scholarly journals Immune Cell Infiltration-Based Characterization of Triple-Negative Breast Cancer Predicts Prognosis and Chemotherapy Response Markers

2021 ◽  
Vol 12 ◽  
Author(s):  
Yufei Lv ◽  
Dongxu Lv ◽  
Xiaohong Lv ◽  
Ping Xing ◽  
Jianguo Zhang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumor Microenvironment ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Molecular Subtype ◽  
Expression Profiles ◽  
Cancer Prognosis ◽  
Functional Enrichment ◽  
Prognostic Biomarkers ◽  
Chemotherapy Response

Breast cancer represents the number one cause of cancer-associated mortality globally. The most aggressive molecular subtype is triple negative breast cancer (TNBC), of which limited therapeutic options are available. It is well known that breast cancer prognosis and tumor sensitivity toward immunotherapy are dictated by the tumor microenvironment. Breast cancer gene expression profiles were extracted from the METABRIC dataset and two TNBC clusters displaying unique immune features were identified. Activated immune cells formed a large proportion of cells in the high infiltration cluster, which correlated to a good prognosis. Differentially expressed genes (DEGs) extracted between two heterogeneous subtypes were used to further explore the underlying immune mechanism and to identify prognostic biomarkers. Functional enrichment analysis revealed that the DEGs were predominately related to some processes involved in activation and regulation of innate immune signaling. Using network analysis, we identified two modules in which genes were selected for further prognostic investigation. Validation by independent datasets revealed that CXCL9 and CXCL13 were good prognostic biomarkers for TNBC. We also performed comparisons between the above two genes and immune markers (CYT, APM, TILs, and TIS), as well as cell checkpoint marker expressions, and found a statistically significant correlation between them in both METABRIC and TCGA datasets. The potential of CXCL9 and CXCL13 to predict chemotherapy sensitivity was also evaluated. We found that the CXCL9 and CXCL13 were good predictors for chemotherapy and their expressions were higher in chemotherapy-responsive patients in contrast to those who were not responsive. In brief, immune infiltrate characterization on TNBC revealed heterogeneous subtypes with unique immune features allowed for the identification of informative and reliable characteristics representative of the local immune tumor microenvironment and were potential candidates to guide the management of TNBC patients.

scholarly journals Identification of Key Genes Affecting the Tumor Microenvironment and Prognosis of Triple-Negative Breast Cancer

2021 ◽  
Vol 11 ◽  
Author(s):  
Jiarong Yi ◽  
Wenjing Zhong ◽  
Haoming Wu ◽  
Jikun Feng ◽  
Xiazi Zouxu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumor Microenvironment ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Enrichment Analysis ◽  
Functional Enrichment Analysis ◽  
The Cancer Genome Atlas ◽  
Functional Enrichment ◽  
Ppi Network ◽  
Key Genes

Although the tumor microenvironment (TME) plays an important role in the development of many cancers, its roles in breast cancer, especially triple-negative breast cancer (TNBC), are not well studied. This study aimed to identify genes related to the TME and prognosis of TNBC. Firstly, we identified differentially expressed genes (DEG) in the TME of TNBC, using Expression data (ESTIMATE) datasets obtained from the Cancer Genome Atlas (TCGA) and Estimation of Stromal and Immune cells in Malignant Tumor tissues. Next, survival analysis was performed to analyze the relationship between TME and prognosis of TNBC, as well as determine DEGs. Genes showing significant differences were scored as alternative genes. A protein-protein interaction (PPI) network was constructed and functional enrichment analysis conducted using the DEG. Proteins with a degree greater than 5 and 10 in the PPI network correspond with hub genes and key genes, respectively. Finally, CCR2 and CCR5 were identified as key genes in TME and prognosis of TNBC. Finally, these results were verified using Gene Expression Omnibus (GEO) datasets and immunohistochemistry of TNBC patients. In conclusion, CCR2 and CCR5 are key genes in the TME and prognosis of TNBC with the potential of prognostic biomarkers in TNBC.

scholarly journals Analysis of gene expression patterns in triple negative breast cancer: MERTK and WHSC1L1.

2021 ◽  
Author(s):  
Shahan Mamoor
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Black Women ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Molecular Subtype ◽  
Expression Profiles ◽  
Expression Patterns ◽  
Gene Expression Profiles ◽  
Primary Tumors

Triple negative breast cancer (TNBC) shares overlap with the basal molecular subtype of breast cancer and is more frequently diagnosed in African-American (black) women for reasons not understood (1,2). To understand genes whose expression may be of pertinence to the development or progression of triple negative breast cancer, we mined published microarray data (3,4) comparing global gene expression profiles of TNBC histology groups, identifying genes whose expression changed the least between among TNBCs, suggesting that these genes may be important for TNBC biology. We identified the MER proto-oncogene tyrosine kinase MERTK and the Wolf-Hirschhorn syndrome candidate 1-like 1 WHSC1L1 among the genes whose expression differed the least when comparing TNBC cases and subtypes. In another dataset, MERTK and WHSCL1 were found to be differentially expressed in TNBC when comparing primary tumors of the breast to normal breast tissue. Kaplan-Meier survival analysis revealed that expression levels of MERTK and WHSCL1 correlated with survival outcomes in human breast cancer, and that this correlation differed based on race of the patient. MERTK and WHSCL1 may be of relevance in understanding the etiology or progression of triple negative breast cancer.

scholarly journals Unraveling Triple-Negative Breast Cancer Tumor Microenvironment Heterogeneity: Towards an Optimized Treatment Approach

2019 ◽  
Vol 112 (7) ◽  
pp. 708-719 ◽  
Author(s):  
Yacine Bareche ◽  
Laurence Buisseret ◽  
Tina Gruosso ◽  
Edwina Girard ◽  
David Venet ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Androgen Receptor ◽  
Tumor Microenvironment ◽  
Spatial Pattern ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Molecular Subtypes ◽  
Molecular Subtype ◽  
Statistical Tests ◽  
Copy Number Loss

Abstract Background Recent efforts of gene expression profiling analyses recognized at least four different triple-negative breast cancer (TNBC) molecular subtypes. However, little is known regarding their tumor microenvironment (TME) heterogeneity. Methods Here, we investigated TME heterogeneity within each TNBC molecular subtype, including immune infiltrate localization and composition together with expression of targetable immune pathways, using publicly available transcriptomic and genomic datasets from a large TNBC series totaling 1512 samples. Associations between molecular subtypes and specific features were assessed using logistic regression models. All statistical tests were two-sided. Results We demonstrated that each TNBC molecular subtype exhibits distinct TME profiles associated with specific immune, vascularization, stroma, and metabolism biological processes together with specific immune composition and localization. The immunomodulatory subtype was associated with the highest expression of adaptive immune-related gene signatures and a fully inflamed spatial pattern appearing to be the optimal candidate for immune check point inhibitors. In contrast, most mesenchymal stem-like and luminal androgen receptor tumors showed an immunosuppressive phenotype as witnessed by high expression levels of stromal signatures. Basal-like, luminal androgen receptor, and mesenchymal subtypes exhibited an immune cold phenotype associated with stromal and metabolism TME signatures and enriched in margin-restricted spatial pattern. Tumors with high chromosomal instability and copy number loss in the chromosome 5q and 15q regions, including genomic loss of major histocompatibility complex related genes, showed reduced cytotoxic activity as a plausible immune escape mechanism. Conclusions Our results demonstrate that each TNBC subtype is associated with specific TME profiles, setting the ground for a rationale tailoring of immunotherapy in TNBC patients.

scholarly journals Exploration of Tumor Microenvironment-Related Biomarkers for the Prognosis of Triple Negative Breast Cancer

2021 ◽  
Author(s):  
Xiaorui Han ◽  
Zaiyi Liu ◽  
Changhong Liang
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Overall Survival ◽  
Tumor Microenvironment ◽  
Triple Negative Breast Cancer ◽  
Stromal Cells ◽  
Prognostic Model ◽  
Triple Negative ◽  
High Efficiency ◽  
Functional Enrichment

Abstract Background: Triple negative breast cancer (TNBC) is one of the most disastrous breast cancer subtypes world widely. The tumor microenvironment (TME), especially the infiltration of immune and stromal cells, are highly related to the occurrence, development and prognosis of breast cancer. Therefore, exploration of TME-related biomarkers is greatly important for improving overall survival rate of TNBC patients. Methods: The open-assess Cancer Genome Atlas (TCGA) database provides gene expression profile for a variety of malignant tumors allowing researchers to explore genes demonstrating TME in the prognosis prediction of TNBC. In our present study, ESTIMATE algorithm was used to calculate the immune and stromal scores in accordance with the characteristics of specific genes in immune and stromal cells, and divide them into high and low-score groups. Limma R package was then utilized to screen differentially expressed genes (DEGs). After that, functional enrichment analysis and protein-protein interaction (PPI) network were performed to explore the bio-information of the DEGs and their encoded proteins. Subsequently, the identified these genes were further verified in the Gene Expression Omnibus (GEO) datasets. Results: Eight genes, including ACAP1, DUSP1, LYZGZMA, SASH3, CCL5, CD74, and DPT, were explored to closely related to the TME of TNBC. A prognostic model containing these selected genes was established with a high efficiency in the prediction of the poor prognosis of TNBC patients.Conclusion: An eight-gene prognostic model was a considerably reliable approach for predicting the overall survival of TNBC patients, and could help clinicians selecting personalized treatments for their TNBC patients.

scholarly journals Analysis of gene expression patterns in triple negative breast cancer II: TNBC molecular subtype.

2021 ◽  
Author(s):  
Shahan Mamoor
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Black Women ◽  
Triple Negative Breast Cancer ◽  
Human Breast Cancer ◽  
Triple Negative ◽  
Molecular Subtype ◽  
Expression Profiles ◽  
Expression Patterns ◽  
Human Breast

Triple negative breast cancer (TNBC) shares overlap with the basal molecular subtype of breast cancer and is more frequently diagnosed in African-American (black) women for reasons not understood (1,2). To understand genes whose expression may be of pertinence to the development or progression of triple negative breast cancer, we mined published microarray data (3) comparing global gene expression profiles of TNBC molecular subtypes, identifying genes whose expression changed the least between among TNBCs, suggesting that these genes may be important for TNBC biology. We identified PVT1, PHC3, WNT8B, MLLT6, MSH3, IHH, and WNT2B among the genes whose expression differed the least when comparing TNBC cases and subtypes. Kaplan-Meier survival analysis revealed that expression levels of each of these genes correlated with survival outcomes in human breast cancer; in some cases, this correlation differed based on race of the patient, and in other cases, this correlation was found in the basal subtype of human breast cancer, which shares significant overlap with triple negative breast cancer at the level of gene expression (2). PVT1, PHC3, WNT8B, MLLT6, MSH3, IHH, and WNT2B may be of relevance in understanding the etiology or progression of triple negative breast cancer.

scholarly journals Expression of Phosphorylated BRD4 Is Markedly Associated with the Activation Status of the PP2A Pathway and Shows a Strong Prognostic Value in Triple Negative Breast Cancer Patients

Cancers ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 1246
Author(s):  
Marta Sanz-Álvarez ◽  
Ion Cristóbal ◽  
Melani Luque ◽  
Andrea Santos ◽  
Sandra Zazo ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Molecular Subtype ◽  
Molecular Target ◽  
Prognostic Impact ◽  
Breast Cancer Patients ◽  
Bet Inhibitors ◽  
Brd4 Inhibition ◽  
Bet Protein

The bromodomain-containing protein 4 (BRD4), a member of the bromodomain and extra-terminal domain (BET) protein family, has emerged in the last years as a promising molecular target in many tumors including breast cancer. The triple negative breast cancer (TNBC) represents the molecular subtype with the worst prognosis and a current therapeutic challenge, and TNBC cells have been reported to show a preferential sensitivity to BET inhibitors. Interestingly, BRD4 phosphorylation (pBRD4) was found as an alteration that confers resistance to BET inhibition and PP2A proposed as the phosphatase responsible to regulate pBRD4 levels. However, the potential clinical significance of pBRD4, as well as its potential correlation with the PP2A pathway in TNBC, remains to be investigated. Here, we evaluated the expression levels of pBRD4 in a series of 132 TNBC patients. We found high pBRD4 levels in 34.1% of cases (45/132), and this alteration was found to be associated with the development of patient recurrences (p = 0.007). Interestingly, BRD4 hyperphosphorylation predicted significantly shorter overall (p < 0.001) and event-free survival (p < 0.001). Moreover, multivariate analyses were performed to confirm its independent prognostic impact in our cohort. In conclusion, our findings show that BRD4 hyperphosphorylation is an alteration associated with PP2A inhibition that defines a subgroup of TNBC patients with unfavorable prognosis, suggesting the potential clinical and therapeutic usefulness of the PP2A/BRD4 axis as a novel molecular target to overcome resistance to treatments based on BRD4 inhibition.

Sign in / Sign up

Export Citation Format

Share Document