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 recurrence. 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. The effect of shedding to oncogenesis will be 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 several strategies for generation of mutants of pl85HER-2 to alter shedding and have investigated approaches to modulate shedding by treatment with exogenous effectors. We have been unsuccessful in development of mutants that specifically alter shedding, but that do not affect other receptor activities. These mutant proteins either are unstable or have altered kinase activity. We conclude that juxtamembrane mutants are problematic for examining the function of shedding on receptor-mediated tumorigenesis. Efforts to use approaches that employ chemical inhibitors and activators of shedding to examine the impact on transformation and tumorigenesis have not yielded interpretable results that distinguish the effects on receptor activity versus receptor shedding. Moreover, these modulators, alone, appeared to affect cell behavior. We conclude that modulation of shedding cannot be clearly separated from direct effects on the activity of the receptor itself or from secondary effects on the cells.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jul 01, 2003
- Accession Number
- ADA418557
Entities
People
- Gail M. Clinton
Organizations
- Oregon Health & Science University