Gene Set: GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_UP

Standard name GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_UP
Systematic name M1106
Brief description Genes up-regulated in ME-A cells (breast cancer, sensitive to apoptotic stimuli) exposed to doxorubicin [PubChem=31703] in the presence of medium concentrate (MC) from ME-C cells (breast cancer, resistant to apoptotic stimuli).
Full description or abstract Impairment of the complex regulatory network of cell death and survival is frequently the reason for therapy resistance of breast cancer cells and a major cause of tumor progression. We established two independent cell lines from a fast growing mouse breast tumor (WAP-SVT/t transgenic animal). Cells from one line (ME-A cells) are sensitive to apoptotic stimuli such as growth factor depletion or treatment with antitumor agents (e.g. doxorubicin). Cells from the second line (ME-C cells), which carry a missense mutation at the p53 codon 242, are very insensitive to apoptotic stimuli. Co-cultivation experiments revealed that the ME-C cells mediate cell death resistance to the ME-A cells. Microarray and Western blot analysis showed that osteopontin (OPN) is selectively overexpressed by the ME-C cells. This glycoprotein is the most abundant protein secreted by the ME-C cells and we obtained strong indications that OPN is the main antiapoptotic factor. However, the OPN containing ME-C cell medium does not alter the expression level of pro- or antiapoptotic genes or known inhibitors of apoptosis (IAPs). Its signaling involves mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) kinase (MEK)1/2 as the kinase inhibitor PD98059 restores apoptosis but not the Akt inhibitor. In the ME-A cells, mitochondrial cytochrome c release occurs with and without external apoptotic stimuli. OPN containing ME-C cell medium does not prevent the mitochondrial cytochrome c release and caspase-9 processing. In serum starved ME-A cells, the OPN containing ME-C cell medium prevents caspase-3 activation. However, in doxorubicin-treated cells, although apoptosis is blocked, it does not inhibit caspase-3. This indicates that the ME-A cells distinguish between the initial apoptotic stimuli and that the cells possess a further uncharacterized control element acting downstream from caspase-3.
Collection C2: curated gene sets
      CGP: chemical and genetic perturbations
Source publication Pubmed 17160024   Authors: Graessmann M,Berg B,Fuchs B,Klein A,Graessmann A
Exact source Online supplement ME-ACellsDoxorubicinAndMC.xls
Related gene sets (show 7 additional gene sets from the source publication)
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Organism Mus musculus
Contributed by Arthur Liberzon (Broad Institute)
Source platform MOUSE_GENE_SYMBOL
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Compendia expression profiles Human tissue compendium (Novartis)
NCI-60 cell lines (National Cancer Institute)
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Version history 3.1: First introduced

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