Differential Phosphoprotein Profiling of Tamoxifen Response
Abstract
Advanced breast cancers that initially respond well to tamoxifen treatment eventually become refractory to this compound. Several mechanisms of acquired resistance have been hypothesized, including crosstalk between ER and growth factor receptor tyrosine kinase pathway. The cumulative data from clinical studies show that overexpression of HER-2 and/or EGFR, and high levels of phosphorylated Akt or ERK, contribute to tamoxifen resistance in some patients. HER-2, EGFR, Akt and ERK are all kinases and components of signaling pathways critical to cell growth and survival, highlighting the need for global phosphoproteome analysis. I have developed a method for comparison of global phosphoprotein profiles involving stable isotope labeling, a phosphoprotein affinity step, 1-D SDS-PAGE and LC-MS/MS. I identified 26 proteins that respond to tamoxifen differently in MCF-7 (tamoxifen sensitive) and MCF-7/HER2-18 (tamoxifen resistant) cells. FADD and PAK1 have previously been described as being involved in generation of tamoxifen resistance showing that phosphoprotein profiling is capable of identifying proteins relevant to tamoxifen resistance. We also observed a striking synergistic interaction between ionizing radiation (IR) and tamoxifen in a model for combining high dose radiation therapy (RT) with hormone therapy for breast cancer and propose the use of tamoxifen as a radiosensitizer during radiation treatment.
Document Details
- Document Type
- Technical Report
- Publication Date
- Aug 01, 2009
- Accession Number
- ADA524493
Entities
People
- Geoffrey L Greene
- Kolbrun Kristjansdottir
- Stephen J. Kron
Organizations
- University of Chicago