Novel Approach to Increase Breast Cancer Cell Chemosensitivity: Disuption of the Anti-Apoptotic Function of Translation Factor eIF4E.

摘要

In this report we present data in support of Aim 2 of our project. Utilizing human breast carcinoma cell lines as an in vitro model for naturally occurring malignancy, we demonstrated that enforced overexpression of translation factor eIF4E in human mammary epithelial cells (HMECs) confers to them a transformed phenotype and protects against apoptotic death. In accord with this, suppression of eIF4E-driven translation by ectopic expression translational repressor 4E-BP1 stimulated apoptosis and abrogated chemoresistance breast carcinoma cells in a manner dependent on the phosphorylation status of ectopic 4E-BP1. Our data show that targeted disruption of cap-dependent translational machinery selectively sensitizes breast carcinoma cells to the subset anti-cancer drugs that includes camptothecin and doxorubicin. These drugs are considered as promising candidates for collaboration with anti-eIF4E pre-treatments in suppression of breast tumor growth. Based on these data, we plan to employ novel pharmacological approaches including disruption of eIF4E-to-cap association by phosphoramidated analogues of the 5' methylguanosine cap of mRNA.