Novel Inhibitors of FGF Signal Transduction in Breast Cancer: Targeting the FGFR adapter Protein SNT-1
Abstract
Acquired tamoxifen resistance is common in breast cancer patients with estrogen receptor positive (ER+) tumors. Growth factor signaling can provide ER positive breast cancer cells with alternative growth stimulus to that which is provided by activation of ER. A lipid-anchored docking protein SNT-l links FGFR molecules with the Ras/MAP kinase signaling pathway. The main objective of this work is evaluation of SNT-l as a useful target for drug development. For this purpose we cloned a phosphotyrosine binding domain (PTB) of SNT-l in the expression vectors pTRE Ins, which provides tetracycline regulation of protein expression, and pEF6. Breast cancer cells transfected with these plasmids expressed the PTB domain, which was shown to inhibit tyrosine phosphorylation of cellular SNT-l protein and greatly decrease MAP kinase activation in FGF-dependent conditions. These data demonstrate dominant negative properties of the PTB domain and validate it as a possible target for drug design. We also found evidence for involvement of SNT-l independent mechanisms in FGFl signaling in breast cancer cells and we are studying these mechanisms. We continued our efforts to crystallize the SNT-l PTB domain and to study its possible binding to different FGF receptors.
Document Details
- Document Type
- Technical Report
- Publication Date
- Mar 01, 2002
- Accession Number
- ADA404654
Entities
People
- Francis G. Kern
Organizations
- Southern Research