E-MTAB-4821
Ontology highlight
ABSTRACT:
PROVIDER: E-MTAB-4821 | ExpressionAtlas | 2017-07-25
REPOSITORIES: ExpressionAtlas
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Project description:Breast cancer metastasis to bone is a critical determinant of long-term survival after treatment of primary tumors. We used a mouse model of spontaneous bone metastasis to determine new molecular mechanisms. Differential transcriptome comparisons of primary and metastatic tumor cells revealed that a substantial set of genes suppressed in bone metastases were highly enriched for promoter elements for the type I interferon (IFN) regulatory factor, Irf7, itself suppressed in mouse and human metastases. The critical function of the Irf7 pathway was demonstrated by restoration of exogenous Irf7 or systemic interferon administration, which significantly reduced bone metastases and prolonged metastasis free survival. Using mice deficient in the type I receptor (Ifnar1-/-) or mature B, T and NK cell responses (NOD Scid IL-2rγ-/- mice) we demonstrated that Irf7-driven suppression of metastasis was reliant on IFN signaling to host immune cells. Metastasis suppression correlated with decreased accumulation of myeloid-derived suppressor cells and increased CD4++, CD8 T cells and NK cells in the peripheral blood and was reversed by depletion of CD8+ cells and NK cells. Clinical importance of our findings was demonstrated as increased primary tumor Irf7 expression predicted prolonged bone and lung metastasis-free survival. Thus we report for the first time, a novel innate immune pathway, intrinsic to breast cancer cells, whose suppression in turn restricts systemic immunosurveillance to enable metastasis. This pathway may constitute a novel therapeutic target for restricting breast cancer metastases. Comparison of basal gene expression in breast cancer 4T1.2 cell line stably transfected using the pMSCV retroviral expression vector system with IRF7 or the base vector. Three independent experiments were performed comparing the IRF7 expressing cells to the base vector cells
2012-07-17 | E-GEOD-37828 | biostudies-arrayexpress
Project description:Background Breast cancer patients who present in the early stage of disease are affected by metastasis to the axillary group of lymph nodes. The first among this group that is affected is called as sentinel lymph node, and metastasis to this lymph node is crucial for the staging of cancer and the quality of surgical intervention. Sentinel Lymph Node Biopsy (SLNB) that is currently used to assess lymph node metastasis is neither sensitive, nor specific, is time-consuming, thereby necessitating the identification of novel biomarkers that can flag sentinel lymph node metastasis. Methods Breast cancer patients were screened, and those with early stage were recruited in the study. Surgical resection of the breast was followed by identification of sentinel lymph nodes by methylene fluorescent technique. Histo-pathology of fresh frozen section biopsy was used as the gold standard to assign the clinical phenotypes of metastatic (SLNM+) and non-metastatic sentinel lymph nodes (SLNM-). Discovery phase of the experiment included isobaric Tags for Relative and Absolute Quantitation (iTRAQ) technique comprising of six comparative experiments coupled with mass spectrometric analysis on Orbitrap Fusion to identify differentially expressed proteins on Proteome Discoverer 2.4. Functional enrichment and pathway analyses of differentially regulated genes was carried out in DAVID functional annotation tool. Validation was done by ELISA and protein concentrations were used to estimate the ROC for computing diagnostic parameters. Results Based on MS/MS spectra there were 2396 unique protein groups and 81 differentially expressed proteins comparing SLNB + and SLNB -. Nineteen proteins up-regulated, and eight proteins that were down regulated in SLNB+ as compared to SLNB-. Bioinformatic analysis showed the implication of extra cellular matrix proteins and ECM-receptor interaction pathways to be implicated in lymph node metastasis. ELISA confirmed the up-regulation of caveolin 1, collagen α-1, desmin, fibrillin-1, and microfibrillar associated glycoprotein 4 in metastatic, as compared to non-metastatic lymph nodes. These proteins are known to be integral in tumorogenesis, cell proliferation, invasion, cell survival and anti-apoptosis. These proteins have 80%-100%, of sensitivity and specificity to differentiate the two clinical phenotypes. Conclusion Identified extra cellular matrix protein biomarkers have requisite diagnostic parameters to be developed as a translational tool to assess the status of sentinel lymph nodes during mastectomy procedure to guide surgical therapy of axillary lymph nodes in early breast oncology.
2022-05-01 | PXD027668 | Pride
Project description:The 5-year survival rate for women with metastatic breast cancer is 29%. Potential biomarkers identification is important for new therapeutic treatment in affected patients. Previous studies have shown that Parathyroid hormone-related peptide (PTHrP) plays a critical role in breast cancer growth and metastasis. The aim of our study was to use a genetically modified breast cancer mouse model to precisely examine the role of PTHrP from early primary breast cancer initiation to late progression. We identified a novel lncRNA, a new target for fatty acid metabolism that can be regulated by PTHrP in our unique mouse breast cancer model. We confirmed that a potential human lncRNA, OLMALINC, plays a similar role in fatty acid metabolism that can be regulated by PTHrP. Therefore, we validated our mouse finding in the human breast cancer cell lines. Genetically engineered mouse models provide valuable tools to study the molecular progression for breast cancer metastasis.
2023-12-30 | GSE225877 | GEO
Project description:Exogenous overexpression of the metastasis suppressor gene Nm23-H1 reduces the metastatic potential of multiple types of cancer cells. In addition, Nm23-H1 expression suppresses in vitro tumor cell motility and invasion, important correlates of metastasis. The molecular mechanism by which Nm23-H1 suppresses metastasis, motility and invasion has yet to be defined. However, mutational analysis of Nm23-H1 has revealed that substitution mutant P96S and S120G are unable to inhibit cell motility. To elucidate the molecular mechanism of Nm23-H1 motility suppression, we performed expression microarray analysis of an MDA-MB- 435 carcinoma cell line overexpressing wild-type Nm23-H1 and cross-compared the expression profile to lines expressing P96S and S120G mutants. Nine genes, MET, PTN, SMO, FZD1, L1CAM, MMP2, NETO2, CTGF and EDG2, were down regulated by wild-type but not by mutant Nm23-H1 expression (p<0.05). Reduced expression of these genes coincident with elevated Nm23-H1 expression was observed in human breast tumor cohorts, a panel of breast carcinoma cell lines and hepatocellular carcinomas from control and Nm23-M1 knockout mice. The functional significance of down regulated genes was assessed by transfection and in vitro motility assays. Only EDG2 overexpression significantly restored motility to Nm23-H1- suppressed cancer cells and it enhanced motility by 60-fold in these cells. In addition, silencing EDG2 expression with siRNA, reduced the motile phenotype of metastatic breast cancer cells. These data suggest that Nm23-H1 suppresses metastasis, at least in part, through downregulation of EDG2 expression and that compounds directed toward EDG2 may be useful for treating aggressive, low Nm23-H1-expressing breast tumors. Keywords: Human MDA-MB-435 Breast cancer derived cell lines
2007-04-30 | GSE7549 | GEO
Project description:Breast cancer brain metastasis has been recognized as one of the central issues in breast cancer research. Elucidation of the process and pathway that mediate this step is expected to provide important clues for a better understanding of breast cancer metastasis. Increasing evidence suggests that the aberrant glycosylation patterns greatly contribute to the cell invasion and cancer metastasis. Herein, we combined next generation RNA sequencing with liquid chromatograph-tandem mass spectrometry based proteomic and N-glycomic analysis from five breast cancer cell lines and one brain cancer cell line to investigate the possible mechanism of breast cancer brain metastasis. 24763 genes were identified including 14551 differentially expressed genes across six cell lines while proteomic analysis allowed the quantitation of 1096 differentially expressed proteins with approximately 83.8% proteins’ regulation matching their gene expression change. The genes/proteins associated with cell movement were highlighted in the breast cancer brain metastasis. Integrin signaling pathway and the up-regulation of α-integrin (ITGA2, ITGA3) associated with the brain metastatic process was shown through Ingenuity Pathway Analysis (IPA). Overall 91 glycosylation genes were selected from transcriptomic data and all exhibited differential expression. 12 glycogenes showed unique expression in 231BR. The regulation of these genes could result in an activation prediction of sialylation function in 231BR by ingenuity pathway analysis. In agreement with the changes of glycogenes, 60 N-glycans out of 63 identified exhibited differential expression among cell lines. The correlation of glycogenes and glycans revealed the importance of sialylation and sialylated glycans in breast cancer brain metastasis. Highly sialylated glycans, which were up-regulated in brain seeking cell line 231BR, probably contributes to brain metastasis.
2020-05-26 | PXD010506 | Pride
Project description:Breast cancer metastasis to bone is a critical determinant of long-term survival after treatment of primary tumors. We used a mouse model of spontaneous bone metastasis to determine new molecular mechanisms. Differential transcriptome comparisons of primary and metastatic tumor cells revealed that a substantial set of genes suppressed in bone metastases were highly enriched for promoter elements for the type I interferon (IFN) regulatory factor, Irf7, itself suppressed in mouse and human metastases. The critical function of the Irf7 pathway was demonstrated by restoration of exogenous Irf7 or systemic interferon administration, which significantly reduced bone metastases and prolonged metastasis-free survival. Using mice deficient in the type I receptor (Ifnar1-/-) or mature B, T and NK cell responses (NOD Scid IL-2rγ-/- mice), we demonstrated that Irf7-driven suppression of metastasis was reliant on IFN signaling to host immune cells. Metastasis suppression correlated with decreased accumulation of myeloid-derived suppressor cells and increased CD4++, CD8 T cells and NK cells in the peripheral blood and was reversed by depletion of CD8+ cells and NK cells. Clinical importance of our findings was demonstrated as increased primary tumor Irf7 expression predicted prolonged bone and lung metastasis-free survival. Thus we report for the first time, a novel innate immune pathway, intrinsic to breast cancer cells, whose suppression in turn restricts systemic immunosurveillance to enable metastasis. This pathway may constitute a novel therapeutic target for restricting breast cancer metastases. Microarrays were used to profile transcriptional alterations inherent in tumor cells growing in bone when compared to matched primary tumor cells in the 4T1.2 murine mammary tumor model. Primary and metastasized tumor were isolated from the same mouse with 4 independent biological replicates.
2012-07-17 | E-GEOD-37975 | biostudies-arrayexpress
Project description:Metastasis is a complex multi-step process requiring the concerted action of many genes and is the primary cause of cancer deaths. Pathways that regulate metastasis enhancement and suppression both contribute to tumor dissemination process. In order to identify novel metastasis suppressors, we set up a forward genetic screen in a mouse model. We transduced a genome-wide RNAi library into the non-metastatic 168FARN breast cancer cell line, orthotopically transplanted the cells into mouse mammary fat pads, and then selected for cells that could metastasize to the lung and identified an RNAi for the KLF17 gene. Conversely, ectopic expression of KLF17 in highly metastatic 4T1 breast cancer cell line inhibited their ability to metastasize from the mammary fat pad to the lung. We showed that suppression of KLF17 expression promotes breast cancer cell invasion and epithelial-mesenchymal transition (EMT). We also showed that KLF17 functions by directly binding to the promoter of Id-1, a key metastasis regulator in breast cancer, to inhibit its transcription. Finally, we demonstrated that KLF17 expression is significantly down-regulated in primary human breast cancer samples and that the combined expression patterns of KLF17 and Id-1 can serve as a potential biomarker for lymph node metastasis in breast cancer.
2009-11-30 | GSE17081 | GEO
Project description:Metastasis is the main cause of mortality of breast cancer. To explore the mechanisms of arsenic trioxide (ATO) in inhibition of breast cancer metastasis, ATO regulated genes in breast cancer MDA-MB-231 and LM2-4175 cells were studied. After data analysis, ATO regulated genes were involved in TP53, TGFβ and TNFα signaling pathways. Furthermore, TGFβ and TNFα activated genes in breast cancer MDA-MB-231 cells were studied.
2023-04-16 | GSE184828 | GEO
Project description:Pre-operative progesterone intervention has been shown to confer a survival benefit to breast cancer patients independent of their progesterone receptor (PR) status, raising a question about how progesterone affects the outcome of PR-negative cells. Here, we identify up-regulation of a Serum- and glucocorticoid-regulated kinase gene, SGK1 and an N-Myc Downstream Regulated Gene 1, NDRG1, along with down-regulation of miR-29a and miR-101-1 targeting 3’UTR region of SGK1, to differential extents in a PR dependent manner in breast cancer cells. We further demonstrate a novel dual-phase transcriptional and post-transcriptional regulation of SGK1 in response to progesterone leading to up-regulation of a tumor metastasis suppressor gene, NDRG1, mediated by a set of AP-1 network genes. The NDRG1 further inactivates a set of kinases impeding the invasion and migration of breast cancer cells. In summary, we propose a model for the mode of action of progesterone in breast cancer deciphering the molecular basis of a randomized clinical trial studying the effect of progesterone in breast cancer with a potential to improve the prognosis of breast cancer patients for receiving pre-operative progesterone treatment.
2018-10-19 | E-MTAB-6742 | biostudies-arrayexpress
Project description:Breast cancer invasive growth, metastasis and therapeutic resistance affects the clinical ourcome. We explored the epigenetic mechanisms that control these process in breast cancer cell line, MDA-MB-231 by knocking down a lysine specific demethylase KDM3A We used microarrays to detail the global programme of gene expression underlying cellularisation and identified distinct classes of up-regulated genes during this process.
2016-06-29 | GSE83818 | GEO