Eukaryotic protein synthesis is regulated at several stages. These include transport of capped messages from the nucleus to the cytoplasm and recruitment of ribosomes to the 5'mRNA terminus. The primary control of both mRNA transport and ribosomal recruitment is exerted by elF4E, which is the rate limiting component of the cap-dependent translation initiation apparatus, eIF4F. When activated by extracellular signals or metabolic cues, elF4E selectively stimulates translation of messages governing differentiated state, cell cycle checkpoints and cell death. Consistent with this, increased elF4E-mediated mRNA transport and elevated levels of other elF4F components are found in a broad spectrum of solid tumors including breast cancers, and the activation state of elF4F shows a strong negative correlation with clinical outcome. Based on a substantial body of evidence including our published and unpublished data confirming a strong link between the functional status of the cap-dependent translation machinery and breast carcinogenesis, in this study we propose to test the hypothesis that aberrant activation of the translation initiation apparatus is required for the genesis and maintenance of breast cancer. To test this hypothesis, we have chosen an experimental design with 2 specific aims that integrate in vivo, in vitro, and mechanistic studies of translational control in breast cancer:
Aim 1. Determine whether sustained activation of the cap-dependent translation initiation machinery functions in the genesis and maintenance of a neoplastic phenotype in human (in vitro) and murine (in vivo) models of breast cancer;
Aim 2. Define the mechanisms governing the pro-neoplastic function of aberrant elF4E-dependent translation. If successful, our experiments will confirm (or refute) elF4E-mediated translation as a legitimate participant in oncogenesis and tumor maintenance, inform the selection of preclinical models of breast cancer, and identify novel molecular targets for breast cancer therapeutics.
| Avdulov, Svetlana; Herrera, Jeremy; Smith, Karen et al. (2015) eIF4E threshold levels differ in governing normal and neoplastic expansion of mammary stem and luminal progenitor cells. Cancer Res 75:687-97 |
| Jia, Yan; Chiu, Ting-Lan; Amin, Elizabeth A et al. (2010) Design, synthesis and evaluation of analogs of initiation factor 4E (eIF4E) cap-binding antagonist Bn7-GMP. Eur J Med Chem 45:1304-13 |
| Larsson, Ola; Li, Shunan; Issaenko, Olga A et al. (2007) Eukaryotic translation initiation factor 4E induced progression of primary human mammary epithelial cells along the cancer pathway is associated with targeted translational deregulation of oncogenic drivers and inhibitors. Cancer Res 67:6814-24 |
