Homo sapiens
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ABSTRACT:
OTHER RELATED OMICS DATASETS IN: E-GEOD-3929S-EPMC2816652E-GEOD-3927
PROVIDER: PRJNA94337 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:Anthracycline resistance in four human cancer cell lines (HGU95A)
| PRJNA94339 | ENA
Project description:BACKGROUND: To date individual markers have failed to correctly predict resistance against anticancer agents in breast cancer. We used gene expression patterns attributable to chemotherapy-resistant cells to detect potential new biomarkers related to anthracycline resistance. One of the genes, PSMB7, was selected for further functional studies and clinical validation. METHODS: We contrasted the expression profiles of four pairs of different human tumour cell lines and of their counterparts resistant to doxorubicin. Observed overexpression of PSMB7 in resistant cell lines was validated by immunohistochemistry. To examine its function in chemoresistance, we silenced the gene by RNA interference (RNAi) in doxorubicin-resistant MCF-7 breast cancer cells, then cell vitality was measured after doxorubicin treatment. Microarray gene expression from GEO raw microarray samples with available progression-free survival data was downloaded, and expression of PSMB7 was used for grouping samples. RESULTS: After doxorubicin treatment, 79.8+/-13.3% of resistant cells survived. Silencing of PSMB7 in resistant cells decreased survival to 31.8+/-6.4% (P>0.001). A similar effect was observed after paclitaxel treatment. In 1592 microarray samples, the patients with high PSMB7 expression had a significantly shorter survival than the patients with low expression (P<0.001). CONCLUSION: Our findings suggest that high PSMB7 expression is an unfavourable prognostic marker in breast cancer.
2010-01-01 | S-EPMC2816652 | BioStudies
Project description:BACKGROUND:Drug resistance in breast cancer is the major obstacle to effective treatment with chemotherapy. While upregulation of multidrug resistance genes is an important component of drug resistance mechanisms in vitro, their clinical relevance remains to be determined. Therefore, identifying pathways that could be targeted in the clinic to eliminate anthracycline-resistant breast cancer remains a major challenge. METHODS:We generated paired native and epirubicin-resistant MDA-MB-231, MCF7, SKBR3 and ZR-75-1 epirubicin-resistant breast cancer cell lines to identify pathways contributing to anthracycline resistance. Native cell lines were exposed to increasing concentrations of epirubicin until resistant cells were generated. To identify mechanisms driving epirubicin resistance, we used a complementary approach including gene expression analyses to identify molecular pathways involved in resistance, and small-molecule inhibitors to reverse resistance. In addition, we tested its clinical relevance in a BR9601 adjuvant clinical trial. RESULTS:Characterisation of epirubicin-resistant cells revealed that they were cross-resistant to doxorubicin and SN-38 and had alterations in apoptosis and cell-cycle profiles. Gene expression analysis identified deregulation of histone H2A and H2B genes in all four cell lines. Histone deacetylase small-molecule inhibitors reversed resistance and were cytotoxic for epirubicin-resistant cell lines, confirming that histone pathways are associated with epirubicin resistance. Gene expression of a novel 18-gene histone pathway module analysis of the BR9601 adjuvant clinical trial revealed that patients with low expression of the 18-gene histone module benefited from anthracycline treatment more than those with high expression (hazard ratio 0.35, 95 % confidence interval 0.13-0.96, p = 0.042). CONCLUSIONS:This study revealed a key pathway that contributes to anthracycline resistance and established model systems for investigating drug resistance in all four major breast cancer subtypes. As the histone modification can be targeted with small-molecule inhibitors, it represents a possible means of reversing clinical anthracycline resistance. TRIAL REGISTRATION:ClinicalTrials.gov identifier NCT00003012 . Registered on 1 November 1999.
2016-01-01 | S-EPMC4744406 | BioStudies
Project description:Reliable clinical tests for predicting cancer chemotherapy response are not available and individual markers failed to correctly predict resistance against anticancer agents. We hypothesized that gene expression patterns attributable to chemotherapy-resistant cells can be used as a classification tool for chemoresistance and provide novel candidate genes involved in anthracycline resistance mechanisms. We contrasted the expression profiles of 4 different human tumor cell lines of gastric, pancreatic, colon and breast origin and of their counterparts resistant to the topoisomerase inhibitors daunorubicin or doxorubicin. We also profiled the sensitive parental cells treated with doxorubicin for 24h. We interrogated Affymetrix HGU133A and U95A arrays independently. We applied two independent methods for data normalization and used Prediction Analysis of Microarrays (PAM) for feature selection. In addition, we established data sets related to drug resistance by using a “virtual array” composed of features represented on both types of oligonucleotide arrays. We identified 71 candidate genes associated with doxorubicine/daunorubicine resistance. To validate the microarray data, we also analyzed the expression of 12 selected genes by quantitative RT-PCR or immunocytochemistry, respectively. While the comparison of drug-sensitive versus drug-resistant cells yields candidates associated with drug resistance, the 24h treatment of sensitive parental cells produced a distinct transcriptional profile related to short-term drug effects. Keywords: superSeries This reference Series links data in the following related Series: GSE3926 Anthracycline treatment and resistance in four human cancer cell lines (HGU133A) GSE3927 Anthracycline resistance in four human cancer cell lines (HGU95A)
2010-04-14 | E-GEOD-3929 | ArrayExpress
Project description:Reliable clinical tests for predicting cancer chemotherapy response are not available and individual markers failed to correctly predict resistance against anticancer agents. We hypothesized that gene expression patterns attributable to chemotherapy-resistant cells can be used as a classification tool for chemoresistance and provide novel candidate genes involved in anthracycline resistance mechanisms. We contrasted the expression profiles of 4 different human tumor cell lines of gastric, pancreatic, colon and breast origin and of their counterparts resistant to the topoisomerase inhibitors daunorubicin or doxorubicin. We also profiled the sensitive parental cells treated with doxorubicin for 24h. We interrogated Affymetrix HGU133A and U95A arrays independently. We applied two independent methods for data normalization and used Prediction Analysis of Microarrays (PAM) for feature selection. In addition, we established data sets related to drug resistance by using a “virtual array” composed of features represented on both types of oligonucleotide arrays. We identified 71 candidate genes associated with doxorubicine/daunorubicine resistance. To validate the microarray data, we also analyzed the expression of 12 selected genes by quantitative RT-PCR or immunocytochemistry, respectively. While the comparison of drug-sensitive versus drug-resistant cells yields candidates associated with drug resistance, the 24h treatment of sensitive parental cells produced a distinct transcriptional profile related to short-term drug effects. This SuperSeries is composed of the SubSeries listed below. Overall design: This reference Series links data in the following related Series: GSE3926 Anthracycline treatment and resistance in four human cancer cell lines (HGU133A) GSE3927 Anthracycline resistance in four human cancer cell lines (HGU95A)
2010-04-15 | GSE3929 | GEO
Project description:Drug resistance in breast cancer is the major obstacle to a successful outcome following chemotherapy treatment. While upregulation of multidrug resistance (MDR) genes is a key component of drug resistance in multiple cancers, the complexity and hierarchy of non-MDR driven drug resistance pathways are still largely unknown. The aim of this study was to identify pathways contributing to anthracycline resistance using isogenic drug resistant breast cancer cell lines. We generated isogenic MDA-MB-231, MCF7, SKBR3 and ZR-75-1 epirubicin-resistant breast cancer cell lines, which were cross-resistant to doxorubicin and SN-38; the SKBR3 cell line was also resistant to taxanes. Epirubicin-resistant cells were morphologically different from native cells, and had alterations in apoptosis and cell cycle profile. Using gene expression and small-molecule inhibitor analyses we identified deregulation of histone H2A and H2B genes in all four cell lines. These genes contribute to several biological pathways, which include cell cycle, chromosomal maintenance, epigenetics, RNA and mitochondrial transcription. Histone deacetylase and cell cycle/DNA damage small molecule inhibitors reversed resistance and were cytotoxic for all four epirubicin-resistant cell lines confirming that histone and cell cycle pathways are associated with epirubicin resistance. This study has established model systems for investigating drug resistance in all four breast cancer subtypes and revealed key pathways that contribute to anthracycline resistance. The global gene expression analysis included 4 parental (anthracycline sensitive) and 4 resistant breast cancer cell lines, in biological triplicates.
2014-01-24 | E-GEOD-54326 | ArrayExpress
Project description:Chemoresistance remains a major obstacle to successful treatment of breast cancer. Although soluble tumor necrosis factor-? (sTNF-?) has been implicated in mediating drug-resistance in human cancers, whether transmembrane tumor necrosis factor-? (tmTNF-?) plays a role in chemoresistance remains unclear. Here we found that over 50% of studied patients expressed tmTNF-? at high levels in breast cancer tissues and tmTNF-? expression positively correlated with resistance to anthracycline chemotherapy. Alteration of tmTNF-? expression changed the sensitivity of primary human breast cancer cells and breast cancer cell lines to doxorubicin (DOX). Overexpression of N-terminal fragment (NTF) of tmTNF-?, a mutant form with intact intracellular domain of tmTNF-? to transmit reverse signals, induced DOX-resistance. Mechanistically, the tmTNF-?/NTF-ERK-GST-? axis and tmTNF-?/NTF-NF-?B-mediated anti-apoptotic functions were required for tmTNF-?-induced DOX-resistance. In a xenograft mouse model, the combination of tmTNF-? suppression with chemotherapy significantly enhanced the efficacy of DOX. Our data indicate that tmTNF-? mediates DOX-resistance through reverse signaling and targeting tmTNF-? may be beneficial for the treatment of DOX-resistant breast cancer.
1000-01-01 | S-EPMC6013421 | BioStudies
Project description:The cytotoxic activity of aloe-emodin (AE), a natural anthranoid that readily permeates anthracycline-resistant tumor cells, was improved by the attachment of an amino-sugar unit to its anthraquinone core. The new class of AE glycosides (AEGs) showed a significant improvement in cytotoxicity-up to more than 2 orders of magnitude greater than those of AE and the clinically used anthracycline doxorubicin (DOX)-against several cancer cell lines with different levels of DOX resistance. Incubation with the synthetic AEGs induced cell death in less than one cell cycle, indicating that these compounds do not directly target the cell division mechanism. Confocal microscopy provided evidence that unlike DOX, AEGs accumulated in anthracycline-resistant tumor cells in which resistance is conferred by P-glycoprotein efflux pumps. The results of this study demonstrate that AEGs may serve as a promising scaffold for the development of cytotoxic agents capable of overcoming anthracycline resistance in tumor cells.
2011-01-01 | S-EPMC4018067 | BioStudies
Project description:The molecular determinants of breast cancer resistance to first-line anthracycline-containing chemotherapy are unknown.We examined the response to doxorubicin of organotypic cultures of primary human breast tumors ex vivo with respect to cell proliferation, DNA damage and modulation of apoptosis. Samples were analyzed for genome-wide modulation of cell death pathways, differential activation of p53, and the role of survivin family molecules in drug resistance. Rational drug combination regimens were explored by high-throughput screening, and validated in model breast cancer cell types.Doxorubicin treatment segregated organotypic human breast tumors into distinct Responder or Non Responder groups, characterized by differential proliferative index, stabilization of p53, and induction of apoptosis. Conversely, tumor histotype, hormone receptor or human epidermal growth factor receptor-2 (HER2) status did not influence chemotherapy sensitivity. Global analysis of cell death pathways identified survivin and its alternatively spliced form, survivin-?Ex3 as uniquely overexpressed in Non Responder breast tumors. Forced expression of survivin-?Ex3 preserved cell viability and prevented doxorubicin-induced apoptosis in breast cancer cell types. High-throughput pharmacologic targeting of survivin family proteins with a small-molecule survivin suppressant currently in the clinic (YM155) selectively potentiated the effect of doxorubicin, but not other chemotherapeutics in breast cancer cell types, and induced tumor cell apoptosis.Survivin family proteins are novel effectors of doxorubicin resistance in chemotherapy-naive breast cancer. The incorporation of survivin antagonist(s) in anthracycline-containing regimens may have improved clinical activity in these patients.
1000-01-01 | S-EPMC4076638 | BioStudies