Gene expression data of sensitive, Docetaxel resistant and Paclitaxel resistant MDA-MB-231 Cells
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ABSTRACT:
ORGANISM(S): Homo sapiens
SUBMITTER: Nesrin Rechache
PROVIDER: E-GEOD-28784 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
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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:Background: Current protocols for the treatment of ovarian cancer include combination chemotherapy with a platinating agent and a taxane. However, many patients experience relapse of their cancer and the development of drug resistance is not uncommon, making successful second line therapy difficult to achieve. The objective of this study was to develop a cell line resistant to both carboplatin and docetaxel (dual drug resistant ovarian cell line A2780CBNDXL), along with single agent resistant lines (docetaxel resistant A2780DXL and carboplatin resistant A2780CBN), to investigate the mechanisms which underlie the development of dual drug resistance. Methods: The A2780 epithelial ovarian cancer cell line was used to select for isogenic carboplatin, docetaxel and dual drug resistant cell lines. A selection method of gradually increasing drug doses was implemented to avoid clonal selection. Resistance was confirmed using a clonogenic assay. Changes in gene expression associated with the development of drug resistance were determined by microarray analysis compared to parental co-culture control A2780CC. Changes in selected genes were validated by QPCR and immunoblotting. Results: Three isogenic cell lines were developed and resistance to each drug or the combination of drugs was confirmed. Development of resistance was accompanied by a reduced growth rate. The microarray and QPCR analyses showed that unique changes in gene expression occurred in the dual drug resistant cell line and that genes known to be involved in resistance could be identified in all cell lines. Conclusions: Novel changes in gene expression can occur in the development of dual drug resistance, indicating that dual drug resistance is not a simple combination of the changes occurring in single agent resistance Carboplatin, docetaxel (GSE26129) and carboplatin/docetaxel dual resistant cell lines of ovarian A2780 were generated for gene expression profilling. Two colour microarray of Agilent whole human genome nucleotide arrays was conducted with two replicate of both forward and reverse labellings for each cell line. Four arrays were used for this experiments. And it was four replicate of both forward and reverse labellings for A2780 cells. Eight arrays were used for this experiments
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Project description:The taxanes are widely used in the treatment of breast and other cancers. While their cytotoxicity has been attributed to the induction of cell cycle arrest in mitosis through the stabilization of microtubules, we found that docetaxel promotes soluble tumor necrosis factor alpha (TNF-alpha production in MCF-7 breast tumor cells. TNF-alpha induces apoptotic cell death in a variety of cell types by binding to one of its receptors (TNFR1) which promotes death-inducing signaling complex (DISC) formation. Consistent with this view, we also report that selection of MCF-7 cells for survival in increasing concentrations of paclitaxel or docetaxel results in selection of drug-resistant variants that are resistant to TNF-alpha cytotoxicity. MCF-7 cells selected to 3-5 nM docetaxel produced >30-fold more TNF-alpha than control MCF-7CC cells but had strongly reduced levels of TNFR1. In contrast, expression of TNFR2 was unchanged, resulting in enhanced cell survival through the activation of the NF-kappaB p50 and p65 subunits. Gene expression profiling of docetaxel resistant MCF-7 cells compared to parental MCF-7 cells was performed for the changes of TNF related genes, and also confirmed in ovarian cell line A2780. Two docetaxel resistant cell lines of breast MCF-7 and ovarian A2780 were generated for gene expression profilling. Two colour microarray of Agilent whole human genome nucleotide arrays was conducted with two replicate of both forward and reverse labellings for MCF-7. Four arrays were used for this experiments. And it was four replicate of both forward and reverse labellings for A2780 cells. Eight arrays were used for this experiments
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2012-01-01 | E-GEOD-33455 | biostudies-arrayexpress
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Project description:Acquired drug resistance represents a major challenge in chemo-therapy treatment for various types of cancers. We have found that the retinoid X receptorâselective agonist bexarotene (LGD1069, Targretin) was efficacious in treating chemo-resistant cancer cells. The goal of this microarray study was to understand the mechanism of bexaroteneâs role in overcoming acquired drug resistance using human breast cancer cells MDA-MB-231 as a model system and paclitaxel as model compound. After MDA-MB-231 cells were repeatedly treated with paclitaxel for 8 cycles with each cycle including a 3-day treatment with 30 nM paclitaxel and followed by a 7-day exposure to control medium, MDA cells resistant to paclitaxel were developed and their growth was no longer inhibited by paclitaxel treatment. Those MDA cells with acquired drug resistance, when treated with paclitaxel and bexarotene in combination, could regain their sensitivity and their growth were again inhibited. Therefore, RNA samples from parental MDA-MB-231 cells, paclitaxel-resistant MDA cells treated with vehicle, paclitaxel alone or in combination with bexarotene, were used for perform global gene expression profiling with Affymetrix HG-U133A gene chips. Keywords: Drug Treatment MDA-MB-231 cells were exposed to regimens on a 10-day cycle: a 3-day treatment with 30 nM paclitaxel and followed by a 7-day exposure to control medium. Paclitaxel resistant MDA-MB-231 cells (MDA-PR) were established within 8 cycles of such treatment (80 days). These MDA-PR cells were then treated with vehicle control, paclitaxel along, or the combination of 30 nM paclitaxel ( 3 days on and 7 days off) and 1 µM Targretin (10 days on) in a new 10-day cycle for 3 months. Thus, there are four treatment groups, parent MDA cells, MDA-PR, MDA-PR treated with paclitaxel, MDA-PR treated with paclitaxel and bexarotene, and each group had four biological replicates.
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Project description:'Prostate cancer is the second cancer diagnosed among men worldwide. Beside approval of new therapies in the last five years, chemotherapeutic agents, docetaxel and cabazitaxel taxanes remain key treatments for metastatic castration resistant prostate cancers. However, primary and acquired resistance to taxanes still emerged in about half of patients. There is therefore an urgent need to discover and understand the taxane resistance mechanisms in order to identify new therapeutic targets. Indeed, targeted therapies that exploit the signaling pathways involved in prostate cancer are required to overcome chemoresistance and improve treatment outcomes. Molecular chaperones play a key role in the regulation of cellular homeostasis and the development of treatment resistance, and are promising therapeutic targets. Using high throughput siRNA functional screening based on a gene expression signature, we identified FKBP7, involved in acquired resistance to docetaxel and cabazitaxel. FKBP7 is a molecular chaperone that has not been studied in human so far. FKBP7 is overexpressed in prostate tumors and its expression is correlated with recurrence in patients who received docetaxel as neoadjuvant therapy. Moreover, FKBP7 is upregulated in taxane resistant prostate cancer cell lines and its expression sustains their growth in vitro and in a mice model of Docetaxel resistance. Using a high throughput proteomic approach, we identified the signaling pathway regulated by FKBP7 which is responsible for the survival of chemoresistant cells. Finally, we proposed a promising therapeutic strategy to overcome both docetaxel and cabazitaxel chemoresistance by targeting the downstream effector of FKBP7. Gene expression was profiled using a 4×44K Human Whole Genome (G4112F, id : 014850) expression array (Agilent Technologies, Santa Clara, Cal.) with a dual color dye-swap competitive hybridization procedure, according to the manufacturer''s instructions. Total RNA from untreated parental IGR-CaP1 cells was used as the RNA reference (NN1). Total RNA from IGR-CaP1 cells resistant to 5nM (NN2), 11.6nM (NN3), 25nM (NN4), 50nM (NN5), 100nM (NN6), and 200nM (NN7) of Docetaxel respectively, were used as samples. Two independent replicates of each samples (a and b) were used. Image analyses (quantification, normalization) were performed with Feature Extraction software (Agilent Technologies) and gene expression analysis was performed using Bioconductor.'
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