Therapy of Breast Tumor Cells Overexpressing c-erbB-2/neu

摘要

Two major independent barriers against the successful therapy of breast cancer are mutation of the tumor suppressor p53 gene and overexpression of the c-erbB-2/neu gene. However, there is little or no information on how, if at all, these molecular defects together influence therapeutic outcome. Of further concern is the absence of any therapeutic agents that could be used against both defects. The present research project was proposed to address these limitations. The results from this project indicate that both p53 (wild-type and mutant) and overexpression of c-erbB-2/neu lead to cisplatin resistance, and that the resistance due to wild-type p53 and c-erbB-2/neu overexpression can be circumvented by DACH-acetato-Pt. The fact that under certain cellular context, wild-type p53 can lead to substantially greater resistance to an antitumor agent is a novel finding that may have greater limitations in the treatment of breast cancer. The data further indicate that overexpression of c-erbB-2/neu can interfere with p53 regulation when the DNA damaging agent is cisplatin, but there is no effect on regulation when the damage is induced by DACH-acetato-Pt. This suggests that the novel compound may have clinical utility in the treatment of breast cancer which overexpresses c-erbB2/neu.