scholarly journals Intratumoral Adipocyte-High Breast Cancer Enrich for Metastatic and Inflammation-Related Pathways but Associated with Less Cancer Cell Proliferation

2020 ◽  
Vol 21 (16) ◽  
pp. 5744 ◽  
Author(s):  
Yoshihisa Tokumaru ◽  
Masanori Oshi ◽  
Eriko Katsuta ◽  
Li Yan ◽  
Jing Li Huang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Proliferation ◽  
Cancer Progression ◽  
Cancer Biology ◽  
The Cancer Genome Atlas ◽  
Related Gene ◽  
Immune Microenvironment ◽  
Gene Sets ◽  
Tumor Immune Microenvironment ◽  
Er Positive

Cancer-associated adipocytes are known to cause inflammation, leading to cancer progression and metastasis. The clinicopathological and transcriptomic data from 2256 patients with breast cancer were obtained based on three cohorts: The Cancer Genome Atlas (TCGA), GSE25066, and a study by Yau et al. For the current study, we defined the adipocyte, which is calculated by utilizing a computational algorithm, xCell, as “intratumoral adipocyte”. These intratumoral adipocytes appropriately reflected mature adipocytes in a bulk tumor. The amount of intratumoral adipocytes demonstrated no relationship with survival. Intratumoral adipocyte-high tumors significantly enriched for metastasis and inflammation-related gene sets and are associated with a favorable tumor immune microenvironment, especially in the ER+/HER2- subtype. On the other hand, intratumoral adipocyte-low tumors significantly enriched for cell cycle and cell proliferation-related gene sets. Correspondingly, intratumoral adipocyte-low tumors are associated with advanced pathological grades and inversely correlated with MKI67 expression. In conclusion, a high amount of intratumoral adipocytes in breast cancer was associated with inflammation, metastatic pathways, cancer stemness, and favorable tumor immune microenvironment. However, a low amount of adipocytes was associated with a highly proliferative tumor in ER-positive breast cancer. This cancer biology may explain the reason why patient survival did not differ by the amount of adipocytes.

scholarly journals Adipogenesis in triple-negative breast cancer is associated with unfavorable tumor immune microenvironment and with worse survival

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Masanori Oshi ◽  
Yoshihisa Tokumaru ◽  
Fernando A. Angarita ◽  
Lan Lee ◽  
Li Yan ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Cancer Biology ◽  
Triple Negative ◽  
Chemotherapy Response ◽  
Related Gene ◽  
Immune Microenvironment ◽  
Gene Set ◽  
Gene Sets ◽  
Tumor Immune Microenvironment

AbstractCancer-associated adipocytes are known to cause inflammation; however, the role of adipogenesis, the formation of adipocytes, in breast cancer is unclear. We hypothesized that intra-tumoral adipogenesis reflects a different cancer biology than abundance of intra-tumoral adipocytes. The Molecular Signatures Database Hallmark adipogenesis gene set of gene set variant analysis was used to quantify adipogenesis. Total of 5,098 breast cancer patients in multiple cohorts (training; GSE96058 (n = 3273), validation; TCGA (n = 1069), treatment response; GSE25066 (n = 508) and GSE20194 (n = 248)) were analyzed. Adipogenesis did not correlate with abundance of adipocytes. Adipogenesis was significantly lower in triple negative breast cancer (TNBC). Elevated adipogenesis was significantly associated with worse survival in TNBC, but not in the other subtypes. High adipogenesis TNBC was significantly associated with low homologous recombination deficiency, but not with mutation load. High adipogenesis TNBC enriched metabolism-related gene sets, but neither of cell proliferation- nor inflammation-related gene sets, which were enriched to adipocytes. High adipogenesis TNBC was infiltrated with low CD8+ T cells and high M2 macrophages. Although adipogenesis was not associated with neoadjuvant chemotherapy response, high adipogenesis TNBC was significantly associated with low expression of PD-L1 and PD-L2 genes, and immune checkpoint molecules index. In conclusion, adipogenesis in TNBC was associated with cancer metabolism and unfavorable tumor immune microenvironment, which is different from abundance of adipocytes.

scholarly journals Enhanced Thermogenesis in Triple-Negative Breast Cancer Is Associated with Pro-Tumor Immune Microenvironment

Cancers ◽  
2021 ◽  
Vol 13 (11) ◽  
pp. 2559
Author(s):  
Shipra Gandhi ◽  
Masanori Oshi ◽  
Vijayashree Murthy ◽  
Elizabeth A. Repasky ◽  
Kazuaki Takabe
Keyword(s):  
Breast Cancer ◽  
T Cells ◽  
Cold Stress ◽  
Triple Negative Breast Cancer ◽  
Cancer Biology ◽  
Triple Negative ◽  
Related Gene ◽  
Immune Microenvironment ◽  
Gene Sets ◽  
Tumor Immune Microenvironment

Mild cold stress induced by housing mice with a 4T1 triple-negative breast cancer (TNBC) cell implantation model at 22 °C increases tumor growth rate with a pro-tumorigenic immune microenvironment (lower CD8 +T cells, higher myeloid-derived suppressor cells (MDSCs) and regulatory T-cells (Tregs)). Since cold stress also activates thermogenesis, we hypothesized that enhanced thermogenesis is associated with more aggressive cancer biology and unfavorable tumor microenvironment (TME) in TNBC patients. A total of 6479 breast cancer patients from METABRIC, TCGA, GSE96058, GSE20194, and GSE25066 cohorts were analyzed using Kyoto Encyclopedia of Genes and Genomes (KEGG) thermogenesis score. High-thermogenesis TNBC was associated with a trend towards worse survival and with angiogenesis, adipogenesis, and fatty acid metabolism pathways. On the other hand, low-thermogenesis TNBC enriched most of the hallmark cell-proliferation-related gene sets (i.e., mitotic spindle, E2F targets, G2M checkpoint, MYC targets), as well as immune-related gene sets (i.e., IFN-α and IFN-γ response). Favorable cytotoxic T-cell-attracting chemokines CCL5, CXCL9, CXCL10, and CXCL11 were lower; while the MDSC- and Treg-attracting chemokine CXCL12 was higher. There were higher M2 but lower M1 macrophages and Tregs. In conclusion, high-thermogenesis TNBC is associated with pro-tumor immune microenvironment and may serve as biomarker for testing strategies to overcome this immunosuppression.

scholarly journals M1 Macrophage and M1/M2 ratio defined by transcriptomic signatures resemble only part of their conventional clinical characteristics in breast cancer

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Masanori Oshi ◽  
Yoshihisa Tokumaru ◽  
Mariko Asaoka ◽  
Li Yan ◽  
Vikas Satyananda ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Biology ◽  
Clinical Characteristics ◽  
Critical Role ◽  
Immune Microenvironment ◽  
Gene Sets ◽  
M1 Macrophage ◽  
Tumor Immune Microenvironment ◽  
Cell Cycle Related Gene ◽  
High Level

Abstract Tumor associated macrophages (TAMs) play a critical role in biology of various cancers, including breast cancer. In the current study, we defined “M1” macrophage and “M1”/“M2” ratio by transcriptomic signatures using xCell. We investigated the association between high level of “M1” macrophage or “M1”/“M2” ratio and the tumor immune microenvironment by analyzing the transcriptome of publicly available cohorts, TCGA and METABRIC. We found that “M1” high tumors were not associated with prolonged survival compared with “M1” low tumors, or with the response to neoadjuvant chemotherapy. “M1” high tumors were associated with clinically aggressive features and “M1” high tumors enriched the cell proliferation and cell cycle related gene sets in GSEA. At the same time, “M1” high tumors were associated with high immune activity and favorable tumor immune microenvironment, as well as high expression of immune check point molecules. Strikingly, all these results were mirrored in “M1”/“M2” ratio high tumors. In conclusion, transcriptomically defined “M1” or “M1”/“M2” high tumors were associated with aggressive cancer biology and favorable tumor immune microenvironment but not with survival benefit, which resembled only part of their conventional clinical characteristics.

Association of Th2 high tumors with aggressive features of breast cancer.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e12584-e12584
Author(s):  
Yoshihisa Tokumaru ◽  
Lan Le ◽  
Masanori Oshi ◽  
Eriko Katsuta ◽  
Nobuhisa Matsuhashi ◽  
...  
Keyword(s):  
Breast Cancer ◽  
T Cells ◽  
Cancer Progression ◽  
Immune Cells ◽  
Gene Set Enrichment Analysis ◽  
The Cancer Genome Atlas ◽  
Th2 Cells ◽  
Immune Microenvironment ◽  
Adaptive Immune Cells ◽  
Tumor Immune Microenvironment

e12584 Background: Recent studies have shown that infiltrating T-lymphocytes have been implicated in the promotion of breast cancer progression. Upon activation, these antigen-presenting cells then recruit adaptive immune cells. It has been proposed that polarization of CD4+ effector T-cells towards the immunosuppressive Th2 cells induce cytokine release and T-cell anergy, which lead to polarization of M2 tumor-associated macrophages (TAM’s), providing a protumorigenic microenvironment. We hypothesized that there is a correlation between high levels of Th2 cells and aggressive features of breast cancer and unfavorable tumor immune environment. Methods: Clinicopathological data and overall survival information was obtained on 1069 breast cancer patients from The Cancer Genome Atlas (TCGA) database. We defined Th2 high and low levels with the median cutoff. Results: Analysis of cell composition of the immune cells within tumor immune microenvironment demonstrated that Th2 high tumors did not consistently associated with unfavorable tumor immune microenvironment. Pro-cancer immune cells, such as macrophage M2 cells were increased with Th2 high tumors whereas, regulatory T cells were decreased with Th2 high tumors (p < 0.01 and p < 0.001 respectively). On the contrary, infiltration of anti-cancer cells, such as macrophage M1 was increased whereas CD8 T cells were decreased with Th2 high tumors (p < 0.05 and p < 0.001 respectively). Th2 was not shown to have correlation with IL-4, IL-6, IL-10 and IL-13, all of which has been reported to associate with Th2 cells. Th2 levels were associated with advanced grades. Also, correlation analysis demonstrated that there was a strong correlation between Th2 levels and Ki-67. These results were further validated with gene set enrichment analysis (GSEA). GSEA revealed that in Th2 high tumors enriched the gene sets associated with cell proliferation and cell cycle. Conclusions: High expression of immunosuppressive Th2 cells was associated with highly proliferative features of breast cancer, but not with unfavorable tumor immune microenvironment.

scholarly journals High Expression of miR-34a Associated with Less Aggressive Cancer Biology but Not with Survival in Breast Cancer

2020 ◽  
Vol 21 (9) ◽  
pp. 3045 ◽  
Author(s):  
Yoshihisa Tokumaru ◽  
Eriko Katsuta ◽  
Masanori Oshi ◽  
Judith C. Sporn ◽  
Li Yan ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Proliferation ◽  
Cancer Biology ◽  
Epithelial Mesenchymal Transition ◽  
Molecular Taxonomy ◽  
The Cancer Genome Atlas ◽  
P53 Pathway ◽  
Mesenchymal Transition ◽  
Gene Sets ◽  
Aggressive Cancer

Most breast cancer (BC) patients succumb to metastatic disease. MiR-34a is a well-known tumor suppressive microRNA which exerts its anti-cancer functions by playing a role in p53, apoptosis induction, and epithelial-mesenchymal transition (EMT) suppression. Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) and The Cancer Genome Atlas (TCGA) cohorts were used to test our hypothesis that miR-34a high BCs translate to less aggressive cancer biology and better survival in large cohorts. There was no association between miR-34a expression levels and clinicopathological features of BC patients except for HER2 positivity. MiR-34a high expressing tumors were associated with lower Nottingham pathological grades and lower MKI67 expression. In agreement, high miR-34a tumors demonstrated lower GSVA scores of cell cycle and cell proliferation-related gene sets. High miR-34a tumors enriched the p53 pathway and apoptosis gene sets. Unexpectedly, high miR-34a tumors also associated with elevated EMT pathway score and ZEB1 and two expressions. MiR-34a expression did not associate with any distant metastasis. Further, high miR-34a tumors did not associate with better survival compared with miR-34a low tumors. In conclusion, the clinical relevance of miR-34a high expressing tumors was associated with suppressed cell proliferation, enhanced p53 pathway and apoptosis, but enhanced EMT and these findings did not reflect better survival outcomes in large BC patient cohorts.

Can Intratumoral neutrophil lymphocyte ratio (NLR) be a prognostic biomarker in breast cancer patients?

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e12573-e12573
Author(s):  
Yoshihisa Tokumaru ◽  
Masanori Oshi ◽  
Vijayashree Murthy ◽  
Eriko Katsuta ◽  
Nobuhisa Matsuhashi ◽  
...  
Keyword(s):  
Breast Cancer ◽  
T Cells ◽  
Cancer Patients ◽  
Immune Cells ◽  
Breast Cancer Patients ◽  
Immune Microenvironment ◽  
High Group ◽  
Anti Cancer ◽  
Tumor Immune Microenvironment ◽  
Er Positive

e12573 Background: In breast cancer patients, it is well known that the elevation of neutrophil lymphocyte ratio (NLR) in the blood are reported to associate with poor prognosis based on the notion that neutrophils represent pro-cancer, and lymphocytes represent anti-cancer immune cells. Tumor immune microenvironment has been demonstrated to play critical roles in the outcome of breast cancer patients. However, there is scarce evidence on the clinical relevance of intratumoral NLR in breast cancer patients. In the current study, we hypothesized that intratumoral NLR high tumors are associated with worse survival particularly in TNBC that is known to have high immune cell infiltration. Methods: A total of 1904 breast cancer patients’ data from METABRIC (Molecular Taxonomy of Breast Cancer International Consortium) and analyzed. NLR was calculated by the gene expressions of CD66b (CEACAM8) and CD8 (CD8A). NLR high and low were divided by the median. Overall Survival (OS) and Disease-Free Survival were calculated utilizing Kaplan Meier method between intratumoral NLR high and low groups. xCell algorithm was used to analyze the infiltrated immune cells within the tumor immune microenvironment as we have previously published. Results: Intratumoral NLR high group was associated with worse OS in whole, ER-positive/HER2-negative, and triple negative (TN) subtypes, in agreement with the previous studies. TN subtype alone demonstrated worse DFS of NLR high group. Surprisingly, gene set enrichment analysis (GSEA) demonstrated no gene set enrichment to NLR high group, which implicates that there is no distinctive mechanism that associate with worse survival. Whereas, immune response-related gene sets significantly enriched to NLR low group in TN subtype. This enrichment was consistent in ER-positive/HER2-negative. Compared with ER-positive/HER2-negative subtype, anti-cancer immune cells such as CD4+ T cells, CD8+ T cells, M1 macrophage, and helper T helper type 1 cells were significantly infiltrated in TN patients (p < 0.001 for all genes), where M2 macrophages and neutrophils were less and regulatory T cells and T helper type 2 cells were more infiltrated in TN subtype. Furthermore, intratumoral NLR was significantly lower in TN compared with ER-positive/HER2-negative subtype (p < 0.001). These results suggest that intratumoral NLR low group is associated with better survival due to favorable tumor immune microenvironment in TN subtype rather than NLR high group has worse survival. Conclusions: Intratumoral NLR low tumor demonstrated more favorable OS and more favorable DFS in TN patients. Intratumoral NLR low breast cancer was associated with enhanced immune response and higher infiltration of anti-cancer immune cells were observed in TN subtype compared to ER-positive/HER2-negative which may contribute to the favorable outcome of in TN breast cancer.

scholarly journals RNA N6-Methyladenosine Regulators Contribute to Tumor Immune Microenvironment and Have Clinical Prognostic Impact in Breast Cancer

2022 ◽  
Vol 12 ◽  
Author(s):  
Lan-Xin Mu ◽  
You-Cheng Shao ◽  
Lei Wei ◽  
Fang-Fang Chen ◽  
Jing-Wei Zhang
Keyword(s):  
Breast Cancer ◽  
Immune Cell ◽  
Risk Model ◽  
Cox Regression ◽  
Gene Set Enrichment Analysis ◽  
The Cancer Genome Atlas ◽  
Prognostic Impact ◽  
Immune Microenvironment ◽  
Model Based ◽  
Tumor Immune Microenvironment

Purpose: This study aims to reveal the relationship between RNA N6-methyladenosine (m6A) regulators and tumor immune microenvironment (TME) in breast cancer, and to establish a risk model for predicting the occurrence and development of tumors.Patients and methods: In the present study, we respectively downloaded the transcriptome dataset of breast cancer from Gene Expression Omnibus (GEO) database and The Cancer Genome Atlas (TCGA) database to analyze the mutation characteristics of m6A regulators and their expression profile in different clinicopathological groups. Then we used the weighted correlation network analysis (WGCNA), the least absolute shrinkage and selection operator (LASSO), and cox regression to construct a risk prediction model based on m6A-associated hub genes. In addition, Immune infiltration analysis and gene set enrichment analysis (GSEA) was used to evaluate the immune cell context and the enriched gene sets among the subgroups.Results: Compared with adjacent normal tissue, differentially expressed 24 m6A regulators were identified in breast cancer. According to the expression features of m6A regulators above, we established two subgroups of breast cancer, which were also surprisingly distinguished by the feature of the immune microenvironment. The Model based on modification patterns of m6A regulators could predict the patient’s T stage and evaluate their prognosis. Besides, the low m6aRiskscore group presents an immune-activated phenotype as well as a lower tumor mutation load, and its 5-years survival rate was 90.5%, while that of the high m6ariskscore group was only 74.1%. Finally, the cohort confirmed that age (p &lt; 0.001) and m6aRiskscore (p &lt; 0.001) are both risk factors for breast cancer in the multivariate regression.Conclusion: The m6A regulators play an important role in the regulation of breast tumor immune microenvironment and is helpful to provide guidance for clinical immunotherapy.

Clinical relevance of miR-143 expression in ER-positive breast cancer patients.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e12574-e12574
Author(s):  
Yoshihisa Tokumaru ◽  
Masanori Oshi ◽  
Eriko Katsuta ◽  
Nobuhisa Matsuhashi ◽  
Manabu Futamura ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Patients ◽  
Immune Cells ◽  
High Expression ◽  
Breast Cancers ◽  
Breast Cancer Patients ◽  
Immune Microenvironment ◽  
Anti Cancer ◽  
Tumor Immune Microenvironment ◽  
Er Positive

e12574 Background: MicroRNA-143(miR-143) is a well-known tumor suppressive microRNA in various malignancies, including breast cancer. Recently, the tumor immune microenvironment has been reported to associate with progression of breast cancers. However, the association with the tumor immune microenvironment and miR-143 in breast cancers remains ambiguous. Given these backgrounds, we hypothesized that high expression of miR-143 is associated with favorable effect to the tumor immune microenvironment which leads to better survival of ER positive breast cancer patients. Methods: Two major publicly available breast cancer cohorts were used for this study. A total of 753 patients from The Cancer Genome Atlas (TCGA) and total of 1283 patients from Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) were used. Results: We defined the higher quartile of miR-143 expression levels as high and the remainder as low expression groups. There was no significant difference in patient clinicopathlogical features between two groups. Gene set enrichment analysis (GSEA) revealed that miR-143 high expression tumors enriched Helper T cell type 1 (Th1) related gene sets indicating the upregulation of anti-cancer immune cells. Also, the cell composition of anti-cancer immune cells, such as Th1 and Macrophage M1 were higher with miR-143 high tumors (p < 0.001 and p < 0.01 respectively) in whole group. On the contrary, pro-cancer immune cells such as Th2 and M1 were lower with miR-143 high tumors (p < 0.01 and p < 0.001 respectively) in whole group. Interestingly, among the subtypes, we found that ER positive subgroup followed this trend of high infiltration rate of anti-cancer immune cells and low infiltration rate of pro-cancer immune cells. Furthermore, only ER positive subgroup demonstrated the survival benefit with miR-143 high expression tumors. Conclusions: We demonstrated that high expression of miR-143 in ER breast cancer associate with favorable tumor immune microenvironment, upregulation of the anti-cancer immune cells and suppression of the pro-cancer immune cells, and associate with better survival of the breast cancer patients.

scholarly journals Lamin B2 promotes the progression of triple negative breast cancer via mediating cell proliferation and apoptosis

2021 ◽  
Vol 41 (1) ◽  
Author(s):  
Cui-Cui Zhao ◽  
Jing Chen ◽  
Li-Ying Zhang ◽  
Hong Liu ◽  
Chuan-Gui Zhang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Proliferation ◽  
Cancer Progression ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
The Cancer Genome Atlas ◽  
Proliferation And Apoptosis

Abstract Triple negative breast cancer (TNBC) is a more common type of breast cancer with high distant metastasis and poor prognosis. The potential role of lamins in cancer progression has been widely revealed. However, the function of lamin B2 (LMNB2) in TNBC progression is still unclear. The present study aimed to investigate the role of LMNB2 in TNBC. The cancer genome atlas (TCGA) database analysis and immunohistochemistry (IHC) were performed to examine LMNB2 expression levels. LMNB2 short hairpin RNA plasmid or lentivirus was used to deplete the expression of LMNB2 in human TNBC cell lines including MDA-MB-468 and MDA-MB-231. Alterations in cell proliferation and apoptosis in vitro and the nude mouse tumorigenicity assay in vivo were subsequently analyzed. The human TNBC tissues shown high expression of LMNB2 according to the bioinformation analysis and IHC assays. LMNB2 expression was correlated with the clinical pathological features of TNBC patients, including pTNM stage and lymph node metastasis. Through in vitro and in vivo assays, we confirmed LMNB2 depletion suppressed the proliferation and induced the apoptosis of TNBC cells, and inhibited tumor growth of TNBC cells in mice, with the decrease in Ki67 expression or the increase in caspase-3 expression. In conclusion, LMNB2 may promote TNBC progression and could serve as a potential therapeutic target for TNBC treatment.

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