scholarly journals Hypoxia-Associated Prognostic Markers and Competing Endogenous RNA Co-Expression Networks in Breast Cancer

2020 ◽  
Vol 10 ◽  
Author(s):  
Peng-Ju Gong ◽  
You-Cheng Shao ◽  
Si-Rui Huang ◽  
Yi-Fan Zeng ◽  
Xiao-Ning Yuan ◽  
...  
Keyword(s):  
Breast Cancer ◽  
T Cell ◽  
Prognostic Markers ◽  
Immune Cell ◽  
Tumor Hypoxia ◽  
Gene Expression Signature ◽  
The Cancer Genome Atlas ◽  
Breast Cancer Patients ◽  
Related Gene ◽  
Primary Tumors

ObjectiveMany primary tumors have insufficient supply of molecular oxygen, called hypoxia. Hypoxia is one of the leading characteristics of solid tumors resulting in a higher risk of local failure and distant metastasis. It is quite necessary to investigate the hypoxia associated molecular hallmarks in breast cancer.Materials and MethodsAccording to the published studies, we selected 13 hypoxia related gene expression signature to define the hypoxia status of breast cancer using ConsensusClusterPlus package based on the data from The Cancer Genome Atlas (TCGA). Subsequently, we characterized the infiltration of 24 immune cell types under different hypoxic conditions. Furthermore, the differentially expressed hypoxia associated microRNAs, mRNAs and related signaling pathways were analyzed and depicted. On this basis, a series of prognostic markers related to hypoxia were identified and ceRNA co-expression networks were constructed.ResultsTwo subgroups (cluster1 and cluster2) were identified and the 13 hypoxia related gene signature were all up-regulated in cluster1. Thus, we defined the cluster1 as “hypoxic subgroup” compared with cluster2. The infiltration of CD8+ T cell and CD4+ T cell were lower in cluster1 while the nTreg cell and iTreg cell were higher, indicating that there was immunosuppressive status in cluster1. We observed widespread hypoxia-associated dysregulation of microRNAs and mRNAs. Next, a risk signature for predicting prognosis of breast cancer patients was established based on 12 dysregulated hypoxia associated prognostic genes. Two microRNAs, hsa-miR-210-3p and hsa-miR-190b, with the most significant absolute logFC value were related to unfavorable and better prognosis, respectively. Several long non-coding RNAs were predicted to be microRNA targets and positively correlated with two selected mRNAs, CPEB2 and BCL11A. Predictions based on the SNHG16-hsa-miR-210-3p-CPEB2 and LINC00899/PSMG3-AS1/PAXIP-AS1-hsa-miR-190b-BCL11A ceRNA regulation networks indicated that the two genes might act as tumor suppressor and oncogene, respectively.ConclusionHypoxia plays an important role in the initiation and progression of breast cancer. Our research provides potential mechanisms into molecular-level understanding of tumor hypoxia.

Co‑expression Network Analysis by WGCNA and Identify Potential Prognostic Markers Associated with Lung Metastasis in Breast Cancer

2021 ◽  
Author(s):  
xixun zhang
Keyword(s):  
Breast Cancer ◽  
Network Analysis ◽  
Lung Metastasis ◽  
Prognostic Markers ◽  
Clinical Information ◽  
Preventive Treatment ◽  
The Cancer Genome Atlas ◽  
Functional Enrichment ◽  
Breast Cancer Patients ◽  
Kaplan Meier

Abstract Backgroud: Breast cancer (BC) is an aggressive cancer with a high percentage recurrence and metastasis. As one of the most common distant metastasis organ in breast cancer, lung metastasis has a worse prognosis than that of liver and bone. Therefore, it’s important to explore some potential prognostic markers associated with the lung metastasis in breast cancer for preventive treatment. Methods: In our study, transcriptomic data and clinical information of breast cancer patients were downloaded from The Cancer Genome Atlas (TCGA) database. Co-expression modules was built by Weighted gene co-expression network analysis (WGCNA) to find out the royalbule modules which is significantly associated with lung metastasis in breast cancer. Then, co-expression genes were analyzed for functional enrichment. Furthermore, the prognostic value of these genes was assessed by GEPIA Database and Kaplan-Meier Plotter. Results: Results showed that the hub genes, LMNB and CDC20, were up-regulated in breast cancer and indicated worse survival. Therefore, we speculate that these two genes play crucial roles in the process of lung metastasis in breast cancer, and can be used as potential prognostic markers in lung metastasis of breast cancer. Conclusion: Collectively, our study identified two potential key genes in the lung metastasis of breast cancer, which might be applied as the prognostic markers of the precise treatment in breast cancer with lung metastasis.

scholarly journals Heterogeneity of Circulating Tumor Cell Neoplastic Subpopulations Outlined by Single-Cell Transcriptomics

Cancers ◽  
2021 ◽  
Vol 13 (19) ◽  
pp. 4885
Author(s):  
Christine M. Pauken ◽  
Shelby Ray Kenney ◽  
Kathryn J. Brayer ◽  
Yan Guo ◽  
Ursa A. Brown-Glaberman ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Single Cell ◽  
Immune Cell ◽  
Metastatic Breast ◽  
Gene Expression Signature ◽  
Circulating Tumor Cell ◽  
Therapeutic Interventions ◽  
Cell Populations ◽  
Breast Cancer Patients ◽  
The Common

Fatal metastasis occurs when circulating tumor cells (CTCs) disperse through the blood to initiate a new tumor at specific sites distant from the primary tumor. CTCs have been classically defined as nucleated cells positive for epithelial cell adhesion molecule and select cytokeratins (EpCAM/CK/DAPI), while negative for the common lymphocyte marker CD45. The enumeration of CTCs allows an estimation of the overall metastatic burden in breast cancer patients, but challenges regarding CTC heterogeneity and metastatic propensities persist, and their decryption could improve therapies. CTCs from metastatic breast cancer (mBC) patients were captured using the RareCyteTM Cytefinder II platform. The Lin− and Lin+ (CD45+) cell populations isolated from the blood of three of these mBC patients were analyzed by single-cell transcriptomic methods, which identified a variety of immune cell populations and a cluster of cells with a distinct gene expression signature, which includes both cells expressing EpCAM/CK (“classic” CTCs) and cells possessing an array of genes not previously associated with CTCs. This study put forward notions that the identification of these genes and their interactions will promote novel areas of analysis by dissecting properties underlying CTC survival, proliferation, and interaction with circulatory immune cells. It improves upon capabilities to measure and interfere with CTCs for impactful therapeutic interventions.

scholarly journals Abundance of Regulatory T Cell (Treg) as a Predictive Biomarker for Neoadjuvant Chemotherapy in Triple-Negative Breast Cancer

Cancers ◽  
2020 ◽  
Vol 12 (10) ◽  
pp. 3038 ◽  
Author(s):  
Masanori Oshi ◽  
Mariko Asaoka ◽  
Yoshihisa Tokumaru ◽  
Fernando A. Angarita ◽  
Li Yan ◽  
...  
Keyword(s):  
Breast Cancer ◽  
T Cell ◽  
Neoadjuvant Chemotherapy ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Tumor Infiltrating Lymphocytes ◽  
Predictive Biomarker ◽  
Breast Cancer Patients ◽  
Primary Tumors ◽  
Cancer Aggressiveness

Regulatory CD4+ T cell (Treg), a subset of tumor-infiltrating lymphocytes (TILs), are known to suppress anticancer immunity but its clinical relevance in human breast cancer remains unclear. In this study, we estimated the relative abundance of Tregs in breast cancer of multiple patient cohorts by using the xCell algorithm on bulk tumor gene expression data. In total, 5177 breast cancer patients from five independent cohorts (TCGA-BRCA, GSE96058, GSE25066, GSE20194, and GSE110590) were analyzed. Treg abundance was not associated with cancer aggressiveness, patient survival, or immune activity markers, but it was lower in metastatic tumors when compared to matched primary tumors. Treg was associated with a high mutation rate of TP53 genes and copy number mutations as well as with increased tumor infiltration of M2 macrophages and decreased infiltration of T helper type 1 (Th1) cells. Pathological complete response (pCR) after neoadjuvant chemotherapy (NAC) was significantly associated with low Treg abundance in triple negative breast cancer (TNBC) but not in ER-positive/Her2-negative subtype. High Treg abundance was significantly associated with high tumor expression of multiple immune checkpoint inhibitor genes. In conclusion, Treg abundance may have potential as a predictive biomarker of pCR after NAC in TNBC.

scholarly journals Gene Signatures and Cancer-Immune Phenotypes Based on m6A Regulators in Breast Cancer

2021 ◽  
Vol 11 ◽  
Author(s):  
Guanghui Zhao ◽  
Junhua An ◽  
Qian Pu ◽  
Wenwen Geng ◽  
Haiyun Song ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Immune Cell ◽  
The Cancer Genome Atlas ◽  
Cell Infiltration ◽  
Clinical Samples ◽  
Immune Cell Infiltration ◽  
Breast Cancer Patients ◽  
Gene Signatures ◽  
Immune Phenotypes ◽  
Processing Stability

The N6-methyladenosine (m6A) has been considered as a new layer of epitranscriptomic regulation on mRNA processing, stability, and translation. However, potential roles of m6A RNA methylation modification in tumor immune microenvironment (TIME) of breast cancer are yet fully understood. In this study, we comprehensively evaluated the genetic variations and transcript expressions of 15 m6A regulators in 1,079 breast cancer samples from the Cancer Genome Atlas (TCGA) database. We validated major regulators had significantly differential mRNA and protein expression in tumor tissue compared to normal tissues from 39 pairs of clinical breast cancer samples with different molecular subtypes, and especially high expression of m6A readers YTHDF1 and YTHDF3 predicted poor survival. Two clusters of breast cancer patients identified by the 15 m6A regulators’ pattern showed distinct overall survival, immune activation status, and immune cell infiltration, and clinical samples confirmed the diversity of lymphocytic infiltration. The profiles of these two clusters accorded with that of two classical cancer-immune phenotypes, immune-excluded and immune-inflamed phenotypes, it suggested that m6A regulators-based patterns might serve as crucial mediators of TIME in breast cancer. Moreover, the m6A phenotype-related gene signatures could also be survival predictor in breast cancer. Therefore, comprehensive evaluation of tumor m6A modification pattern will contribute to enhance our understanding of the characterization of immune cell infiltration in the tumor microenvironment and promote the responsiveness of breast cancer to immunotherapy.

scholarly journals Identifies Immune-Related Gene Pair Signature Associated with Breast Cancer Prognosis

2021 ◽  
Author(s):  
Tianwei Sun ◽  
Qixing Tan ◽  
Changyuan Wei
Keyword(s):  
Breast Cancer ◽  
Cancer Patients ◽  
Gene Pair ◽  
The Cancer Genome Atlas ◽  
Cancer Prognosis ◽  
Future Research ◽  
Breast Cancer Patients ◽  
Related Gene ◽  
Immune Related Gene ◽  
Immune Related Genes

Abstract Background: Breast cancer (BC) is the cancer with the largest number of deaths in women. There is growing evidence that immunity plays an important role in the prognosis of breast cancer. Methods: In this study, we developed and validated an immune-related gene pair signature (IRGPs) to predict the survival of breast cancer patients. Screening immune-related genes from The Cancer Genome Atlas (TCGA) database and the Gene Expression Omnibus (GEO) database for the construction of IRGPs, and patients with breast cancer in these two cohorts were assigned to low- and high- risk subgroups. Additionally, we used Kaplan-Meier survival analysis, univariate and multivariate Cox analysis to investigate IRGPs and their individualized prognostic characteristics, and analysis of immune cell infiltration in breast cancer. Results: A 47-IRGP signature was constructed from 2498 immune genes, which could significantly predict the overall survival (OS) of breast cancer patients in the TCGA and GEO cohorts. Immune infiltration analysis showed that a variety of immune cells are significantly related to the prognostic effects of IRGP characteristics in breast cancer patients, especially CD8+ T cells and macrophages. Conclusions: The IRGP signature constructed in this study can help determine the prognosis of breast cancer and provide new ideas and basis for future research on the role of immune-related genes in breast cancer patients.

scholarly journals TIGIT-related transcriptome profile and its association with tumor immune microenvironment in breast cancer

2021 ◽  
Vol 41 (3) ◽  
Author(s):  
Qin Zhang ◽  
Chaowei Gao ◽  
Jianqiang Shao ◽  
Zunyi Wang
Keyword(s):  
Breast Cancer ◽  
Immune Responses ◽  
Cancer Immunotherapy ◽  
Large Scale ◽  
Immune Cell ◽  
Molecular Taxonomy ◽  
The Cancer Genome Atlas ◽  
Immune Checkpoints ◽  
Breast Cancer Patients ◽  
Transcriptome Profile

Abstract Immune checkpoints are intensively investigated as targets in cancer immunotherapy. T-cell immunoreceptor with immunoglobulin (Ig) and ITIM domains (TIGIT) are recently emerging as a novel promising target in cancer immunotherapy. Herein, we systematically investigated TIGIT-related transcriptome profile and relevant clinical information derived from a total of 2994 breast cancer patients recorded in The Cancer Genome Atlas (TCGA) and Molecular Taxonomy of Breast Cancer International Consortium (METABRIC). We uncovered the relationship between TIGIT and major molecular and clinical characteristics in breast cancer. More importantly, we depicted the landscape of associations between TIGIT and other immune cell populations. Gene ontology analyses and Gene Set Variation Analysis (GSVA) of genes correlated with TIGIT revealed that TIGIT were mainly involved in immune responses and inflammatory activities. In summary, TIGIT expression was tightly related to the aggressiveness of breast cancer; TIGIT might manipulate anti-tumor immune responses by impacting not only T cells but also other immune cells. To the best of our knowledge, this is by far the most comprehensive and largest study characterizing the molecular and clinical features of TIGIT in breast cancer through large-scale transcriptome data.

scholarly journals The Immune Landscape of Breast Cancer: Strategies for Overcoming Immunotherapy Resistance

Cancers ◽  
2021 ◽  
Vol 13 (23) ◽  
pp. 6012
Author(s):  
Kuba Retecki ◽  
Milena Seweryn ◽  
Agnieszka Graczyk-Jarzynka ◽  
Malgorzata Bajor
Keyword(s):  
Breast Cancer ◽  
Immune Cell ◽  
Checkpoint Inhibitors ◽  
Tumor Infiltrating Lymphocytes ◽  
Breast Cancer Patients ◽  
Her2 Positive ◽  
Primary Tumors ◽  
Cell Therapies ◽  
Recent Developments ◽  
Immunosuppressive Tumor Microenvironment

Breast cancer (BC) has traditionally been considered to be not inherently immunogenic and insufficiently represented by immune cell infiltrates. Therefore, for a long time, it was thought that the immunotherapies targeting this type of cancer and its microenvironment were not justified and would not bring benefits for breast cancer patients. Nevertheless, to date, a considerable number of reports have indicated tumor-infiltrating lymphocytes (TILs) as a prognostic and clinically relevant biomarker in breast cancer. A high TILs expression has been demonstrated in primary tumors, of both, HER2-positive BC and triple-negative (TNBC), of patients before treatment, as well as after treatment with adjuvant and neoadjuvant chemotherapy. Another milestone was reached in advanced TNBC immunotherapy with the help of the immune checkpoint inhibitors directed against the PD-L1 molecule. Although those findings, together with the recent developments in chimeric antigen receptor T cell therapies, show immense promise for significant advancements in breast cancer treatments, there are still various obstacles to the optimal activity of immunotherapeutics in BC treatment. Of these, the immunosuppressive tumor microenvironment constitutes a key barrier that greatly hinders the success of immunotherapies in the most aggressive types of breast cancer, HER2-positive and TNBC. Therefore, the improvement of the current and the demand for the development of new immunotherapeutic strategies is strongly warranted.

scholarly journals Upregulation of Long Non-Coding RNA DRAIC Correlates with Adverse Features of Breast Cancer

2018 ◽  
Vol 4 (4) ◽  
pp. 39 ◽  
Author(s):  
Dan Zhao ◽  
Jin-Tang Dong
Keyword(s):  
Breast Cancer ◽  
Immune Cell ◽  
Growth Factor Receptor ◽  
The Cancer Genome Atlas ◽  
Her2 Status ◽  
Breast Cancer Patients ◽  
Non Coding Rna ◽  
Er Positive ◽  
Invasive Breast Carcinomas ◽  
Long Non Coding Rna

DRAIC (also known as LOC145837 and RP11-279F6.1), is a long non-coding RNA associated with several types of cancer including prostate cancer, lung cancer, and breast cancer. Its expression is elevated in tumor tissues compared to adjacent benign tissues in breast cancer patients and is regulated by estrogen treatment in breast cancer cells. In addition, expression analysis of DRAIC in more than 100 cell lines showed that DRAIC expression is high in luminal and basal subtypes compared to claudin low subtype, suggesting a prognostic value of DRAIC expression in breast cancer. In the present study, we analyzed DRAIC expression in 828 invasive breast carcinomas and 105 normal samples of RNA sequencing datasets from The Cancer Genome Atlas (TCGA) and found that DRAIC expression was correlated with estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) status, and is increased in cancerous tissues. Additionally, higher DRAIC expression was associated with poorer survival of patients, especially in ER positive breast cancer. DRAIC was also investigated in the Oncomine database and we found that DRAIC expression predicted patients’ response to paclitaxel and FEC as well as lapatinib, which are commonly used therapy options for breast cancer. Finally, DRAIC expression in breast cancer was negatively correlated with immune cell infiltration. These results reinforce the importance of DRAIC in breast cancer.

Role of CD8+ T-cell infiltration in breast tumors of Black women compared to White women.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e13608-e13608
Author(s):  
Yara Abdou ◽  
Kristopher Attwood ◽  
Song Yao ◽  
Ting-Yuan David Cheng ◽  
Elisa Bandera ◽  
...  
Keyword(s):  
Breast Cancer ◽  
T Cells ◽  
Black Women ◽  
T Cell ◽  
Cell Density ◽  
Immune Cell ◽  
Beta Blockers ◽  
Breast Cancer Patients ◽  
T Cell Infiltration ◽  
Black Patients

e13608 Background: Literature regarding racial differences in tumor immune responses in breast cancer remains sparse. To address this research gap, we assessed CD8+ T-cells in breast tumor samples from the Women’s Circle of Health Study (WCHS) population of predominantly Black breast cancer patients. We characterized and compared the density of CD8+ T cells, their prognostic value and their association with pharmacologic beta-blockers. Prior studies suggest that reducing adrenergic signaling through beta blockers can stimulate CD8+ T-cells. Methods: Tumor-infiltrating CD8+ T-cells were assessed by IHC staining of tissue microarray cores from 688 breast cancer patients, including 550 Blacks and 138 Whites. CD8+ T cells were scored with digital image analysis. Comparisons of demographic and clinical variables (including CD8+ T cell density) were made using the Mann-Whitney U or Kruskal-Wallis and Fisher’s exact tests. Associations with overall survival (OS) and disease-specific (DSS) survival were evaluated using the log-rank test of Cox regression. Analyses were performed in the overall sample and by disease sub-type. Results: Higher CD8+ T cell density was seen in Black women compared to White, with mean values of 756.2/mm2 and 292.4/mm2 respectively (p < 0.001). Within the overall population and in black women, CD8+ T cell density was significantly higher in younger patients, patients with high grade, and ER negative tumors. No significant associations were observed between CD8+ T cell density and OS or DSS. However, when stratified by subtype, Black patients with triple negative breast cancer and high CD8+ T cell density showed a trend towards improved OS in comparison to patients with low CD8+ T cell density (p = 0.065). 170 patients with information on beta blocker usage were analyzed. No significant associations were noted between CD8+ T cell density and beta blocker use. Conclusions: We observe a significantly higher CD8+ T cell density in Blacks compared to Whites, but this does not confer a survival advantage. Additionally, beta-blockers did not seem to enhance CD8+ T cell infiltration in tumors from Black patients. Our data raise the possibility that distinct mechanisms of immune cell action may occur in different racial groups. Future studies are needed to determine the functional properties of CD8+ T cells in Black women and to characterize additional immune cell subtypes that may also play a role.

scholarly journals MCM3 upregulation confers endocrine resistance in breast cancer and is a predictive marker of diminished tamoxifen benefit

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Sanne Løkkegaard ◽  
Daniel Elias ◽  
Carla L. Alves ◽  
Martin V. Bennetzen ◽  
Anne-Vibeke Lænkholm ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Cycle ◽  
Cancer Patients ◽  
Endocrine Therapy ◽  
Endocrine Resistance ◽  
Predictive Marker ◽  
Endocrine Treatment ◽  
Breast Cancer Patients ◽  
Minichromosome Maintenance ◽  
Primary Tumors

AbstractResistance to endocrine therapy in estrogen receptor-positive (ER+) breast cancer is a major clinical problem with poorly understood mechanisms. There is an unmet need for prognostic and predictive biomarkers to allow appropriate therapeutic targeting. We evaluated the mechanism by which minichromosome maintenance protein 3 (MCM3) influences endocrine resistance and its predictive/prognostic potential in ER+ breast cancer. We discovered that ER+ breast cancer cells survive tamoxifen and letrozole treatments through upregulation of minichromosome maintenance proteins (MCMs), including MCM3, which are key molecules in the cell cycle and DNA replication. Lowering MCM3 expression in endocrine-resistant cells restored drug sensitivity and altered phosphorylation of cell cycle regulators, including p53(Ser315,33), CHK1(Ser317), and cdc25b(Ser323), suggesting that the interaction of MCM3 with cell cycle proteins is an important mechanism of overcoming replicative stress and anti-proliferative effects of endocrine treatments. Interestingly, the MCM3 levels did not affect the efficacy of growth inhibitory by CDK4/6 inhibitors. Evaluation of MCM3 levels in primary tumors from four independent cohorts of breast cancer patients receiving adjuvant tamoxifen mono-therapy or no adjuvant treatment, including the Stockholm tamoxifen (STO-3) trial, showed MCM3 to be an independent prognostic marker adding information beyond Ki67. In addition, MCM3 was shown to be a predictive marker of response to endocrine treatment. Our study reveals a coordinated signaling network centered around MCM3 that limits response to endocrine therapy in ER+ breast cancer and identifies MCM3 as a clinically useful prognostic and predictive biomarker that allows personalized treatment of ER+ breast cancer patients.

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