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Abstract:
In this report we present data in support of Aim 3 of our project We demonstrate that ectopic expression of wild type or phosphorylation site mutants of 4E-BPl in breast cancer cells increases apoptosis, reduces the ability of cells to form colonies in vitro, and markedly inhibits xenograft tumor growth in vivo in a manner dependent on the potency of 4E-BPl to inhibit cap-dependent translation During in vitro and in vivo progression, transfected breast cancer cells tend to lose expression of exogenous 4E-BPl. Silence of ectopic 4E-BPl is associated with restoration of cell malignant phenotype and chemoresistance We conclude that intensification of 4E-BPl phosphorylation and other event leading to inactivation of 4E- BPl are under strong selective pressure and contribute to tumor progression by providing cell survival advantages Together, these findings suggest that the sustained activation of the cap-dependent translation apparatus is an important mechanism by which cancer cells evade apoptosis and acquire chemoresistance Targeted disruption of aberrant cap-dependent translation provides the opportunity to utilize this cancer cell-selective death pathway for anticancer therapy which spares normal cells.
| Limitations: |
 APPROVED FOR PUBLIC RELEASE |
| Description: |
Annual rept. 1 Oct 2001-30 Sep 2002 |
| Pages: |
21 |
| Report Date: |
OCT 2002 |
| Report Number: |
A219214 |
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