Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

Transcription profiling of human MCF-7 cells treated with Fulvestrant (ICI 182,780) and vehicle reveals origins and phenotypic variations of antiestrogen resistance in breast cancer

ABSTRACT: Expression profiles of MCF-7 cells treated with Fulvestrant (ICI 182,780) and vehicle Experiment Overall Design: MCF7 cells were grown in DMEM supplemented with 5% FCS (Hyclone, "Defined" grade). Growth medium was changed immediately before addition of 100 nM of ICI 182,780 or vehicle alone (0.1% ethanol) and cells incubated for 48h before they were harvested for profiling. Note that MCF7 cells show no signs of cell damage at this time point.

ORGANISM(S): Homo sapiens

SUBMITTER: Ben Wittner

PROVIDER: E-GEOD-14986 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Antiestrogen-resistant subclones of MCF-7 human breast cancer cells are derived from a common monoclonal drug-resistant progenitor.

Coser Kathryn R KR Wittner Ben S BS Rosenthal Noël F NF Collins Sabrina C SC Melas Antonia A Smith Shannon L SL Mahoney Crystal J CJ Shioda Keiko K Isselbacher Kurt J KJ Ramaswamy Sridhar S Shioda Toshi T

Proceedings of the National Academy of Sciences of the United States of America 20090801 34

Emergence of antiestrogen-resistant cells in MCF-7 cells during suppression of estrogen signaling is a widely accepted model of acquired breast cancer resistance to endocrine therapy. To obtain insight into the genomic basis of endocrine therapy resistance, we characterized MCF-7 monoclonal sublines that survived 21-day exposure to tamoxifen (T-series sublines) or fulvestrant (F-series sublines) and sublines unselected by drugs (U-series). All T/F-sublines were resistant to the cytocidal effects ...[more]

PMID: 19706540

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Project description:Multiple gene expression studies have demonstrated that breast cancer biological diversity is associated with distinct transcriptional programs. Transcription factors, because of their unique ability to coordinate the expression of multiple genes, are speculated to play a role in generating phenotypic plasticity associated with cancer progression including acquired drug resistance. Combinatorial libraries of artificial zinc-finger transcription factors (ZF-TFs) provide a robust means for inducing and understanding various functional components of the cancer phenotype. Herein, we utilized combinatorial ZF-TF library technology to better understand how breast cancer cells acquire resistance to a fulvestrant, a clinically important anti-endocrine therapeutic agent. We isolated six ZF-TF library members capable of inducing stable, long-term anti-endocrine drug-resistance in two independent estrogen receptor positive breast cancer cell lines. Comparative gene expression profile analysis of the ZF-TF-transduced breast cancer cell lines revealed a 72-gene cluster that constituted a common signature for the fulvestrant-resistance phenotype. Pathway enrichment-analysis of gene expression data revealed that the ZF-TF-induced fulvestrant resistance is associated with an estrogen receptor negative-like gene set and four unique myb-regulated gene sets. Furthermore, we identified a set of genes strongly expressed in the ZF-TF-induced fulvestrant-resistant cells that was correlated with a lower probability of distant metastasis-free or death-from-relapse-free survival of breast cancer patients. MCF7-R73 cells, a monoclonal MCF7 subline that is highly sensitive to fulvestrant-induced cytocidal activity, underwent retroviral transduction with the zinc finger transcription factor (ZF-TF) activator library or with a control plasmid encoding only the NF-kB p65 activation domain. Both populations of cells were enriched for transduced cells by selecting for growth in puromycin and for fulvestrant-resistant cells by selecting with 100 nM fulvestrant. After 6 weeks of continuous treatment with fulvestrant, hundreds of drug-resistant colonies emerged from the population of cells infected with the ZF-TF activator library. By contrast, as expected, the control MCF7cell line transduced by NF-kB p65-only underwent massive cell death resulting in the complete absence of resistant colonies. DNA encoding the zinc-finger arrays was rescued by PCR from genomic DNA of pooled fulvestrant-resistant cells. The sequences of the ZF-TFs were determined and 46 unique ZF-TF clones identified. These 46 unique ZF-TFs were re-cloned into the retroviral vector and converted into clonal virus stocks that were used to transduce MCF7-R73 cells. These 46 retrovirally transduced cell populations were then challenged with fulvestrant. As compared with the control MCF-238 cells, MCF7-R73 cells transduced with six unique ZF-TFs demonstrated survival and growth in the presence of 100nM fulvestrant.

Dataset Information

Transcription profiling of human MCF-7 cells treated with Fulvestrant (ICI 182,780) and vehicle reveals origins and phenotypic variations of antiestrogen resistance in breast cancer

Publications

Antiestrogen-resistant subclones of MCF-7 human breast cancer cells are derived from a common monoclonal drug-resistant progenitor.

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