restored effector function of HPV16E7-specific CD8+T cells, natural killer cells, and DCs, and conferred tumor re-challenge protection.ConclusionsTIGIT-PVR/NECTIN receptors/ligands are more abundant than PD-1/L1 in the TIME of HPV+ HNSCC. Co-blockade of TIGIT and PD-1 immune checkpoints enhanced anti-tumor efficacy in a CD8+ T-cell-dependent manner and conferred long-term immune protection in a murine model. Our study nominates TIGIT as a therapeutic target for HPV+ HNSCC.

scholarly journals APOBEC3-Mediated RNA Editing in Breast Cancer is Associated with Heightened Immune Activity and Improved Survival

2019 ◽  
Vol 20 (22) ◽  
pp. 5621 ◽  
Author(s):  
Mariko Asaoka ◽  
Takashi Ishikawa ◽  
Kazuaki Takabe ◽  
Santosh K. Patnaik
Keyword(s):  
Breast Cancer ◽  
T Cell ◽  
Rna Editing ◽  
Cell Receptor ◽  
Cytolytic Activity ◽  
Sequencing Data ◽  
Immune Activity ◽  
Normal Tissues ◽  
Gene Sets ◽  
M1 Macrophage

APOBEC3 enzymes contribute significantly to DNA mutagenesis in cancer. These enzymes are also capable of converting C bases at specific positions of RNAs to U. However, the prevalence and significance of this C-to-U RNA editing in any cancer is currently unknown. We developed a bioinformatics workflow to determine RNA editing levels at known APOBEC3-mediated RNA editing sites using exome and mRNA sequencing data of 1040 breast cancer tumors. Although reliable editing determinations were limited due to sequencing depth, editing was observed in both tumor and adjacent normal tissues. For 440 sites (411 genes), editing was determinable for ≥5 tumors, with editing occurring in 0.6%–100% of tumors (mean 20%, SD 14%) at an average level of 0.6%–20% (mean 7%, SD 4%). Compared to tumors with low RNA editing, editing-high tumors had enriched expression of immune-related gene sets, and higher T cell and M1 macrophage infiltration, B and T cell receptor diversity, and immune cytolytic activity. Concordant with this, patients with increased RNA editing in tumors had better disease- and progression-free survivals (hazard ratio = 1.67–1.75, p < 0.05). Our study identifies that APOBEC3-mediated RNA editing occurs in breast cancer tumors and is positively associated with elevated immune activity and improved survival.

scholarly journals LIFR inhibition enhances the therapeutic efficacy of HDAC inhibitors in triple negative breast cancer

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Mengxing Li ◽  
Suryavathi Viswanadhapalli ◽  
Bindu Santhamma ◽  
Uday P. Pratap ◽  
Yiliao Luo ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Therapeutic Efficacy ◽  
Histone Deacetylase Inhibitors ◽  
Triple Negative ◽  
Hdac Inhibitors ◽  
Rna Seq ◽  
Leukemia Inhibitory Factor Receptor ◽  
Targeted Inhibition

AbstractHistone deacetylase inhibitors (HDACi) are identified as novel therapeutic agents, however, recent clinical studies suggested that they are marginally effective in treating triple negative breast cancer (TNBC). Here, we show that first-in-class Leukemia Inhibitory Factor Receptor (LIFRα) inhibitor EC359 could enhance the therapeutic efficacy of HDACi against TNBC. We observed that both targeted knockdown of LIFR with CRISPR or treatment with EC359 enhanced the potency of four different HDACi in reducing cell viability, cell survival, and enhanced apoptosis compared to monotherapy in TNBC cells. RNA-seq studies demonstrated oncogenic/survival signaling pathways activated by HDACi were attenuated by the EC359 + HDACi therapy. Importantly, combination therapy potently inhibited the growth of TNBC patient derived explants, cell derived xenografts and patient-derived xenografts in vivo. Collectively, our results suggest that targeted inhibition of LIFR can enhance the therapeutic efficacy of HDACi in TNBC.

scholarly journals Genomic Features of Rapid Versus Late Relapse in Triple Negative Breast Cancer 

2021 ◽  
Author(s):  
Yiqing Zhang ◽  
Sarah Asad ◽  
Zachary Weber ◽  
David Tallman ◽  
William Nock ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Logistic Regression ◽  
T Cell ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Late Relapse ◽  
Primary Tumors ◽  
Genomic Features ◽  
Immune Signatures ◽  
M1 Macrophage

Abstract Background: Triple-negative breast cancer (TNBC) is a heterogeneous disease and we have previously shown that rapid relapse of TNBC is associated with distinct sociodemographic features. We hypothesized that rapid versus late relapse in TNBC is also defined by distinct clinical and genomic features of primary tumors.Methods: Using three publicly-available datasets, we identified 453 patients diagnosed with primary TNBC with adequate follow-up to be characterized as ‘rapid relapse’ (rrTNBC; relapse/death ≤2 years of diagnosis), ‘late relapse’ (lrTNBC; >2 years) or ‘no relapse’ (nrTNBC: >5 years no relapse/death). We explored basic clinical and primary tumor multi-omic data, including whole transcriptome (n=453), and whole genome copy number and mutation data for 171 cancer-related genes (n=317). Association of rapid relapse with clinical and genomic features were assessed using Pearson chi-squared tests, t-tests, ANOVA, and Fisher exact tests. We evaluated logistic regression models of clinical features with subtype versus two models that integrated significant genomic features.Results: Relative to nrTNBC, both rrTNBC and lrTNBC had significantly lower immune signatures and immune signatures were highly correlated to anti-tumor CD8 T-cell, M1 macrophage, and gamma-delta T-cell CIBERSORT inferred immune subsets. Intriguingly, lrTNBCs were enriched for luminal signatures. There was no difference in tumor mutation burden or percent genome altered across groups. Logistic regression mModels that incorporate genomic features significantly outperformed standard clinical/subtype models in training (n=63 patients), testing (n=63) and independent validation (n=34) cohorts, although performance of all models were overall modest. Conclusions: We identify clinical and genomic features associated with rapid relapse TNBC for further study of this aggressive TNBC subset.

scholarly journals Differential methylation relative to breast cancer subtype and matched normal tissue reveals distinct patterns

2013 ◽  
Vol 142 (2) ◽  
pp. 365-380 ◽  
Author(s):  
Sabrina A. Bardowell ◽  
Joel Parker ◽  
Cheng Fan ◽  
Jamie Crandell ◽  
Charles M. Perou ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Normal Tissue ◽  
Breast Cancer Subtype ◽  
Differential Methylation ◽  
Matched Normal Tissue ◽  
Cancer Subtype

scholarly journals Genomic features of rapid versus late relapse in triple negative breast cancer

BMC Cancer ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Yiqing Zhang ◽  
Sarah Asad ◽  
Zachary Weber ◽  
David Tallman ◽  
William Nock ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Logistic Regression ◽  
T Cell ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Late Relapse ◽  
Primary Tumors ◽  
Genomic Features ◽  
Immune Signatures ◽  
M1 Macrophage

Abstract Background Triple-negative breast cancer (TNBC) is a heterogeneous disease and we have previously shown that rapid relapse of TNBC is associated with distinct sociodemographic features. We hypothesized that rapid versus late relapse in TNBC is also defined by distinct clinical and genomic features of primary tumors. Methods Using three publicly-available datasets, we identified 453 patients diagnosed with primary TNBC with adequate follow-up to be characterized as ‘rapid relapse’ (rrTNBC; distant relapse or death ≤2 years of diagnosis), ‘late relapse’ (lrTNBC; > 2 years) or ‘no relapse’ (nrTNBC: > 5 years no relapse/death). We explored basic clinical and primary tumor multi-omic data, including whole transcriptome (n = 453), and whole genome copy number and mutation data for 171 cancer-related genes (n = 317). Association of rapid relapse with clinical and genomic features were assessed using Pearson chi-squared tests, t-tests, ANOVA, and Fisher exact tests. We evaluated logistic regression models of clinical features with subtype versus two models that integrated significant genomic features. Results Relative to nrTNBC, both rrTNBC and lrTNBC had significantly lower immune signatures and immune signatures were highly correlated to anti-tumor CD8 T-cell, M1 macrophage, and gamma-delta T-cell CIBERSORT inferred immune subsets. Intriguingly, lrTNBCs were enriched for luminal signatures. There was no difference in tumor mutation burden or percent genome altered across groups. Logistic regression mModels that incorporate genomic features significantly outperformed standard clinical/subtype models in training (n = 63 patients), testing (n = 63) and independent validation (n = 34) cohorts, although performance of all models were overall modest. Conclusions We identify clinical and genomic features associated with rapid relapse TNBC for further study of this aggressive TNBC subset.

scholarly journals ADCY2, ADCY5, and GRIA1 are the key genes of cAMP signaling pathway to participate in osteoporotic peripheral and spinal fracture after the manipulation of Wnt signaling

2020 ◽  
Author(s):  
Xiaohua Zuo ◽  
Changdong Zhou ◽  
Xuepiao Zhu ◽  
Dan Liu ◽  
Yan Wang ◽  
...  
Keyword(s):  
Wnt Signaling ◽  
Signaling Pathway ◽  
Wnt Signaling Pathway ◽  
R Package ◽  
Spinal Fracture ◽  
Camp Signaling ◽  
Pathway Enrichment ◽  
Go Enrichment ◽  
Camp Signaling Pathway ◽  
Key Genes

Abstract Background Osteoporotic peripheral and spinal fracture, characterized by high morbidity and mortality, has become a health burden for the aging population. The inactivation of the Wnt signaling has been proved to promote osteoporotic fractures. Our study is to identify the key genes, miRNAs, and pathways that possibly lead to osteoporosis and osteoporotic peripheral and spinal fracture after the aberrant activation or mutation of Wnt signaling pathway. Methods Impute R package was used to screen out the differently expressed genes (DEGs) and differently expressed miRNAs in GEO datasets. STRING and Metascape were used to construct protein-protein interactions (PPI) network, gene ontology (GO) enrichment and pathway enrichment. Results 562 DEGs were screened out using Impute R package, and a PPI network involving the 562 DEGs was constructed using STRING and Metascape. GO enrichment and pathway enrichment showed that the 562 DEGs were associated with membrane protein-related signaling pathways. Then, 75 genes between the target genes of miR-18a-3p and 562 DEGs were overlapped using Venny 2.1.0. Finally, the cAMP signaling pathway was identified as the key pathway, whilst ADCY2, ADCY5, and GRIA1 were identified the key genes that possibly participate in osteoporotic peripheral and spinal fracture after the manipulation of Wnt signaling pathway. Conclusions The results demonstrated that ADCY2, ADCY5, and GRIA1 were the key genes to regulate the cAMP signaling pathway in osteoporotic peripheral and spinal fracture after abnormal Wnt signaling.

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