Tetraspanin Metastasis Supressor Gene, KAI1/CD82, and the Proto- Oncogene, Her-2/neu, as Molecular Determinants of Metastasis in Breast Cancer Patients

摘要

The purpose of this research is to demonstrate that gene amplification of HER-2/neu is associated with loss of expression of the tetraspanin metastasis suppressor gene, KAI1/CD82, in breast cancer cell lines and patients' primary breast tumors. The scope is limited to breast cancer and mechanisms of metastasis. Results: 1) We identified three cell lines with gene amplification of HER-2/neu and negative KAI1/CD82 expression to serve as model systems and corroborated these results in primary breast tumors. 2) We found that CO-029, a tetraspanin metastasis promoter gene, was up-regulated in HER- 2/neu+ lines. 3) We ectopically expressed HER-2/neu in MCF-7 cells and demonstrated that over-expression of HER-2/neu resulted in loss of expression of KAI1/CD82, but increased expression of CO-029. 4) Finally, we knocked down expression of HER-2/neu by RNAi and demonstrated that KAI1/CD82 levels increased four-fold. Significance: HER-2/neu signaling regulates tetraspanin gene expression to promote metastatic potential. This novel mechanism may explain why women with gene amplification of HER-2/neu in their breast tumors are at higher risk for metastasis and death. This is the first demonstration of a receptor tyrosine kinase (RTX) that regulates tetraspanin metastasis genes, and this may be the first example of a broader paradigm linking RTK oncogenes to metastasis genes.