scholarly journals High Expression of microRNA-143 is Associated with Favorable Tumor Immune Microenvironment and Better Survival in Estrogen Receptor Positive Breast Cancer

2020 ◽  
Vol 21 (9) ◽  
pp. 3213 ◽  
Author(s):  
Yoshihisa Tokumaru ◽  
Mariko Asaoka ◽  
Masanori Oshi ◽  
Eriko Katsuta ◽  
Li Yan ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Patients ◽  
Immune Cells ◽  
High Expression ◽  
Breast Cancer Patients ◽  
Immune Microenvironment ◽  
Anti Cancer ◽  
Tumor Immune Microenvironment ◽  
Er Positive ◽  
Positive Breast Cancer

microRNA-143 (miR-143) is a well-known tumor suppressive microRNA that exhibits anti-tumoral function by targeting KRAS signaling pathways in various malignancies. We hypothesized that miR-143 suppresses breast cancer progression by targeting KRAS and its effector molecules. We further hypothesized that high expression of miR-143 is associated with a favorable tumor immune microenvironment of estrogen receptor (ER)-positive breast cancer patients which result in improved survival. Two major publicly available breast cancer cohorts; The Cancer Genome Atlas (TCGA) and Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) were used. The miR-143 high expression group was associated with increased infiltration of anti-cancer immune cells and decreased pro-cancer immune cells, as well as enrichment of the genes relating to T helper (Th1) cells resulting in improved overall survival (OS) in ER-positive breast cancer patients. To the best of our knowledge, this is the first study to demonstrate that high expression of miR-143 in cancer cells associates with a favorable tumor immune microenvironment, upregulation of anti-cancer immune cells, and suppression of the pro-cancer immune cells, associating with better survival of the breast cancer patients.

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.

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.

Modulating tumor immune microenvironment by the STK11/LKB1 signaling in breast cancer.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e15185-e15185
Author(s):  
Hui-Ping Hsu ◽  
Chih-Yang Wang ◽  
Yao-Lung Kuo ◽  
Kuo-Ting Lee ◽  
Pai-Sheng Chen ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Cancer Patients ◽  
Rna Sequencing ◽  
Immune Cells ◽  
Breast Cancer Patients ◽  
Immune Microenvironment ◽  
Stk11 Gene ◽  
Tumor Immune Microenvironment ◽  
Cytokine Array

e15185 Background: Standard treatment for breast cancer patients includes surgery, chemotherapy, radiotherapy, target and endocrine therapy. Immune checkpoint inhibitors are newly developing medications. The theoretical basis of immunotherapy is the interaction between cancer cells and tumor-infiltrating immune cells. Cancer cells secrete cytokines and create a specific tumor immune microenvironment (TIME) to attract or modulate immune cells. Further, genetic mutations or copy-number variations in cancer cells contribute to immunosuppression. Liver kinase B1 (LKB1) protein ( STK11 gene) is the upstream of AMP activated Protein Kinase (AMPK)/mammalian Target of Rapamycin Complex 1 (mTORC1) signaling pathway. STK11/LKB1 is one of the possible pathways modulating TIME. Methods: Twenty-seven breast cancer patients who developed recurrence within postoperative 24 months and 22 control cancer patients without recurrence were enrolled from National Cheng Kung University Hospital in Taiwan. Targeted deep sequencing was performed to assess the mutations among individuals with breast cancer using a panel of 143 cancer-associated genes. Bioinformatics and public databases were used to predict the protein functions of the STK11 genes. Immunohistochemical staining of LKB1 protein was performed in clinical specimens. Immune-related molecules were analyzed by RNA sequencing and cytokine array after suppression of STK11. Results: Mutations of STK11 gene were detected in recurrent patients and associated with poor prognosis of patients. From immunohistochemical study, the patients with low LKB1 expression had a worse survival. We utilized CRISPER/Cas9 system to transfect sgRNA into three mouse cell lines, including M158, NF639 and PY8119. RNA sequencing was performed in parental and Stk11-sgRNA cells. Immune-related pathways were ranked in the top 10 networks. Increased mRNA expression of Csf3 (protein G-CSF), Cxcl5, and Ccl2 was detected. The results are confirmed by cytokine array. The expression of G-CSF (gene Csf3) and CXCL5 (gene Cxcl5) proteins was increased in Stk11-sgRNA cells. The results were similar with RNA sequencing. Conclusions: Our findings suggest that suppression of STK11/LKB1 is correlated with early recurrence of breast cancer patients and contributes to modulate TIME. The STK11/LKB1 and downstream AMPK/mTORC1 pathways may be potential targets for immunotherapy.

scholarly journals Clinical CYP2D6 Genotyping to Personalize Adjuvant Tamoxifen Treatment in ER-Positive Breast Cancer Patients: Current Status of a Controversy

Cancers ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 771
Author(s):  
Tessa A. M. Mulder ◽  
Mirjam de With ◽  
Marzia del Re ◽  
Romano Danesi ◽  
Ron H. J. Mathijssen ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Clinical Outcome ◽  
Cancer Patients ◽  
Plasma Concentrations ◽  
Tamoxifen Treatment ◽  
Current Status ◽  
Endocrine Treatment ◽  
Breast Cancer Patients ◽  
Er Positive ◽  
Positive Breast Cancer

Tamoxifen is a major option for adjuvant endocrine treatment in estrogen receptor (ER) positive breast cancer patients. The conversion of the prodrug tamoxifen into the most active metabolite endoxifen is mainly catalyzed by the enzyme cytochrome P450 2D6 (CYP2D6). Genetic variation in the CYP2D6 gene leads to altered enzyme activity, which influences endoxifen formation and thereby potentially therapy outcome. The association between genetically compromised CYP2D6 activity and low endoxifen plasma concentrations is generally accepted, and it was shown that tamoxifen dose increments in compromised patients resulted in higher endoxifen concentrations. However, the correlation between CYP2D6 genotype and clinical outcome is still under debate. This has led to genotype-based tamoxifen dosing recommendations by the Clinical Pharmacogenetic Implementation Consortium (CPIC) in 2018, whereas in 2019, the European Society of Medical Oncology (ESMO) discouraged the use of CYP2D6 genotyping in clinical practice for tamoxifen therapy. This paper describes the latest developments on CYP2D6 genotyping in relation to endoxifen plasma concentrations and tamoxifen-related clinical outcome. Therefore, we focused on Pharmacogenetic publications from 2018 (CPIC publication) to 2021 in order to shed a light on the current status of this debate.

scholarly journals Analysis of ESR1 and PIK3CA mutations in plasma cell-free DNA from ER-positive breast cancer patients

Oncotarget ◽  
2017 ◽  
Vol 8 (32) ◽  
pp. 52142-52155 ◽  
Author(s):  
Takashi Takeshita ◽  
Yutaka Yamamoto ◽  
Mutsuko Yamamoto-Ibusuki ◽  
Mai Tomiguchi ◽  
Aiko Sueta ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Patients ◽  
Plasma Cell ◽  
Breast Cancer Patients ◽  
Cell Free Dna ◽  
Pik3ca Mutations ◽  
Free Dna ◽  
Er Positive ◽  
Positive Breast Cancer
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