Intraductal Adaptation of the 4T1 Mouse Model of Breast Cancer Reveals Effects of the Epithelial Microenvironment on Tumor Progression and Metastasis
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE129106 | GEO | 2019/04/02
REPOSITORIES: GEO
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Project description:The present study was designed to identify Mkl1 target genes whose expression requires either the B1 site of Mkl1 and serum response factor (SRF), respectively, or the SAP domain of Mkl1. For this purpose, we obtained the transcriptomes of four stable 4T1 cell lines that either overexpress full length Mkl1-RFP (4T1-FL), Mkl1-RFP with a mutated SRF-interaction site (4T1-mutB1), Mkl1-RFP with a deletion of the SAP domain (4T1-ΔSAP) or an empty vector encoding RFP alone (4T1 control).
2016-07-15 | GSE59459 | GEO
Project description:The present study was designed to identify Mkl1 target genes whose expression requires either the B1 site of Mkl1 and serum response factor (SRF), respectively, or the SAP domain of Mkl1. For this purpose, we obtained the transcriptomes of four stable 4T1 cell lines that either overexpress full length Mkl1-RFP (4T1-FL), Mkl1-RFP with a mutated SRF-interaction site (4T1-mutB1), Mkl1-RFP with a deletion of the SAP domain (4T1-ÎSAP) or an empty vector encoding RFP alone (4T1 control). Stable 4T1 cell lines were grown in triplicates in 0.03% FCS/DMEM medium for 48 h before total RNA was extracted. RNA was converted into labeled cDNA and hybridized to Affymetrix GeneChip Mouse Gene 1.0 ST arrays. RMA normalized expression values were calculated with the affy package from the Bioconductor 2.4 release (1) and differentially expressed genes were identified using moderated t-statistics calculated with the empirical Bayes method as implemented in the Bioconductor limma package (2). To be considered as differentially expressed between 4T1-FL and 4T1-mutB1 or 4T1-âSAP cells, genes had to pass the filters: adjusted P-value ⤠0.01 (with Benjamin-Hochberg false discovery correction), a minimum absolute linear fold change difference of 2.0 and a minimum average expression value of 4.0 (log2). References: (1) Gentleman, R., Carey, V., Bates, D., Bolstad, B., Dettling, M., Dudoit, S., Ellis, B., Gautier, L., Ge, Y., Gentry, J., Hornik, K., Hothorn, T., Huber, W., Iacus, S., Irizarry, R., Leisch, F., Li, C., Maechler, M., Rossini, A., Sawitzki, G., Smith, C., Smyth, G., Tierney, L., Yang, J., Zhang, J. (2004) Bioconductor: open software development for computational biology and bioinformatics. Genome Biology 5, R80 (2) Smyth, G. K., Speed, T. (2003) Normalization of cDNA microarray data. Methods 31, 265-273
2016-07-15 | E-GEOD-59459 | biostudies-arrayexpress
Project description:Novel therapies targeting cancer stem cells (CSCs), which play critical roles in chemo- and radio-resistance, metastasis, and possibly resistance against cancer immunotherapy including granulocyte-macrophage colony-stimulating factor (GM-CSF) gene-transduced tumor cell vaccines, may provide beneficial clinical outcomes. Here, we used syngeneic immunocompetent mice that allowed precise evaluation of the immunogenicity of the side population (SP) isolated from 4T1 murine breast carcinoma (4T1-SP) cells as putative CSCs. 4T1-SP cells showed various stem cell properties including high capacities for colony formation and tumorigenicity as well as high expression of phosphorylated signal transducer and activator of transcription-3 and vascular endothelial growth factor that are inductive of immune tolerance. Despite these progressive malignant characteristics of 4T1-SP cells, subcutaneous injection of non-transmissible Sendai virus-mediated GM-CSF gene-transduced 4T1-SP (4T1-SP/GM) cells remarkably impaired their tumorigenicity compared with that of the controls. This impairment of tumorigenicity was partially dependent on CD8+ T cells in concert with CD4+ T cells and natural killer cells. Notably, therapeutic vaccinations using irradiated 4T1-SP/GM cells markedly suppressed tumor development of subcutaneously transplanted 4T1-SP cells compared with that of the controls including irradiated 4T1-non-SP/GM cells. Tumor suppression was accompanied by robust accumulation of mature dendritic cells at vaccination sites and systemic Th1-based cellular immunity. Moreover, vaccinations comprising primary 4T1-SP cells isolated from transplanted 4T1-SP tumors elicited antitumor effects. cDNA microarray analysis showed that 4T1-SP cells predominantly expressed genes of cancer-related antigens including cancer/testis antigens. Collectively, we demonstrate that SP cell-based vaccinations induce effective antitumor immunity that may improve the efficacy of SP cell-based immunotherapy. Gene expression profiles were compared between sorted 4T1-SP and 4T1-NSP cells.
2014-04-01 | E-GEOD-53444 | biostudies-arrayexpress
Project description:Purpose: Compare the tumor outgrowth and immunology of an immunocompetent 4T1- and Py230-based intraductal model for triple-negative breast cancer (TNBC). Methods: BALB/c-derived 4T1 and C57BL/6-derived Py230 mammary tumor cells were side-by-side intraductally inoculated in lactating and syngeneic mice, 4T1 and Py230 primary tumors were subsequently resected at 1, 3 and 6 weeks (w) post-inoculation (p.i.), and RNA was isolated from the 4T1 and Py230 primary tumors using in house developed protocols. Results: The differentially expressed genes in the 4T1 versus Py230 primary tumor datasets at the 3 different time points were categorized into 28 hallmark gene sets using GSEA. Nine hallmarks could be related to tumor immunology and collectively showed a decreased difference in expression over time, although every immunology-related gene set remained most expressed in 4T1 primary tumors across all time points. Seven hallmarks could be related to cellular mitosis and tumor progression and were significantly upregulated at 1 w p.i. in 4T1 primary tumors, whereas at 3 w p.i. they became significantly upregulated in Py230 primary tumors, indicative for enhanced Py230 tumor proliferation. The hallmark epithelial-mesenchymal transition was significantly upregulated at 3 w p.i. in 4T1 compared to Py230 primary tumors, indicative for metastatic progression. Gene sets involved in adipose/stromal processes within the mammary gland were downregulated or weakly expressed at 1 w p.i., but became upregulated at 3 w p.i. in 4T1 compared to Py230 primary tumors, indicating that at the time 4T1 tumor cells were less proliferative compared to Py230 tumor cells, the surrounding stroma and fat tissue were more active in the 4T1- compared to the Py230-based intraductal model. The hallmark androgen response also showed a significantly upregulated expression in Py230 tumors at 3 and 6 w p.i., indicating that androgen signaling is important in invasive Py230 tumors. Conclusion: Our findings highlight an innovative 4T1- and Py230-based intraductal mouse model for TNBC with a different tumor outgrowth and associated tumor microenvironment. These differential models may broadly represent the clinically observed TNBC diversity and together provide a powerful tool to evaluate therapeutics.
2019-11-20 | GSE140192 | GEO
Project description:Novel therapies targeting cancer stem cells (CSCs), which play critical roles in chemo- and radio-resistance, metastasis, and possibly resistance against cancer immunotherapy including granulocyte-macrophage colony-stimulating factor (GM-CSF) gene-transduced tumor cell vaccines, may provide beneficial clinical outcomes. Here, we used syngeneic immunocompetent mice that allowed precise evaluation of the immunogenicity of the side population (SP) isolated from 4T1 murine breast carcinoma (4T1-SP) cells as putative CSCs. 4T1-SP cells showed various stem cell properties including high capacities for colony formation and tumorigenicity as well as high expression of phosphorylated signal transducer and activator of transcription-3 and vascular endothelial growth factor that are inductive of immune tolerance. Despite these progressive malignant characteristics of 4T1-SP cells, subcutaneous injection of non-transmissible Sendai virus-mediated GM-CSF gene-transduced 4T1-SP (4T1-SP/GM) cells remarkably impaired their tumorigenicity compared with that of the controls. This impairment of tumorigenicity was partially dependent on CD8+ T cells in concert with CD4+ T cells and natural killer cells. Notably, therapeutic vaccinations using irradiated 4T1-SP/GM cells markedly suppressed tumor development of subcutaneously transplanted 4T1-SP cells compared with that of the controls including irradiated 4T1-non-SP/GM cells. Tumor suppression was accompanied by robust accumulation of mature dendritic cells at vaccination sites and systemic Th1-based cellular immunity. Moreover, vaccinations comprising primary 4T1-SP cells isolated from transplanted 4T1-SP tumors elicited antitumor effects. cDNA microarray analysis showed that 4T1-SP cells predominantly expressed genes of cancer-related antigens including cancer/testis antigens. Collectively, we demonstrate that SP cell-based vaccinations induce effective antitumor immunity that may improve the efficacy of SP cell-based immunotherapy.
2014-04-01 | GSE53444 | GEO
Project description:Molecular comparison between control 4T1 cells with MMP3-low 4T1 cells RNA extracted from biological triplicates of each of the above mentioned cell populations were subjected to microarray analysis
2015-04-22 | E-GEOD-68100 | biostudies-arrayexpress
Project description:In this project, 4T1 parental cells (4T1/WT) were exposed to increasing concentrations of epirubicin (EPB) to establish a novel multi-drug resistant CSC-like breast cancer cell line (4T1/EPB). The ubiquitinated proteins were enriched from 4T1/WT or 4T1/EPB derived cell lysate using a-Al2O3-Vx3 nanoparticles to produce the covalently linked product UPs nanovaccine. Label-free LC-MS/MS mass spectrometry was used to detect the type and amount of enriched proteins of UPs from the 4T1/WT cells and the 4T1/EPB cells.
2021-08-20 | PXD027822 | Pride
Project description:Molecular comparison between control 4T1 cells with MMP3-low 4T1 cells
2015-04-22 | GSE68100 | GEO
Project description:This SuperSeries is composed of the following subset Series: GSE19220: Expression data from TKI258 treated 4T1 cells GSE19221: Expression data from TKI258 treated 4T1 tumors Refer to individual Series
2010-07-07 | E-GEOD-19222 | biostudies-arrayexpress