scholarly journals Effects of Molecular Iodine/Chemotherapy in the Immune Component of Breast Cancer Tumoral Microenvironment

Biomolecules ◽  
2021 ◽  
Vol 11 (10) ◽  
pp. 1501
Author(s):  
Olga Cuenca-Micó ◽  
Evangelina Delgado-González ◽  
Brenda Anguiano ◽  
Felipe Vaca-Paniagua ◽  
Alejandra Medina-Rivera ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Molecular Mechanisms ◽  
Gene Promoter ◽  
Molecular Iodine ◽  
Rna Seq ◽  
Deconvolution Analysis ◽  
Antiproliferative Effects ◽  
Tumor Growth Factor ◽  
Tumor Immune Microenvironment ◽  
Growth Factor Beta

Molecular iodine (I2) induces apoptotic, antiangiogenic, and antiproliferative effects in breast cancer cells. Little is known about its effects on the tumor immune microenvironment. We studied the effect of oral (5 mg/day) I2 supplementation alone (I2) or together with conventional chemotherapy (Cht+I2) on the immune component of breast cancer tumors from a previously published pilot study conducted in Mexico. RNA-seq, I2 and Cht+I2 samples showed significant increases in the expression of Th1 and Th17 pathways. Tumor immune composition determined by deconvolution analysis revealed significant increases in M0 macrophages and B lymphocytes in both I2 groups. Real-time RT-PCR showed that I2 tumors overexpress T-BET (p = 0.019) and interferon-gamma (IFNγ; p = 0.020) and silence tumor growth factor-beta (TGFβ; p = 0.049), whereas in Cht+I2 tumors, GATA3 is silenced (p = 0.014). Preliminary methylation analysis shows that I2 activates IFNγ gene promoter (by increasing its unmethylated form) and silences TGFβ in Cht+I2. In conclusion, our data showed that I2 supplements induce the activation of the immune response and that when combined with Cht, the Th1 pathways are stimulated. The molecular mechanisms involved in these responses are being analyzed, but preliminary data suggest that methylation/demethylation mechanisms could also participate.

scholarly journals Effects of Molecular Iodine/Chemotherapy in the Immune Component of Breast Cancer Tumoral Microenvironment

2021 ◽  
Author(s):  
Olga Cuenca-Micó ◽  
Evangelina Delgado-González ◽  
Brenda Anguiano ◽  
Felipe Vaca-Paniagua ◽  
Alejandra Medina-Rivera ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Molecular Mechanisms ◽  
Gene Promoter ◽  
Molecular Iodine ◽  
Rna Seq ◽  
Deconvolution Analysis ◽  
Antiproliferative Effects ◽  
Tumor Growth Factor ◽  
Tumor Immune Microenvironment ◽  
Growth Factor Beta

Molecular iodine (I2) induces apoptotic, antiangiogenic, and antiproliferative effects in breast cancer cells. Little is known about its effects on the tumor immune microenvironment. We studied the effect of oral (5 mg/day) I2 supplementation alone (I2) or together with conventional chemotherapy (Cht+I2) on the im-mune component of breast cancer tumors from a previously published pilot study conducted in Mexico. RNA-seq, I2 and Cht+I2 samples showed significant increases in expression of Th1 and Th17 pathways. Tumor immune composition determined by deconvolution analysis revealed significant increases in M0 macrophages and B lymphocytes in both I2 groups. Real-time RT-PCR showed that I2 tumors overexpress T-BET (p = 0.019) and interferon-gamma (IFNγ; p = 0.020) and silence tumor growth factor-beta (TGFβ; p = 0.049); whereas in Cht+I2 tumors, GATA3 is silenced (p = 0.014). Preliminary methylation analysis shows that I2 activates IFNγ gene promoter (by increasing its unmethylated form) and silences TGFβ in Cht+I2. In conclusion, our data showed that I2 supplements induce the activation of the immune response and that when combined with Cht, the Th1 pathways are stimulated. The molecular mechanisms involved in these responses are being analyzed, but preliminary data suggest that methylation/demethylation mechanisms could also participate.

scholarly journals Comprehensive analysis based on DNA methylation and RNA-seq reveals hypermethylation of the up-regulated WT1 gene with potential mechanisms in PAM50 subtypes of breast cancer

PeerJ ◽  
2021 ◽  
Vol 9 ◽  
pp. e11377
Author(s):  
Chongyang Ren ◽  
Xiaojiang Tang ◽  
Haitao Lan
Keyword(s):  
Breast Cancer ◽  
Dna Methylation ◽  
Molecular Mechanisms ◽  
Molecular Subtypes ◽  
Wilms Tumor ◽  
Expression Profiles ◽  
Gene Signature ◽  
The Cancer Genome Atlas ◽  
Body Region ◽  
Rna Seq

Background Breast cancer (BC), one of the most widespread cancers worldwide, caused the deaths of more than 600,000 women in 2018, accounting for about 15% of all cancer-associated deaths in women that year. In this study, we aimed to discover potential prognostic biomarkers and explore their molecular mechanisms in different BC subtypes using DNA methylation and RNA-seq. Methods We downloaded the DNA methylation datasets and the RNA expression profiles of primary tissues of the four BC molecular subtypes (luminal A, luminal B, basal-like, and HER2-enriched), as well as the survival information from The Cancer Genome Atlas (TCGA). The highly expressed and hypermethylated genes across all the four subtypes were screened. We examined the methylation sites and the downstream co-expressed genes of the selected genes and validated their prognostic value using a different dataset (GSE20685). For selected transcription factors, the downstream genes were predicted based on the Gene Transcription Regulation Database (GTRD). The tumor microenvironment was also evaluated based on the TCGA dataset. Results We found that Wilms tumor gene 1 (WT1), a transcription factor, was highly expressed and hypermethylated in all the four BC subtypes. All the WT1 methylation sites exhibited hypermethylation. The methylation levels of the TSS200 and 1stExon regions were negatively correlated with WT1 expression in two BC subtypes, while that of the gene body region was positively associated with WT1 expression in three BC subtypes. Patients with low WT1 expression had better overall survival (OS). Five genes including COL11A1, GFAP, FGF5, CD300LG, and IGFL2 were predicted as the downstream genes of WT1. Those five genes were dysregulated in the four BC subtypes. Patients with a favorable 6-gene signature (low expression of WT1 and its five predicted downstream genes) exhibited better OS than that with an unfavorable 6-gene signature. We also found a correlation between WT1 and tamoxifen using STITCH. Higher infiltration rates of CD8 T cells, plasma cells, and monocytes were found in the lower quartile WT1 group and the favorable 6-gene signature group. In conclusion, we demonstrated that WT1 is hypermethylated and up-regulated in the four BC molecular subtypes and a 6-gene signature may predict BC prognosis.

scholarly journals PD-L1 Blockade by Atezolizumab Downregulates Signaling Pathways Associated with Tumor Growth, Metastasis, and Hypoxia in Human Triple Negative Breast Cancer

Cancers ◽  
2019 ◽  
Vol 11 (8) ◽  
pp. 1050 ◽  
Author(s):  
Reem Saleh ◽  
Rowaida Z. Taha ◽  
Varun Sasidharan Nair ◽  
Nehad M. Alajez ◽  
Eyad Elkord
Keyword(s):  
Breast Cancer ◽  
Tumor Growth ◽  
Signaling Pathways ◽  
Triple Negative Breast Cancer ◽  
Molecular Mechanisms ◽  
Triple Negative ◽  
Epithelial Mesenchymal Transition ◽  
Cancer Therapies ◽  
Rna Seq ◽  
Mesenchymal Transition

Triple negative breast cancer (TNBC) is the most aggressive type of breast cancer, which shows resistance to common breast cancer therapies, as it lacks the expression of the most common breast cancer targets. Therefore, TNBC treatment remains a challenge. Targeting programmed cell death-ligand 1 (PD-L1) by monoclonal antibodies (mAbs), for example, atezolizumab, has revolutionized the treatment for various cancer types. However, the therapeutic efficacy of targeting PD-L1 in TNBC is currently under investigation. In this study, we investigated the molecular mechanisms by which the human TNBC cell line MDA-MB-231, expressing PD-L1, responds to atezolizumab, using RNA-Seq. Transcriptome analysis revealed 388 upregulated and 362 downregulated genes in response to atezolizumab treatment. The expression of selected genes, from RNA-Seq data, was subsequently validated using RT-qPCR in the MDA-MB-231 and MDA-MB-468 TNBC cells following atezolizumab treatment. Bioinformatics analysis revealed that atezolizumab downregulates genes promoting cell migration/invasion and metastasis, epithelial-mesenchymal transition (EMT), cell growth/proliferation/survival, and hypoxia. On the contrary, genes associated with apoptosis and DNA repair were upregulated in response to atezolizumab treatment. Gene set enrichment analyses revealed that a significant number of these genes are related to the NF-kB, PI3K/Akt/mTOR, MAPK, and CD40 signaling pathways. Using functional assays, we confirmed that atezolizumab increases MDA-MB-231 cell apoptosis/necrosis, and reduces their proliferation and viability. Collectively, our findings provide novel insights into the molecular mechanisms/signaling pathways by which atezolizumab exerts inhibitory effects on TNBC, thereby inhibiting EMT/metastasis, tumor growth/survival, and the induction of hypoxia.

scholarly journals DEK Expression in Breast Cancer Cells Leads to the Alternative Activation of Tumor Associated Macrophages

Cancers ◽  
2020 ◽  
Vol 12 (7) ◽  
pp. 1936 ◽  
Author(s):  
Nicholas A. Pease ◽  
Miranda S. Shephard ◽  
Mathieu Sertorio ◽  
Susan E. Waltz ◽  
Lisa M. Privette Vinnedge
Keyword(s):  
Breast Cancer ◽  
Tumor Microenvironment ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Molecular Mechanisms ◽  
Alternative Activation ◽  
M2 Macrophage ◽  
Breast Cancers ◽  
Rna Seq

Breast cancer (BC) is the second leading cause of cancer deaths among women. DEK is a known oncoprotein that is highly expressed in over 60% of breast cancers and is an independent marker of poor prognosis. However, the molecular mechanisms by which DEK promotes tumor progression are poorly understood. To identify novel oncogenic functions of DEK, we performed RNA-Seq analysis on isogenic Dek-knockout and complemented murine BC cells. Gene ontology analyses identified gene sets associated with immune system regulation and cytokine-mediated signaling and differential cytokine and chemokine expression was confirmed across Dek-proficient versus Dek-deficient cells. By exposing murine bone marrow-derived macrophages (BMDM) to tumor cell conditioned media (TCM) to mimic a tumor microenvironment, we showed that Dek-expressing breast cancer cells produce a cytokine milieu, including up-regulated Tslp and Ccl5 and down-regulated Cxcl1, Il-6, and GM-CSF, that drives the M2 polarization of macrophages. We validated this finding in primary murine mammary tumors and show that Dek expression in vivo is also associated with increased expression of M2 macrophage markers in murine tumors. Using TCGA data, we verified that DEK expression in primary human breast cancers correlates with the expression of several genes identified by RNA-Seq in our murine model and with M2 macrophage phenotypes. Together, our data demonstrate that by regulating the production of multiple secreted factors, DEK expression in BC cells creates a potentially immune suppressed tumor microenvironment, particularly by inducing M2 tumor associated macrophage (TAM) polarization.

scholarly journals A Phenylacetamide Resveratrol Derivative Exerts Inhibitory Effects on Breast Cancer Cell Growth

2021 ◽  
Vol 22 (10) ◽  
pp. 5255
Author(s):  
Adele Chimento ◽  
Anna Santarsiero ◽  
Domenico Iacopetta ◽  
Jessica Ceramella ◽  
Arianna De Luca ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Cycle ◽  
Estrogen Receptor ◽  
Cell Lines ◽  
Cancer Cell ◽  
Breast Cancer Cell ◽  
Molecular Mechanisms ◽  
Cancer Cell Lines ◽  
Breast Cancer Cell Lines ◽  
Antiproliferative Effects

Resveratrol (RSV) is a natural compound that displays several pharmacological properties, including anti-cancer actions. However, its clinical application is limited because of its low solubility and bioavailability. Here, the antiproliferative and anti-inflammatory activity of a series of phenylacetamide RSV derivatives has been evaluated in several cancer cell lines. These derivatives contain a monosubstituted aromatic ring that could mimic the RSV phenolic nucleus and a longer flexible chain that could confer a better stability and bioavailability than RSV. Using MTT assay, we demonstrated that most derivatives exerted antiproliferative effects in almost all of the cancer cell lines tested. Among them, derivative 2, that showed greater bioavailability than RSV, was the most active, particularly against estrogen receptor positive (ER+) MCF7 and estrogen receptor negative (ER-) MDA-MB231 breast cancer cell lines. Moreover, we demonstrated that these derivatives, particularly derivative 2, were able to inhibit NO and ROS synthesis and PGE2 secretion in lipopolysaccharide (LPS)-activated U937 human monocytic cells (derived from a histiocytoma). In order to define the molecular mechanisms underlying the antiproliferative effects of derivative 2, we found that it determined cell cycle arrest at the G1 phase, modified the expression of cell cycle regulatory proteins, and ultimately triggered apoptotic cell death in both breast cancer cell lines. Taken together, these results highlight the studied RSV derivatives, particularly derivative 2, as promising tools for the development of new and more bioavailable derivatives useful in the treatment of breast cancer.

scholarly journals RNA-seq from archival FFPE breast cancer samples: molecular pathway fidelity and novel discovery

2019 ◽  
Vol 12 (1) ◽  
Author(s):  
Nathan D. Pennock ◽  
Sonali Jindal ◽  
Wesley Horton ◽  
Duanchen Sun ◽  
Jayasri Narasimhan ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Molecular Mechanisms ◽  
Single Gene ◽  
Prognostic Significance ◽  
Breast Cancers ◽  
Rna Seq ◽  
Gene Set ◽  
Public Data ◽  
Ffpe Tissues

Abstract Background Formalin-fixed, paraffin-embedded (FFPE) tissues for RNA-seq have advantages over fresh frozen tissue including abundance and availability, connection to rich clinical data, and association with patient outcomes. However, FFPE-derived RNA is highly degraded and chemically modified, which impacts its utility as a faithful source for biological inquiry. Methods True archival FFPE breast cancer cases (n = 58), stored at room temperature for 2–23 years, were utilized to identify key steps in tissue selection, RNA isolation, and library choice. Gene expression fidelity was evaluated by comparing FFPE data to public data obtained from fresh tissues, and by employing single-gene, gene set and transcription network-based regulon analyses. Results We report a single 10 μm section of breast tissue yields sufficient RNA for RNA-seq, and a relationship between RNA quality and block age that was not linear. We find single-gene analysis is limiting with FFPE tissues, while targeted gene set approaches effectively distinguish ER+ from ER- breast cancers. Novel utilization of regulon analysis identified the transcription factor KDM4B to associate with ER+ disease, with KDM4B regulon activity and gene expression having prognostic significance in an independent cohort of ER+ cases. Conclusion Our results, which outline a robust FFPE-RNA-seq pipeline for broad use, support utilizing FFPE tissues to address key questions in the breast cancer field, including the delineation between indolent and life-threatening disease, biological stratification and molecular mechanisms of treatment resistance.

Identification of immune-related genes in thymus of breast cancer mouse model exposed to different calorie restriction

2019 ◽  
Vol 44 (5) ◽  
pp. 635-645
Author(s):  
Zehra Omeroglu Ulu ◽  
Salih Ulu ◽  
Soner Dogan ◽  
Bilge Guvenc Tuna ◽  
Nehir Ozdemir Ozgenturk
Keyword(s):  
Breast Cancer ◽  
Mouse Model ◽  
Calorie Restriction ◽  
Molecular Mechanisms ◽  
Transcriptional Profiling ◽  
Rna Seq ◽  
Expression Levels ◽  
Thymus Tissue ◽  
Different Types ◽  
Immune Related Genes

Abstract Introduction In the present study, RNA sequencing-mediated transcriptome analysis was performed in order to elucidate the molecular mechanisms of the immune response for different types of calorie restriction (CR) application using MMTV-TGF-α breast cancer mouse model. Methods Animals were applied to three different dietary regiments; ad libitum (AL), chronic calorie restriction (CCR) and intermittent calorie restriction (ICR). Using thymus tissues, 6091 differentially expressed genes (DEGs) were identified in three dietary groups. After clustering of total of 6091 DEGs using Gene Ontology (GO) categories, a total of 400 genes were identified to be involved in immune system process (GO:0002376) GO categories. KEGG pathway and gene co-expression network analysis of these immune-related DEGs were done using String database. The results were confirmed with measuring mRNA expression levels of four selected immune-related DEGs genes (Casp3, Thy1, IL-16 and CD4) using quantitative real-time PCR (qPCR). Results The expression levels of immune-related genes were different in three RNA-seq data. Conclusion The results provide useful information to investigate the immune-related transcriptional profiling in thymus tissue of breast cancer mouse model applied to two different types of CR and to identify the specific functional immune related genes in response to CR during cancer development.

Biochemical and molecular mechanisms associated with the effect of Phoenix dactylifera seeds on cyclophosphamide-induced hepato-renal toxicities in mice

2021 ◽  
Author(s):  
Sabry Ali El-Naggar ◽  
Mohamed A. Basyouny ◽  
Mohammed Alqarni ◽  
Ahmed S. Haidyrah ◽  
Samer Ezat Amin ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Phoenix Dactylifera ◽  
Negative Control ◽  
Nuclear Factor ◽  
Tumor Growth Factor ◽  
Cyclooxygenase 1 ◽  
Peak Areas ◽  
Nuclear Factor Kappa Beta ◽  
Growth Factor Beta ◽  
Cox 1

Abstract Cyclophosphamide (CTX) causes severe side effects. Phoenix dactylifera L. showed biomedical values. This study aims to address the biochemical and molecular mechanisms of Phoenix dactylifera seeds extract (PDSE) effects on CTX-induced hepato-renal toxicities in mice. Forty male albino mice were divided into four groups: Gp 1 was served as a negative control, Gp2 was injected intraperitoneally (i.p) with PDSE (200 mg/kg) for 30 consecutive days. Gp3 was injected with CTX single dose (200 mg/kg) and Gp4 was injected with CTX then injected with PDSE. Hematological, biochemical, histopathological alterations, and gene expression for pro-inflammatory cytokine were assessed. GC-MS analysis showed the highest percentages of the peak areas were by Ethyl iso-allocholate, 1-Heptatriacotanol, and 9-12-15-Octadecatrienoic acid 2-3-dihydroxypropyl ester. Treatment with PDSE post-CTX-injection ameliorated the hematological, biochemical, and histological alterations by up-regulating the antioxidant biomarkers and downregulating tumor growth factor beta-1 (TGFβ-1), nuclear factor Kappa-beta (NFκ-β), cyclooxygenase-1 (COX-1) genes.

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