The Role of elF4E Activity in Breast Cancer
Abstract
Increased expression of eIF4E occurs in breast cancers and contributes to carcinogenesis by stimulating expression of cancer-related genes. However, eIF4E activity is a function of activating and inhibitory influences determined by expression and phosphorylation of eIF4E and eIF4E-binding proteins (4E-BPs). Rapamycin and everolimus are potential cancer drugs that target eIF4E indirectly by modifying 4E-BP function. Our hypothesis was that combined analyses of eIF4E and 4E-BPs would allow insights into eIF4E activity and into which tumours will respond to eIF4E-directed therapies. We determined expression of eIF4E, 4E-BP1 and 2, and phosph-4E-BP1 in breast tumours using immunohistochemistry (IHC). Data were analysed to estimate eIF4E activity. eIF4E activity estimates gave greater prognostic insights than analysis of eIF4E alone. In cell lines we used a reporter to measure eIF4E activity and showed that this was a significant predictor of rapamycin sensitivity. However, IHC based estimates of eIF4E activity in breast cancer biopsies taken at diagnosis did not predict sensitivity to pre-operative treatment with rapamycin derivative everolimus. An explanation for this lack of correlation was that tumours with higher pre-treatment eIF4E activity undergo potent and rapid selection for everolimus resistance. We concluded that estimates of eIF4E activity have prognostic value in breast cancer but little predictive value for everolimus therapy. Acquired resistance may limit the worth of everolimus monotherapy in breast cancer treatment.
Document Details
- Document Type
- Technical Report
- Publication Date
- Aug 01, 2011
- Accession Number
- ADA552946
Entities
People
- Thomas Hughes
Organizations
- University of Leeds