HER-2/neu Shedding and Oncogenesis
Abstract
The HER-2/neu extracellular domain (ECD) is shed from breast carcinoma cells in culture and is found at elevated levels in sera of patients with metastatic breast cancer where it may predict poor prognosis. Our studies show that an N-terminally truncated HER-2/neu product, p95, is produced when the ECD is shed, that p95 has kinase activity, and is expressed to a greater extent in breast cancer patients with lymph node metastasis. Purpose. The objective of this proposal is to directly test the hypothesis that shedding of the extracellular domain of HER-2/neu, which creates the truncated p95 kinase, promotes oncogenesis. Scope. Thc effect of shedding to oncogenesis will he examined by further characterizing the control of shedding and genetically altering shedding activity to test the impact on tumorigenesis and oncogenesis. Results: We have developed and characterized strategies for generation of mutants of p185HER-2 to alter shedding. We have characterized the activity of mutants with altered juxtamembrane sequences. We have been unsuccessful in development of mutants that specifically alter shedding, kit that do not affect other receptor activities. These mutant proteins either are unstable or have altered kinase activity. Other recent studies lend further support to the concept that the region of the ectodomain, adjacent to the transmembrane region is critical in the regulation of dimerization and kinase activation. Therefore juxtamembrane mutants are considered problematic for examining the function of shedding on receptor-mediated tumorigenesis. We now propose to introduce additional approaches that employ chemical inhibitors and activators of shedding to examine the impact on transformation and tumorigenesis.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jul 01, 2001
- Accession Number
- ADA405497
Entities
People
- Gail Clinton
Organizations
- Oregon Health & Science University