Gene Expression Profile of Resistant vs Sensitive Breast Cancer Tissues to Taxane Treatment
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE99225 | GEO | 2017/05/24
SECONDARY ACCESSION(S): PRJNA387596
REPOSITORIES: GEO
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2016-03-01 | GSE67256 | GEO
Project description:Clusterin (CLU) is a stress-activated molecular chaperone that confers treatment resistance to taxanes when highly expressed. While CLU inhibition potentiates activity of taxanes and other anti-cancer therapies in preclinical models, progression to treatment resistant disease still occurs implicating additional compensatory survival mechanisms. Taxanes are believed to selectively target cells in mitosis, a complex mechanism controlled in part by balancing antagonistic roles of Cdc25C and Wee1 in mitosis progression. Our data indicate that CLU silencing induces a constitutive activation of Cdc25C, which delays mitotic exit and hence sensitizes cancer cells to mitotic-targeting agents such taxanes. Unchecked Cdc25C activation leads to mitotic catastrophe and cell death unless cells upregulate protective mechanisms mediated through the cell cycle regulators Wee1 and Cdc2. In this study we show that CLU silencing induces a constitutive activation of Cdc25C via the phosphatase PP2A but leads to relief of negative feedback inhibition and activation of Wee1-Cdc2 to promote survival and limit therapeutic efficacy. Simultaneous inhibition of CLU-regulated cell cycle effectors, like PP2A and Wee1, may improve synergistic responses of biologically rational combinatorial regimens using taxanes and CLU inhibitors Biological triplicate of PC3 treated with siClusterin were compared to biological trplicate of PC3 treated with siScramblein
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Project description:The taxanes, namely Paclitaxel and Docetaxel, are important and widely used cancer chemotherapy drugs in the treatment of invasive and metastatic human breast cancer. Although treatment with the taxanes is beneficial to many patients, drug-responsive tumors in patients with metastatic breast cancer often display resistance to these drugs, either initially or over time following the continued administration of chemotherapy drugs. To investigate the patterns of cross-resistance with the taxane drugs and to identify potential mechanisms of resistance, we generated a series of MDA-MB-231 taxane resistant cell lines. We then used microarrays to determine gene expression differences between sensitive, Docetaxel and Paclitaxel resistant MDA-MB-231 cells.
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Project description:The taxanes, namely Paclitaxel and Docetaxel, are important and widely used cancer chemotherapy drugs in the treatment of invasive and metastatic human breast cancer. Although treatment with the taxanes is beneficial to many patients, drug-responsive tumors in patients with metastatic breast cancer often display resistance to these drugs, either initially or over time following the continued administration of chemotherapy drugs. To investigate the patterns of cross-resistance with the taxane drugs and to identify potential mechanisms of resistance, we generated a series of MDA-MB-231 taxane resistant cell lines. We then used microarrays to determine gene expression differences between sensitive, Docetaxel and Paclitaxel resistant MDA-MB-231 cells. RNA isolated from three independent passages of sensitive, Docetaxel and Paclitaxel resistant cell lines and purified using the Qiagen RNeasy Mini Kit. Total RNA was processed and hybridized to Affymetrix Genechip HU133A arrays.
2011-04-22 | E-GEOD-28784 | biostudies-arrayexpress
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Project description:Metastatic castrate-resistant prostate cancer (mCRPC) is a genetically and phenotypically heterogeneous cancer where advancements are needed in biomarker discovery and targeted therapy. A critical and often effective component of treatment includes taxanes. We performed one of the first high throughput screens across a cohort of 30 diverse patient-derived CRPC organoids to a library of 78 drugs. Combining quantitative response measures with transcriptomic analyses demonstrated that HNF1 Homeobox A (HNF1A) drives a transcriptional program of taxane resistance, dependent upon cellular inhibitor of apoptosis protein 2 (cIAP2). Monotherapy with cIAP2 inhibitor LCL161 was sufficient to treat HNF1A+ models of mCRPC previously resistant to docetaxel.
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Project description:Taxane resistant breast cancer cells
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Project description:Each of the six ovarian carcinoma cell lines was exposed to docetaxel or paclitaxel at IC50 levels (the concentration required to kill 50% of the population). After several passages at this initial concentration of taxanes, drug concentrations were escalated, and this process was repeated until variants displayed at least a 10-fold resistance to the selecting agents. mRNA and genomic DNA were isolated from the parental and resistant variants, and hybridized onto Stanford human cDNA microarrays containing about 42000 elements. We analyzed the gene expression profiles and copy number alterations, and identified a cluster of genes co-activated with MDR1 on chromosome arm 7q21. In six of these variants, regional activation was driven by gene copy number alterations, with low-level gains or high-level amplifications spanning the involved region. However, three variants displayed a regional increases in gene expression even without concomitant gene copy number changes. These results suggest that regional gene activation may be a fundamental mechanism for acquired drug resistance, with or without changes in gene dosage. In addition to numerical and structural chromosomal changes driven by genome instability in cancer cells, other mechanisms might be involved in MDR1 regional activation, such as chromatin remodeling and DNA or histone modifications of the 7q21 region. A compound treatment design type is where the response to administration of a compound or chemical (including biological compounds such as hormones) is assayed. Keywords: compound treatment design, arrayCGH, expression profiles
2006-02-25 | GSE4173 | GEO
Project description:The development of taxane resistance remains a major challenge for castration resistant prostate cancer (CR-PCa), despite the effectiveness of taxanes in prolonging patient survival. To uncover novel targets, we performed an epigenetic drug screen on taxane (docetaxel and cabazitaxel) resistant CR-PCa cells. We identified BRPF reader proteins, along with several epigenetic groups (CBP/p300, Menin-MLL, PRMT5 and SIRT1) that act as targets effectively reversing the resistance mediated by ABCB1. Targeting BRPFs specifically resulted in the resensitization of resistant cells, while no such effect was observed on the sensitive compartment. These cells were successfully arrested at the G2/M phase of cell cycle and underwent apoptosis upon BRPF inhibition, confirming the restoration of taxane susceptibility. Pharmacological inhibition of BRPFs reduced ABCB1 activity, indicating that BRPFs may be involved in an efflux-related mechanism. Indeed, ChIP-qPCR analysis confirmed binding of BRPF1 to the ABCB1 promoter suggesting direct regulation of the ABCB1 gene at the transcriptional level. RNA-seq analysis revealed that BRPF1 knockdown affects the genes enriched in mTORC1 and UPR signaling pathways, revealing potential mechanisms underlying its functional impact, which is further supported by the enhancement of taxane response through the combined inhibition of ABCB1 and mTOR pathways, providing evidence for the involvement of multiple BRPF1-regulated pathways. Beyond clinical attributes (Gleason score, tumor stage, therapy outcome, recurrence), metastatic PCa databases further supported the significance of BRPF1 in taxane resistance, as evidenced by its upregulation in taxane-exposed PCa patients.
2023-11-17 | GSE247557 | GEO
Project description:Each of the six ovarian carcinoma cell lines was exposed to docetaxel or paclitaxel at IC50 levels (the concentration required to kill 50% of the population). After several passages at this initial concentration of taxanes, drug concentrations were escalated, and this process was repeated until variants displayed at least a 10-fold resistance to the selecting agents. mRNA and genomic DNA were isolated from the parental and resistant variants, and hybridized onto Stanford human cDNA microarrays containing about 42000 elements. We analyzed the gene expression profiles and copy number alterations, and identified a cluster of genes co-activated with MDR1 on chromosome arm 7q21. In six of these variants, regional activation was driven by gene copy number alterations, with low-level gains or high-level amplifications spanning the involved region. However, three variants displayed a regional increases in gene expression even without concomitant gene copy number changes. These results suggest that regional gene activation may be a fundamental mechanism for acquired drug resistance, with or without changes in gene dosage. In addition to numerical and structural chromosomal changes driven by genome instability in cancer cells, other mechanisms might be involved in MDR1 regional activation, such as chromatin remodeling and DNA or histone modifications of the 7q21 region. A compound treatment design type is where the response to administration of a compound or chemical (including biological compounds such as hormones) is assayed. Computed
2006-02-24 | E-GEOD-4173 | biostudies-arrayexpress