The Role of eIF4E Activity in Breast Cancer
Annual rept. 1 Aug 2008-31 Jul 2009
LEEDS UNIV (UNITED KINGDOM)
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Increased eIF4E expression occurs in many breast cancers and makes fundamental contributions to carcinogenesis by stimulating expression of cancer-related genes at post-transcriptional levels. This key role is highlighted by the facts that eIF4E levels can predict prognosis and that eIF4E is an established therapeutic target. However, eIF4E activity is a complex function of expression levels and phosphorylation statuses of eIF4E and its regulatory proteins. Our hypothesis was that combined analyses of these pathway components would allow insights into eIF4E activity and its influence on cancer. We have established that mathematically combining assessments of expressions of eIF4E-regulators with assessments of expression of eIF4E in clinical tumors provides improved prognostic insights over examination of eIF4E alone. In doing so we have determined the mathematical relationships between expression of each pathway component and pathway activity. Using human cell lines, we have experimentally demonstrated that this combinatorial estimate of eIF4E activity does indeed reflect eIF4E activity in breast cells. This represents a critical validation of our technique for estimation of eIF4E activity and allows us to propose that the estimate may act as a potentially powerful therapy predictive marker for cancer therapies directed against the eIF4E pathway.
- Medicine and Medical Research
- Organic Chemistry
- Statistics and Probability