IRE1 modulates expression of a set of tumor suppressor miRNAs in luminal breast cancer cells.
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ABSTRACT:
PROVIDER: PRJNA657550 | ENA |
REPOSITORIES: ENA
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Project description:To explore the regulatory mechanism by which inositol-requiring enzyme 1 (IRE1) regulates oncogenic factors, particularly RAB3B, in luminal breast cancer cells, we blocked IRE1 activity in breast cancer cell lines by using the IRE1 inhibitor 4μ8C or expressing IRE1 dominant-negative for miRNA microarray analysis. SUM52 and SUM225 lines with high-level IRE1 expression were treated with 4μ8C for 2 days. The IRE1 kinase dominant-negative mutant K599A or K907A was also used to suppress IRE1 kinase or RNase activity in SUM52 cells. The miRNA microarray analysis revealed a landscape change in miRNA expression profiling in IRE1-inhibited luminal breast cancer cells. Using a criterion of p < 0.05 in miRNA analysis, we identified 41 miRNAs in both SUM52 and SUM225 cells that were altered after inhibiting IRE1 activity. Additionally, we exogenously overexpressed wild-type IRE1 in human nontumorigenic mammary epithelial MCF10A cells and then performed miRNA array assays. When we combined miRNA data from both IRE1 inhibition models in breast cancer cells and exogenous overexpression of IRE1 in MCF10A cells (p<0.05), we identified 5 miRNAs (3607-3p, 374a-5p, 4764-3p, 516a-3p, and 6073) that were upregulated in IRE1-inhibited breast cancer cells and downregulated in MCF10A-IRE1 cells.
2021-01-15 | GSE156331 | GEO
Project description:To understand the mechanistic basis by which inositol-requiring enzyme 1 (IRE1) is involved in luminal breast cancer malignancy, we analyzed the transcriptomic signature that IRE1 regulates in breast cancer. We suppressed the activity of IRE1 RNase in luminal breast cancer SUM52 line by adenoviral-based over-expression of the IRE1 dominant-negative K599A or K907A, and then performed RNA-sequencing (RNA-seq) analysis with IRE1 dominant-negative and control SUM52 cells. Through the RNA-seq analysis, we identified 98 genes that were commonly upregulated (65 genes) or downregulated (33 genes) in K599A-expressing SUM52 (SUM52-K599A) or K907A-expressing SUM52 (SUM52-K907A) cells.
2021-01-15 | GSE156332 | GEO
Project description:The transcription factor c-Myb has been well characterized as an oncogene in several human tumor types, and its expression in the hematopoietic stem/progenitor cell population is essential for proper hematopoiesis. However, the role of c-Myb in mammopoeisis and breast tumorigenesis is poorly understood, despite its high expression in the majority of breast cancer cases (60-80%). We find that c-Myb high expression in human breast tumors correlates with the luminal/ER+ phenotype and a good prognosis. RNAi knock-down of endogenous c-Myb levels in the MCF7 luminal breast tumor cell line increases tumorigenesis both in vitro and in vivo, suggesting a tumor suppressor role in luminal breast cancer. We created a mammary-derived c-Myb expression signature and found it to be highly correlated with a published mature luminal mammary cell signature and least correlated with a mammary stem/progenitor lineage gene signature. These data describe, for the first time, a tumor suppressor role for the c-Myb proto-oncogene in breast cancer that has implications for understanding luminal tumorigenesis and for guiding treatment. refXsample
2010-10-15 | E-GEOD-21371 | biostudies-arrayexpress
Project description:BACKGROUND: The transcription factor c-Myb has been well characterized as an oncogene in several human tumor types, and its expression in the hematopoietic stem/progenitor cell population is essential for proper hematopoiesis. However, the role of c-Myb in mammopoeisis and breast tumorigenesis is poorly understood, despite its high expression in the majority of breast cancer cases (60-80%). METHODOLOGY/PRINCIPAL FINDINGS: We find that c-Myb high expression in human breast tumors correlates with the luminal/ER+ phenotype and a good prognosis. Stable RNAi knock-down of endogenous c-Myb in the MCF7 luminal breast tumor cell line increased tumorigenesis both in vitro and in vivo, suggesting a possible tumor suppressor role in luminal breast cancer. We created a mammary-derived c-Myb expression signature, comprised of both direct and indirect c-Myb target genes, and found it to be highly correlated with a published mature luminal mammary cell signature and least correlated with a mammary stem/progenitor lineage gene signature. CONCLUSIONS/SIGNIFICANCE: These data describe, for the first time, a possible tumor suppressor role for the c-Myb proto-oncogene in breast cancer that has implications for the understanding of luminal tumorigenesis and for guiding treatment.
2010-10-15 | GSE21371 | GEO
Project description:The UPR Transducer IRE1 Promotes Breast Cancer Malignancy by Degrading Tumor Suppressor microRNAs
| PRJNA657549 | ENA
Project description:We investigate the contribution of IRE1 signaling to the modulation of U87 glioma cells transcriptome upon various stresses. To this end, IRE1 control and IRE1 dominant negative expressing U87 glioma cells were subjected to environmental or chemical challenges and their transcriptome monitored using Affymetrix microarrays. Stress-induced transcriptome modulation in function of IRE1 proficiency/deficiency
2011-12-31 | E-GEOD-27306 | biostudies-arrayexpress
Project description:Activation of the IRE1/XBP1s signaling arm of the unfolded protein response (UPR) is a promising strategy to correct defects in endoplasmic reticulum (ER) proteostasis implicated in diverse diseases. However, no pharmacologic activators of this pathway identified to date are suitable for ER proteostasis remodeling through selective activation of IRE1/XBP1s signaling. Here, we use high-throughput screening to identify non-toxic compounds that induce ER proteostasis remodeling through IRE1/XBP1s activation. We employ transcriptional profiling to stringently confirm that our prioritized compounds selectively activate IRE1/XBP1s signaling without activating other cellular stress-responsive signaling pathways. Furthermore, we demonstrate that our compounds improve ER proteostasis of destabilized variants of amyloid precursor protein (APP) through an IRE1-dependent mechanism and reduce APP-associated mitochondrial toxicity in cellular models. These results establish highly-selective IRE1 activating compounds that can be widely employed to define the functional importance of IRE1/XBP1s activity for ER proteostasis regulation in the context of health and disease.
2020-04-17 | GSE148802 | GEO
Project description:We investigate the contribution of IRE1 signaling to the modulation of U87 glioma cells transcriptome upon various stresses. To this end, IRE1 control and IRE1 dominant negative expressing U87 glioma cells were subjected to environmental or chemical challenges and their transcriptome monitored using Affymetrix microarrays.
2011-12-31 | GSE27306 | GEO
Project description:We measured steady-state mRNA levels by microarray hybridization, comparing WT, (delta)ire1, (delta)gcn4, and (delta)gcn2 cells treated with 2 mM DTT for 30 min (by which time the UPR is qualitatively complete) to untreated samples of the same genotype. WT cells were taken as a positive control for UPR induction, and (delta)ire1 cells as a negative control. Fold change in expression of a given gene was computed as the ratio of mRNA level in the treated sample to the level in an untreated sample of the same genotype. Values reported here are the log2 fold change. Keywords = unfolded protein response Keywords = UPR Keywords = ire1 Keywords = gcn4 Keywords = gcn2
2010-06-06 | E-GEOD-1688 | biostudies-arrayexpress
Project description:The role of the unfolded protein response (UPR) in the cellular innate response to RSV infection is not fully understood. To better the genomic targets for the IRE1-XBP1 pathway, RNA seq was conducted on RSV-infected small airway cells in the absence or presence of RSV infection and in the absence or presence of a selective IRE1a RNAse inhibitor. We identified expression changes in ~3.2K genes; of these, 279 required IRE1 and were enriched in IL-10 signaling and cytokine signaling pathways. These data indicate that IRE1a-XBP1s regulates genes important in epithelial mesenchymal transition, hexosamine biosynthesis and anti-viral signaling.
2023-04-30 | GSE228327 | GEO