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, response to adjuvant endocrine and chemotherapy, and allow tumor cells to escape immune surveillance. Our studies show that an N- terminally truncated HER-2/neu product, p95, is produced when the ECD is shed, has kinase activity, and is expressed to a greater extent in breast cancer patients with lymph node metastasis (1). Purpose: The objective of this proposal is to directly test the hypothesis that shedding of the extracellular domain of HER-2/neu and creating of the truncated p95 kinase promotes oncogenesis. Scope: To examine the impact of shedding on oncogenesis: (a) We will genetically alter shedding of HER-2/neu. To alter shedding, deletion and domain replacement mutants will be constructed within the HER-2/neu juxtamembrane cleavage domain. The mutations to be made will be based on known structural determinants of shedding defined through studies of diverse transmembrane proteins. A second approach to genetically alter shedding will be pursued by expressing HER-2/neu in cells that are null for shedding enzyme. (b) The impact of altered shedding to oncogenesis will be examined in cell culture and animal models. The transforming activity of HER-2/neu with genetically altered levels of shedding will be examined by well-established cell culture models of transformation, by tumorigenesis as says in nude mice, and by metastatic potential in immune compromised mice.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jul 01, 2002
- Accession Number
- ADA410783
Entities
People
- Gail M. Clinton
Organizations
- Oregon Health & Science University