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 Prognostic Role of Androgen Receptor in Triple Negative Breast Cancer: A Multi-Institutional Study

Cancers ◽  
2019 ◽  
Vol 11 (7) ◽  
pp. 995 ◽  
Author(s):  
Shristi Bhattarai ◽  
Sergey Klimov ◽  
Karuna Mittal ◽  
Uma Krishnamurti ◽  
Xiaoxian Li ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Androgen Receptor ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Molecular Subtype ◽  
Good Prognosis ◽  
Prognostic Role ◽  
Primary Tumors ◽  
Total N

Background: The androgen receptor (AR) has emerged as a potential therapeutic target for AR-positive triple-negative breast cancer (TNBC). However, conflicting reports regarding AR’s prognostic role in TNBC are putting its usefulness in question. Some studies conclude that AR positivity indicates a good prognosis in TNBC, whereas others suggest the opposite, and some show that AR status has no significant bearing on the patients’ prognosis. Methods: We evaluated the prognostic value of AR in resected primary tumors from TNBC patients from six international cohorts {US (n = 420), UK (n = 239), Norway (n = 104), Ireland (n = 222), Nigeria (n = 180), and India (n = 242); total n = 1407}. All TNBC samples were stained with the same anti-AR antibody using the same immunohistochemistry protocol, and samples with ≥1% of AR-positive nuclei were deemed AR-positive TNBCs. Results: AR status shows population-specific patterns of association with patients’ overall survival after controlling for age, grade, population, and chemotherapy. We found AR-positive status to be a marker of good prognosis in US and Nigerian cohorts, a marker of poor prognosis in Norway, Ireland and Indian cohorts, and neutral in UK cohort. Conclusion: AR status, on its own, is not a reliable prognostic marker. More research to investigate molecular subtype composition among the different cohorts is warranted.

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 Multiple Molecular Subtypes of Triple-Negative Breast Cancer Critically Rely on Androgen Receptor and Respond to Enzalutamide In Vivo

2015 ◽  
Vol 14 (3) ◽  
pp. 769-778 ◽  
Author(s):  
Valerie N. Barton ◽  
Nicholas C. D'Amato ◽  
Michael A. Gordon ◽  
Hanne T. Lind ◽  
Nicole S. Spoelstra ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Androgen Receptor ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Molecular Subtypes

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.

scholarly journals Tumor microenvironment in triple-negative breast cancer: the correlation of tumor-associated macrophages and tumor-infiltrating lymphocytes

2021 ◽  
Author(s):  
H. Kuroda ◽  
T. Jamiyan ◽  
R. Yamaguchi ◽  
A. Kakumoto ◽  
A. Abe ◽  
...  
Keyword(s):  
Breast Cancer ◽  
T Cells ◽  
Tumor Microenvironment ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Cytotoxic T Cells ◽  
Tumor Infiltrating Lymphocytes ◽  
Tumor Associated Macrophages ◽  
Free Survival ◽  
Infiltrating Lymphocytes

Abstract Purpose Immune cells such as cytotoxic T cells, helper T cells, B cells or tumor-associated macrophages (TAMs) contribute to the anti-tumor response or pro-tumorigenic effect in triple negative breast cancer (TNBC). The interrelation of TAMs, T and B tumor-infiltrating lymphocytes (TILs) in TNBC has not been fully elucidated. Methods We evaluated the association of tumor-associated macrophages, T and B TILs in TNBC. Results TNBCs with a high CD68+, CD163+ TAMs and low CD4+, CD8+, CD20+ TILs had a significantly shorter relapse-free survival (RFS) and overall survival (OS) than those with low CD68+, CD163+ TAMs and high CD4+, CD8+, CD20+ TILs. TNBCs with high CD68+ TAMs/low CD8+ TILs showed a significantly shorter RFS and OS and a significantly poorer prognosis than those with high CD68+ TAMs/high CD8+ TILs, low CD68+ TAMs/high CD8+ TILs, and low CD68+/low CD8+. TNBCs with high CD163+ TAMs/low CD8+, low CD20 + TILs showed a significantly shorter RFS and OS and a significantly poorer prognosis than those with high CD163+ TAMs/high CD8+ TILs and high CD163+ TAMs /high CD20+ TILs. Conclusions Our study suggests that TAMs further create an optimal tumor microenvironment (TME) for growth and invasion of cancer cells when evasion of immunoreactions due to T and B TILs occurs. In TNBCs, all these events combine to affect prognosis. The process of TME is highly complex in TNBCs and for an improved understanding, larger validation studies are necessary to confirm these findings.

scholarly journals Antiproliferative Effect of Androgen Receptor Inhibition in Mesenchymal Stem-Like Triple-Negative Breast Cancer

2016 ◽  
Vol 38 (3) ◽  
pp. 1003-1014 ◽  
Author(s):  
Aiyu Zhu ◽  
Yan Li ◽  
Wei Song ◽  
Yumei Xu ◽  
Fang Yang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Androgen Receptor ◽  
Cyclin D1 ◽  
Cancer Cells ◽  
Triple Negative Breast Cancer ◽  
Breast Cancer Cells ◽  
Triple Negative

Background/Aims: Androgen receptor (AR), a steroid hormone receptor, has recently emerged as prognostic and treatment-predictive marker in breast cancer. Previous studies have shown that AR is widely expressed in up to one-third of triple-negative breast cancer (TNBC). However, the role of AR in TNBC is still not fully understood, especially in mesenchymal stem-like (MSL) TNBC cells. Methods: MSL TNBC MDA-MB-231 and Hs578T breast cancer cells were exposed to various concentration of agonist 5-α-dihydrotestosterone (DHT) or nonsteroidal antagonist bicalutamide or untreated. The effects of AR on cell viability and apoptosis were determined by MTT assay, cell counting, flow cytometry analysis and protein expression of p53, p73, p21 and Cyclin D1 were analyzed by western blotting. The bindings of AR to p73 and p21 promoter were detected by ChIP assay. MDA-MB-231 cells were transplanted into nude mice and the tumor growth curves were determined and expression of AR, p73 and p21 were detected by Immunohistochemistry (IHC) staining after treatment of DHT or bicalutamide. Results: We demonstrate that AR agonist DHT induces MSL TNBC breast cancer cells proliferation and inhibits apoptosis in vitro. Similarly, activated AR significantly increases viability of MDA-MB-231 xenografts in vivo. On the contrary, AR antagonist, bicalutamide, causes apoptosis and exerts inhibitory effects on the growth of breast cancer. Moreover, DHT-dependent activation of AR involves regulation in the cell cycle related genes, including p73, p21 and Cyclin D1. Further investigations indicate the modulation of AR on p73 and p21 mediated by direct binding of AR to their promoters, and DHT could make these binding more effectively. Conclusions: Our study demonstrates the tumorigenesis role of AR and the inhibitory effect of bicalutamide in AR-positive MSL TNBC both in vitro and in vivo, suggesting that AR inhibition could be a potential therapeutic approach for AR-positive TNBC patients.

scholarly journals Tumor Microenvironment: Key Players in Triple Negative Breast Cancer Immunomodulation

Cancers ◽  
2021 ◽  
Vol 13 (13) ◽  
pp. 3357
Author(s):  
Hongmei Zheng ◽  
Sumit Siddharth ◽  
Sheetal Parida ◽  
Xinhong Wu ◽  
Dipali Sharma
Keyword(s):  
Breast Cancer ◽  
Tumor Microenvironment ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Treatment Options ◽  
Combined Treatment ◽  
High Mobility ◽  
Sphingosine 1 Phosphate ◽  
Molecular Patterns

Triple negative breast cancer (TNBC) is a heterogeneous disease and is highly related to immunomodulation. As we know, the most effective approach to treat TNBC so far is still chemotherapy. Chemotherapy can induce immunogenic cell death, release of damage-associated molecular patterns (DAMPs), and tumor microenvironment (TME) remodeling; therefore, it will be interesting to investigate the relationship between chemotherapy-induced TME changes and TNBC immunomodulation. In this review, we focus on the immunosuppressive and immunoreactive role of TME in TNBC immunomodulation and the contribution of TME constituents to TNBC subtype classification. Further, we also discuss the role of chemotherapy-induced TME remodeling in modulating TNBC immune response and tumor progression with emphasis on DAMPs-associated molecules including high mobility group box1 (HMGB1), exosomes, and sphingosine-1-phosphate receptor 1 (S1PR1), which may provide us with new clues to explore effective combined treatment options for TNBC.

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