Role of erB-2 and erbB-3 in the Activation of Phosphatidylinositol 3-Kinase
Abstract
We sought to determine the critical threshold level of c-erbB-2 overexpression that is required to transform human mammary epithelial cells and to assess the importance of cooperative interactions between p185erbB2 and erbB-3 in the neoplastic transformation of breast cancer cells with c-erbB-2 gene amplification. We have now successfully produced cell populations derived from MCF-10A non-neoplastic human mammary epithelial cells that overexpress c-erbB-2 at very high levels truly comparable to that seen in breast cancer cells with c-erbB-2 gene amplification. While the original clones of genetically engineered MCF-1OAerbB-2 cells overexpressed c-erbB-2 at only moderate levels and were not tumorigenic in nude mice, cells selected for high-level c-erbB-2 overexpression with growth factor independence in culture showed a high level of constitutive PI 3-kinase activity and a highly transformed phenotype both in culture and in vivo. In addition, key observations were made during the course of these studies which provide important information concerning the survival and growth of cells in the absence of growth factors that occurs as a function of the level of c-erbB-2 gene overexpression. Finally, we have recently constructed a bicistronic retroviral expression vector containing a dominant negative form of c-erbB-3 that specifically inhibits p185erbB-2/erbB-3 activation, and this has now allowed us to begin to directly test the relative importance of p185erbB-2/erbB-3 heterodimer function in cells in response to HRG and in various breast cancer cell lines with c-erbB-2 gene amplification.
Document Details
- Document Type
- Technical Report
- Publication Date
- Dec 01, 1999
- Accession Number
- ADA378731
Entities
People
- Stephen P. Ethier
Organizations
- University of Michigan