Gene expression data in Control, Doxorubicin-resistant, and Epirubicin-resistant breast cancer cells
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE125187 | GEO | 2021/06/14
REPOSITORIES: GEO
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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 | biostudies-arrayexpress
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.
2014-01-24 | GSE54326 | GEO
Project description:PURPOSE: Validated biomarkers predictive of response/resistance to anthracyclines in breast cancer are currently lacking. The neoadjuvant TOP trial, in which patients with estrogen receptor (ER)-negative tumors were treated with anthracycline (epirubicin) monotherapy, was specifically designed to evaluate the predictive value of topoisomerase IIα (TOP2A) and to develop a gene expression signature to identify those patients who do not benefit from anthracyclines. METHODS: The TOP trial included 149 patients, of which 141 were evaluable for response prediction analyses. The primary endpoint was pathological complete response (pCR). TOP2A and gene expression profiles were evaluated using pre-epirubicin biopsies. Gene expression data from ER-negative samples of the EORTC 10994/BIG 00-01 and MDACC 2003-0321 neoadjuvant trials were used for validation purposes. RESULTS: A pCR was obtained in 14% of the evaluable TOP patients. TOP2A amplification, but not protein overexpression, was significantly associated with pCR (p=0.001 and 0.22). We developed an “anthracycline-based score (A-Score)” that combines three signatures: a TOP2A gene signature and two previously published signatures related to tumor invasion and immune response. The A-Score was characterized by a high negative predictive value (NPV=0.98 [95% CI: 0.90-1.00]) overall, and in the HER2-negative and HER2-positive subpopulations. Its performance was independently confirmed in the anthracycline-based (FAC/FEC) arms of the two validation trials (BIG 00-01: 0.80 [0.61-0.92] and MDACC 2003-0321: 1.00 [0.80-1.00]). CONCLUSION: Given its high NPV, the A-Score could become, if further validated, a useful clinical tool to identify those patients who do not benefit from anthracyclines and could therefore be spared the non-negligible side effects. Predicting the efficacy of anthracyclines (epirubicin) in breast cancer (BC) patients (TOP trial) 120 microarray experiments from primary ER-negative breast tumors of anthracycline-treated patients. No replicate, no reference sample.
2010-01-26 | E-GEOD-16446 | biostudies-arrayexpress
Project description:Recent studies have suggested that elevated expression of aldoketoreductase (AKR) 1C1 or 1C2 in tumour cells is associated with increased resistance to DNA damaging agents such as cisplatin and doxorubicin. However, it has not been shown whether selection of tumour cells for resistance to DNA-damaging anthracyclines actually results in increased expression of AKRs and increased conversion of anthracyclines to 10-fold less toxic 13-hydroxy metabolites. It is also unclear whether the induction of aldokeoreductases is temporally correlated with the onset of anthracycline resistance and whether there is a direct relationship between the level of AKR expression or activity and the magnitude of drug resistance. Through microarray profiling of MCF-7 breast cancer cells selected for progressive resistance to doxorubicin or epirubicin, we have identified several genes whose expression has been correlated with both the onset and magnitude of drug resistance, including a “1C” AKR. AKR 1C overexpression was verified by quantitative PCR. Also associated with the onset of anthracycline resistance were genes involved in drug transport (ABCB1), cell signaling and transcription (RDC1, CXCR4), cell proliferation or apoptosis (BMP7, CAV1), ROS protection (TXNRD1, MT2A), and structural or immune system proteins (IFI30, STMN1). Consistent with the role of AKRs in anthracycline resistance, doxorubicin- and epirubicin-resistant breast tumour cells exhibited 2.2-fold and 6.1-fold higher levels of the 13-hydroxy metabolite of doxorubicin (doxorubicinol) than wildtype MCF-7 cells. In addition, an inhibitor of AKR 1C2 (5beta-cholanic acid) almost completely restored sensitivity to doxorubicin in Abcb1-deficient doxorubicin-resistant cells, while having no effect on Abcb1-expressing epirubicin-resistant cells. Taken together, our findings strongly suggest the involvement of multiple genes in the acquisition of anthracycline resistance in breast tumor cells---in particular redox genes such as the 1C AKRs. Keywords: Drug resistance of breast cancer cells
2008-07-16 | GSE12115 | GEO
Project description:Recent studies have suggested that elevated expression of aldoketoreductase (AKR) 1C1 or 1C2 in tumour cells is associated with increased resistance to DNA damaging agents such as cisplatin and doxorubicin. However, it has not been shown whether selection of tumour cells for resistance to DNA-damaging anthracyclines actually results in increased expression of AKRs and increased conversion of anthracyclines to 10-fold less toxic 13-hydroxy metabolites. It is also unclear whether the induction of aldokeoreductases is temporally correlated with the onset of anthracycline resistance and whether there is a direct relationship between the level of AKR expression or activity and the magnitude of drug resistance. Through microarray profiling of MCF-7 breast cancer cells selected for progressive resistance to doxorubicin or epirubicin, we have identified several genes whose expression has been correlated with both the onset and magnitude of drug resistance, including a “1C” AKR. AKR 1C overexpression was verified by quantitative PCR. Also associated with the onset of anthracycline resistance were genes involved in drug transport (ABCB1), cell signaling and transcription (RDC1, CXCR4), cell proliferation or apoptosis (BMP7, CAV1), ROS protection (TXNRD1, MT2A), and structural or immune system proteins (IFI30, STMN1). Consistent with the role of AKRs in anthracycline resistance, doxorubicin- and epirubicin-resistant breast tumour cells exhibited 2.2-fold and 6.1-fold higher levels of the 13-hydroxy metabolite of doxorubicin (doxorubicinol) than wildtype MCF-7 cells. In addition, an inhibitor of AKR 1C2 (5- cholanic acid) almost completely restored sensitivity to doxorubicin in Abcb1-deficient doxorubicin-resistant cells, while having no effect on Abcb1-expressing epirubicin-resistant cells. Taken together, our findings strongly suggest the involvement of multiple genes in the acquisition of anthracycline resistance in breast tumor cells---in particular redox genes such as the 1C AKRs. Keywords: Drug resistance of breast cancer cells In order to identify genes whose expression strongly correlates with the acquisition or magnitude of drug resistance or are temporally related with the acquisition of resistance, we selected MCF-7 breast tumor cells for survival in increasing concentrations (doses) of doxorubicin or epirubicin. Panels of cells exhibiting progressive resistance to either doxorubicin (MCF-7DOX-2) or epirubicin (MCF-7EPI) were obtained. Cells were also “selected” in the absence of drug at each step during selection to serve as co-cultured control (MCF-7CC) cells. In this study, we have used cDNA microarray analysis of these cell lines to identify a variety of “redox” genes whose expression can be correlated with the acquisition or magnitude of drug resistance in MCF-7DOX-2 and MCF-7EPI cells, including a “1C” aldoketoreductase (AKR).
2008-07-16 | E-GEOD-12115 | biostudies-arrayexpress
Project description:Gene expression data in Control, Doxorubicin-resistant, and Epirubicin-resistant breast cancer cells
| PRJNA515492 | ENA
Project description:The goal of the study was to identify a gene expression signature capable of predicting a pathological complete response following neoadjuvant anthracycline-based chemotherapy of breast cancer. The samples were taken from the FEC arm (5-fluorouracil, epirubicin, cyclophosphamide) of the EORTC 10994 trial. EORTC 10994 is a phase III clinical trial comparing FEC with ET (epirubicin, docetaxel) in patients with large operable, locally advanced or inflammatory breast cancer (www.eortc.be). Frozen biopsies were taken at randomisation. RNA was extracted from 100um thickness of 14G core needle biopsies. Adjacent sections were tested by H&E to confirm >20% tumour cell content. 200 ng total RNA per chip was amplified using the Affymetrix small sample protocol (IVT then Enzo). 102 tumours were tested on Affymetrix X3P chips. Single biopsies were tested per tumour. The CEL files were quantile normalised using rma. The clinical response measure was pathological complete response (pCR, disappearance of the tumour after chemotherapy with at most scattered invasive cells detected by histology). 102 tumors
2008-12-19 | E-GEOD-4779 | biostudies-arrayexpress
Project description:The goal of the study was to identify a gene expression signature capable of predicting a pathological complete response following neoadjuvant anthracycline-based chemotherapy of breast cancer. The samples were taken from the FEC arm (5-fluorouracil, epirubicin, cyclophosphamide) of the EORTC 10994 trial. EORTC 10994 is a phase III clinical trial comparing FEC with ET (epirubicin, docetaxel) in patients with large operable, locally advanced or inflammatory breast cancer (www.eortc.be). Frozen biopsies were taken at randomisation. RNA was extracted from 100um thickness of 14G core needle biopsies. Adjacent sections were tested by H&E to confirm >20% tumour cell content. 200 ng total RNA per chip was amplified using the Affymetrix small sample protocol (IVT then Enzo). 102 tumours were tested on Affymetrix X3P chips. Single biopsies were tested per tumour. The CEL files were quantile normalised using rma. The clinical response measure was pathological complete response (pCR, disappearance of the tumour after chemotherapy with at most scattered invasive cells detected by histology).
2008-12-19 | GSE4779 | GEO
Project description:PURPOSE: Validated biomarkers predictive of response/resistance to anthracyclines in breast cancer are currently lacking. The neoadjuvant TOP trial, in which patients with estrogen receptor (ER)-negative tumors were treated with anthracycline (epirubicin) monotherapy, was specifically designed to evaluate the predictive value of topoisomerase IIα (TOP2A) and to develop a gene expression signature to identify those patients who do not benefit from anthracyclines. METHODS: The TOP trial included 149 patients, of which 141 were evaluable for response prediction analyses. The primary endpoint was pathological complete response (pCR). TOP2A and gene expression profiles were evaluated using pre-epirubicin biopsies. Gene expression data from ER-negative samples of the EORTC 10994/BIG 00-01 and MDACC 2003-0321 neoadjuvant trials were used for validation purposes. RESULTS: A pCR was obtained in 14% of the evaluable TOP patients. TOP2A amplification, but not protein overexpression, was significantly associated with pCR (p=0.001 and 0.22). We developed an “anthracycline-based score (A-Score)” that combines three signatures: a TOP2A gene signature and two previously published signatures related to tumor invasion and immune response. The A-Score was characterized by a high negative predictive value (NPV=0.98 [95% CI: 0.90-1.00]) overall, and in the HER2-negative and HER2-positive subpopulations. Its performance was independently confirmed in the anthracycline-based (FAC/FEC) arms of the two validation trials (BIG 00-01: 0.80 [0.61-0.92] and MDACC 2003-0321: 1.00 [0.80-1.00]). CONCLUSION: Given its high NPV, the A-Score could become, if further validated, a useful clinical tool to identify those patients who do not benefit from anthracyclines and could therefore be spared the non-negligible side effects.
2010-01-26 | GSE16446 | GEO
Project description:A "Cartes d'Identite des Tumeurs" (CIT) project from the french Ligue Nationale Contre le Cancer (http://cit.ligue-cancer.net). 37 samples hybridized on Affymetrix HG-U133A arrays. Analysis of advanced breast cancers treated with a dose-intense epirubicin /cyclophosphamide regimen followed by mastectomy; Validation of TP53-related genes in breast and bladder cancers. We found that a complete response to chemotherapy was only observed in TP53 mutant tumours. We further show that, among TP53 mutant tumours, high basalcytokeratin and low ESR1 expression levels were associated with complete responses. These observations pave the way to molecular tailoring of chemotherapy in breast cancer.
2007-03-26 | E-TABM-43 | biostudies-arrayexpress