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Gene expression profiles of Herceptin-resistant breast cancer cells

ABSTRACT: Herceptin (trastuzumab) is a humanized monoclonal antibody targeted to the Her2 receptor tyrosine kinase. Despite a robust response rate to Herceptin-based therapies in Her2-positive patients, resistance frequently arises within one year of the initial response. To address the mechanism of Herceptin resistance, we selected clonal variants of Her2-positive BT474 human breast cancer cells (BT/HerR) that are highly resistant to the anti-proliferative effects of Herceptin in the presence of 0.2 uM or 1.0 uM Herceptin. Our original report on these cell lines demonstrated sustained PI3K/Akt signaling and sensitivity to PI3K inhibitors in BT/HerR cells in the presence of Herceptin, suggesting dysregulation of that pathway as an essential component of Herceptin-resistant proliferation. To address the mechanism by which BT/HerR cells and their PI3K/Akt signaling pathway became resistant to Herceptin, we analyzed gene expression profiles of two clones (BT/HerR1.0C and BT/HerR 1.0E) that were selected in 1.0 uM Herceptin and two clones (BT/HerR0.2D and BT/HerR 0.2J) that were selected in 0.2 uM Herceptin, in comparison to the Herceptin sensitive BT474 parent cells.

ORGANISM(S): Homo sapiens

PROVIDER: GSE15043 | GEO | 2009/08/21

SECONDARY ACCESSION(S): PRJNA114809

REPOSITORIES: GEO

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Gene expression profiles of Herceptin-resistant breast cancer cells

Project description:Herceptin (trastuzumab) is a humanized monoclonal antibody targeted to the Her2 receptor tyrosine kinase. Despite a robust response rate to Herceptin-based therapies in Her2-positive patients, resistance frequently arises within one year of the initial response. To address the mechanism of Herceptin resistance, we selected clonal variants of Her2-positive BT474 human breast cancer cells (BT/HerR) that are highly resistant to the anti-proliferative effects of Herceptin in the presence of 0.2 uM or 1.0 uM Herceptin. Our original report on these cell lines demonstrated sustained PI3K/Akt signaling and sensitivity to PI3K inhibitors in BT/HerR cells in the presence of Herceptin, suggesting dysregulation of that pathway as an essential component of Herceptin-resistant proliferation. To address the mechanism by which BT/HerR cells and their PI3K/Akt signaling pathway became resistant to Herceptin, we analyzed gene expression profiles of two clones (BT/HerR1.0C and BT/HerR 1.0E) that were selected in 1.0 uM Herceptin and two clones (BT/HerR0.2D and BT/HerR 0.2J) that were selected in 0.2 uM Herceptin, in comparison to the Herceptin sensitive BT474 parent cells. Total cellular RNAs were extracted from BT474 (control) and four BT/HerR subclones, two that were originally selected in 1.0 uM Herceptin and two that were originally selected in 0.2 uM Herceptin. Two RNA samples independently prepared from each clone were analyzed.

2009-08-21 | E-GEOD-15043 | biostudies-arrayexpress

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Project description:We report the application of specific antibodies and high-throughput sequencing technologies (methylated RNA immunoprecipitation sequencing, MeRIP-seq) for high-throughput profiling of m6A modifications in breast cancer herceptin resistant cells. We generated maps of m6A modified transcripts in BT474 and BT474.TtzmR cells. We find that the m6A level was significantly increased in BT474.TtzmR cells compared to the BT474 cells. We show that there was a close correlation between the m6A modification and herceptin resistance.

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