Translational control of malignancy and chemoresistance in breast cancer cells: antiapoptotic function of the translational factor eIF4E

SA Avdulov,PhD,a, S Li, PhD,a, D Burrichter,a, M Peterson,a, N Sonenberg,PhD,b, PB Bitterman,MD,PhDa, VA Polunovsky,PhD,a

aDepartment of Medicine, University of Minnesota, Minneapolis, MN United States, bDepartment of Biochemistry, McGill University, Quebec, Canada

AIM: The mRNA cap binding protein, eukaryotic translation initiation factor 4E (eIF4E), is overexpressed in many tumor types. Our objective was to examine whether the aberrantly upregulated status of the eIF4E-dependent translational apparatus is essential for human breast cancer cells to express the transformed phenotype and acquire chemoresistance. METHODS: Human mammary epithelial cells (HMECs) were transduced with a retroviral vector encoding eIF4E, while eIF4E antagonist 4E-BP was introduced into human breast carcinoma cells by using either plasmid or retroviral vectors. Both parental and the genetically modified cells were analyzed for their ability to form transformed foci in vitro and undergo apoptosis. RESULTS: We demonstrate that cells of six different breast carcinoma lines all functioned in a translationally activated state. This includes elevated steady state levels of initiation factors eIF4E and eIF4G1, hyperphosphorylation of 4E-BP1, and increased integrity of the translational complex in some cell lines, an alteration that is associated with cell resistance to apoptosis. Ectopic expression of eIF4E in non-tranformed HMECs converted them into apoptosis resistant cells that were able to form transformed foci in vitro. Accordingly, overexpressed 4E-BP1 reduced the ability of breast cancer cells to form colonies in vitro and increases spontaneous and drug-induced apoptosis in a manner dependent on its phosphorylation status and the potency to inhibit cap-dependent translation. CONCLUSIONS: These findings suggest that hyperactivated cap-dependent translation is a characteristic trait of breast carcinogenesis and an important mechanism by which cancer cells evade apoptosis and acquire chemoresistance. Therefore, targeted disruption of the activated cap-dependent translation complex may be a novel approach to adjuvant therapy in cancer treatment.

KEY WORDS: multistep carcinogenesis, translational apparatus, acquired chemoresistance, adjuvant chemotherapy.

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Paper presented at the International Symposium on Predictive Oncology and Intervention Strategies; Paris, France; February 9 - 12, 2002; in the section on Gene Therapy, Part 2.