The BET inhibitor JQ1 selectively impairs the tumour response to hypoxia and downregulates CA9 and angiogenesis in triple receptor negative breast cancer
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
SUBMITTER: Syed Haider
PROVIDER: E-MTAB-4604 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
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Project description:During tumour growth cancer cells are subject to and selected by microenvironmental stress. The selection of such cells allows for continued growth and survival, during hypoxia, acidosis, nutritional deprivation, drug treatment and radiation. However, there is great microenvironmental heterogeneity in every tumour. Must studies of gene regulation in vitro investigate whole cell populations, often by western blotting or mRNA expression. Thus, the individual variability of gene induction that could lead to selection, and basal cell molecular variability on which the selection operates, basic Darwinian principles, are not defined. We previously showed that two distinct populations can often be induced in epithelial tumour cell lines under hypoxia, identified by induction of Carbonic Anhydrase 9 [CA9].Here, we investigated the heterogeneity of breast cancer cells, and the relationship to the CA9 positive population in hypoxia, by using single cell sequencing analysis.
2021-09-09 | GSE134038 | GEO
Project description:MCF7 cells exposed in 0.1% hypoxia for 72h and then stained and sorted into CA9+ve and CA9-ve populations and a differential gene expression analysis was performed between the 2 cell populations.
2013-05-05 | E-MTAB-1387 | biostudies-arrayexpress
Project description:Estrogen signaling pathway is critical for breast cancer development and has remained the major adjuvant therapeutic target for this disease. Tamoxifen has been used in clinic for many years to treat ER-positive breast cancer. However a great many (30%) suffer relapse due to drug resistance. In this study, the bromodomain inhibitor JQ1 was found to down-regulate ERalpha gene expression and have anti-tumor effect in cultured tamoxifen-resisant breast cancer cells. We used microarrays to detail the global programme of gene expression in tamoxifen-resistant MCF7 cells treated with the bromodomain inhibitor JQ1. Tamoxifen-resistant breast cancer MCF7 cells were treated with DMSO (vehicle) or JQ1 (0.2 uM) for 24 hours before total RNA was purified for microarray. Each sample was triplicated.
2014-03-01 | E-GEOD-49124 | biostudies-arrayexpress
Project description:Background: Gene expression profiling has been used extensively within breast cancer research. Patient matched transcriptomic studies of tumour samples before and after treatment offer great potential and have been initiated, but tend not to include a control group. Here we examine gene expression changes between patient-matched core biopsies and surgical resection samples in the absence of treatment, to consider sampling methods and tumour heterogeneity. Patients and Methods: Illumina BeadArray technology was used to measure dynamic changes in gene expression from thirty-seven paired baseline and surgically excised breast tumour samples obtained from women receiving no treatment prior to surgery. Results: Patient-matched sample pairs had significantly higher correlations than samples between different individuals, demonstrating that tumour heterogeneity and intra-tumour differences are less prominent than inter-tumour/patient differences. Perhaps surprisingly, consistent changes in gene expression were identified during the diagnosis-surgery interval, despite a lack of treatment. 50 genes were significantly differentially expressed (48 up, 2 down; FDR 0.05) in a manner that appears independent of both subtype and the sampling-interval length. Gene set enrichment analysis using four independent treated datasets has implicated the tumour sampling method as the likely cause of these expression changes which include increases in early growth response genes such as EGR1, 2 and 3 along with DUSP1 and FOS. Our data does not support the idea that there is a significant wounding or immune response. Conclusion: This is the largest cohort of patient-matched transcriptome profiling of tumours from patients receiving no treatment between diagnosis and surgery to date. It has revealed that consistent changes in gene expression do exist between diagnostic core biopsy and the surgical excision sample. We have confirmed these findings in a number of published breast cancer datasets. Ultimately, researchers should be aware of the potential for the tumour sampling method to introduce a confounding factor in future neoadjuvant studies. 37 paired patient-matched whole-transcriptome profiled primary breast tumours from patients receiving no treatment between diagnosis and surgery. Superseries is a product of two integrated individual batches.
2016-08-08 | E-GEOD-76726 | biostudies-arrayexpress
Project description:Background: Gene expression profiling has been used extensively within breast cancer research. Patient matched transcriptomic studies of tumour samples before and after treatment offer great potential and have been initiated, but tend not to include a control group. Here we examine gene expression changes between patient-matched core biopsies and surgical resection samples in the absence of treatment, to consider sampling methods and tumour heterogeneity. Patients and Methods: Illumina BeadArray technology was used to measure dynamic changes in gene expression from thirty-seven paired baseline and surgically excised breast tumour samples obtained from women receiving no treatment prior to surgery. Results: Patient-matched sample pairs had significantly higher correlations than samples between different individuals, demonstrating that tumour heterogeneity and intra-tumour differences are less prominent than inter-tumour/patient differences. Perhaps surprisingly, consistent changes in gene expression were identified during the diagnosis-surgery interval, despite a lack of treatment. 50 genes were significantly differentially expressed (48 up, 2 down; FDR 0.05) in a manner that appears independent of both subtype and the sampling-interval length. Gene set enrichment analysis using four independent treated datasets has implicated the tumour sampling method as the likely cause of these expression changes which include increases in early growth response genes such as EGR1, 2 and 3 along with DUSP1 and FOS. Our data does not support the idea that there is a significant wounding or immune response. Conclusion: This is the largest cohort of patient-matched transcriptome profiling of tumours from patients receiving no treatment between diagnosis and surgery to date. It has revealed that consistent changes in gene expression do exist between diagnostic core biopsy and the surgical excision sample. We have confirmed these findings in a number of published breast cancer datasets. Ultimately, researchers should be aware of the potential for the tumour sampling method to introduce a confounding factor in future neoadjuvant studies. 37 paired patient-matched whole-transcriptome profiled primary breast tumours from patients receiving no treatment between diagnosis and surgery. Superseries is a product of two integrated individual batches.
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Project description:Cancer cells frequently depend on chromatin regulatory activities to maintain a malignant phenotype. Here, we show that leukemia cells require the mammalian SWI/SNF chromatin remodeling complex for their survival and aberrant self-renewal potential. While Brg1, an ATPase subunit of SWI/SNF, is known to suppress tumor formation in several cancer types, we found that leukemia cells instead rely on Brg1 to support their oncogenic transcriptional program, which includes Myc as one of its key targets. To account for this context-specific function, we identify a cluster of lineage-specific enhancers located 1.7 megabases downstream of Myc that are occupied by SWI/SNF, as well as the BET protein Brd4. Brg1 is required at these distal elements to maintain transcription factor occupancy and for long-range chromatin looping interactions with the Myc promoter. Notably, these distal Myc enhancers coincide with a region that is focally amplified in 3% of acute myeloid leukemia. Together, these findings define a leukemia maintenance function for SWI/SNF that is linked to enhancer-mediated gene regulation, providing general insights into how cancer cells exploit transcriptional coactivators to maintain oncogenic gene expression programs To profile the basal transcription level, we performed NSR and PolyA+ (illumine TruSeq) in a murine AML RN2 cell lines. To define the rapid downregulated genes in response to JQ1, BET bromodomian inhibitor, in RN2 cell, we performed RNA-seq in RN2 exposing to 250nM JQ1 for 48h time course.
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Project description:Transcriptome profiling of tumour-initiating cells was performed under normoxia and hypoxia conditions for two time points: 3 and 7 days. The cell culture was established from fresh patient material (colorectal tumour) and maintained in spheroid culture condition.
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Project description:A hallmark of solid tumours is the development of hypoxic regions where rapidly growing transformed cells outstrip their blood supply. Tumour cells in these starved regions sense reduced levels of oxygen and switch on genes that help them to adapt, survive and continue growing. Since hypoxia is a key physiological difference between normal and cancer tissue, an opportunity exists to selectively kill tumour cells by exploiting the differences in protein expression between normal and hypoxic tumour tissue. However, a major challenge is to identify druggable hypoxia-induced proteins critical for tumour cell survival. This is especially important in cancers of unmet need where hypoxia gene signatures correlate with poor prognosis (for example, colorectal cancers). To identify new hypoxia-induced proteins, we performed SILAC-based proteomics on colorectal cancer cells exposed to normoxia and hypoxia. In this study, we identify a new hypoxia-activated GPCR signalling axis that enables colorectal tumour cells to survive the microenvironmental stress of hypoxia. Our findings uncover a previously unappreciated role for this GPCR-axis as a key regulator of the adaptive response to hypoxia and highlght an opportunity to exploit tumour-associated hypoxia for therapy.
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