Unknown,Transcriptomics,Genomics,Proteomics

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Transcription profiling of human T4-2 neoplastic breast epithelial cells that overexpressed N-CoR2 in response to death induction

ABSTRACT: The series represent gene expression profiles of T4-2 neoplastic breast epithelial cells that overexpressed N-CoR2 and were treated with the death ligand TRAIL in three-dimensional reconstituted basement membrane culture. Experiment Overall Design: Four replicate cultures were established for each of the 4 experiment groups, including those using T4-2 cells that stably expressed N-CoR2 (T4-2_NCOR2), T4-2 cells expressing the empty vector (T4-2_vector), TRAIL-treated T4-2 N-CoR2 cells (T4-2_NCOR2_TRAIL), and TRAIL-treated T4-2 vector cells (T4-2_vector_TRAIL). Cells were grown on top of reconstituted basement membrane for 6 days and then treated with TRAIL (1 Î¼g/mL) or vehicles for 4 hours before the collection of RNA samples.

ORGANISM(S): Homo sapiens

SUBMITTER: Kelvin Kun-Chih Tsai

PROVIDER: E-GEOD-8346 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:In this study, we subjected the phenomenon of fractional killing in a clonal population of TRAIL-sensitive cells to careful analysis. We asked whether cells that survive initial exposure to TRAIL are sensitive or resistant to subsequent treatment with TRAIL or other apoptosis-inducing agents. We observed that TRAIL survivor cells were highly resistant to a subsequent treatment with TRAIL 24hr later but that this resistance disappeared following several days in culture. Resistance did not involve downregulation of TRAIL receptors and extended to death ligands that bind different classes of receptors: TRAIL survivors were transiently resistant to FasL and vice versa. Gene expression analysis revealed that NF-kB-mediated inflammatory genes were activated in transiently resistant survivor cells leading to an inflammatory phenotype, but resistance was mediated by an independent mechanism related to changes in signaling at the DISC. Periodic exposure to TRAIL sustained resistance, demonstrating a component of induced survival signaling leading to transient acquired resistance to TRAIL. Based on these results we propose that TRAIL treatment leads to a transient adaptation in survivor cells that can be sustained in cells exposed to long-term TRAIL treatments, leading to acquired resistance. Minimizing the impact of cell-to-cell variability on TRAIL-mediated killing will thus require appropriate spacing of stimuli as well as the use of additional agents that inhibit pro-survival pathways. RNA was collected from Control (untreated) MCF10A cells, Survivors of TRAIL treatment (Day 1), Reset cells (survivors on Day 7), and Repeat cells (Survivors treated with TRAIL on 2 subsequent days). RNA was also collected from Control and Survivor MCF10A cells expressing an IKB-super-repressor construct (Addgene, Plasmid 15291; Boehm et al., 2007), or treated with caspase inhibitors. Three biological experiments were performed (on different days) with 1-2 replicates of each sample collected for each experiment. The total number of samples was 31, on 4 IlluminaRef8 BeadChips (one sample was from an unrelated experiment and was not included). The number of total replicates for each treatment is as follows: Control (7); Survivors (6); Reset (3); Repeat (3); Control-IKB-super-repressor (2); Survivors-IKB-super-repressor (2); Control-zVADinhibitor (2); Survivors-zVADinhibitor (2); Control-IETDinhibitor (2); Survivors-IETDinhibitor (2).

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Transcription profiling of human T4-2 neoplastic breast epithelial cells that overexpressed N-CoR2 in response to death induction

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