Identification of functional pathways associated with clinical tamoxifen-resistance in breast cancer by advanced mass spectrometry
EMSL Project ID
7190
Abstract
There is a need to identify specific target proteins that may lead to newly-designed drugs, and individual treatment strategies for patients with (advanced) breast cancer. In particular, the mechanisms underlying endocrine resistance are a major clinical problem. This problem can be better understood and tackled when the proteins, their modifications, their expression levels, and their interacting partners are identified at the cellular level. The final aim of this 3-year project is to identify functional pathways that lead to clinical resistance to tamoxifen (anti-estrogen) by identifying the responsible key proteins with their specific modifications.
To achieve these goals we will use tamoxifen-resistant and tamoxifen-responsive breast cancer tissues and employ state-of-the-art proteomic technologies and bioinformatics, in different expert laboratories. Tumor material will be laser microdissected to obtain relatively pure populations of cells. Protein expression profiles will be studied by generating complex peptide mixtures of these proteins. The complex peptide mixtures will be analyzed by Fourier-transform ion cyclotron resonance mass spectrometry (FTICR MS), which has the possibility to separate large numbers of peptides at extremely high resolution and accuracy. Using bioinformatics tools, expression profiles of tamoxifen-resistant and -responsive cells will be compared and differentially expressed proteins will be identified. Differential expression may be the result of either up- or down-regulation of proteins or of post-translational modifications. Advanced mass spectrometry gives the possibility to investigate this in detail. Once differentially expressed proteins are identified, functional proteomics studies are required for unraveling the underlying molecular pathways. Protein-protein, protein-DNA, and protein-ligand interactions will be studied by mass spectrometry using high-throughput protein and antibody arrays.
Project Details
Project type
Exploratory Research
Start Date
2004-05-31
End Date
2007-06-03
Status
Closed
Released Data Link
Team
Principal Investigator
Team Members
Related Publications
A. Umar, H. Kang, A.M. Timmermans, M.P. Look, M.E. Meijer-van Gelder, N. Jaitly, M. Den Bakker, J.W.M. Martens, T.M. Luider, J.A. Foekens, L. Pa?a-Tolić. Identification of a putative protein-profile associating with tamoxifen therapy-resistance in breast cancer. Molecular & Cellular Proteomics, 8 (6):1278-1294 (2009)
A. Umar, H. Kang, A.M. Timmermans, M.P. Look, M.E. Meijer-van Gelder, N. Jaitly, M. Den Bakker, J.W.M. Martens, T.M. Luider, J.A. Foekens, L. Pasa-Tolić. Identification of a putative protein-profile associating with tamoxifen therapy-resistance in breast cancer. Molecular & Cellular Proteomics, 8 (6):1278-1294 (2009)
nLC-FTICR in BC
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