Role of eIF4E Activity in Breast Cancer

摘要

Increased expression of eIF4E has frequently been reported in breast cancers and is thought to make fundamental contributions to disease development and progression. Increased eIF4E activity acts to enhance the translation of oncogenic cancer-related transcripts that contain highly structured 5' untranslated regions (UTRs) in their mRNAs. Over-expression of eIF4E has been shown to correlate with poor prognosis in breast cancer therefore the level of eIF4E over-expression has been studied extensively as a prognostic marker with some success. Furthermore, eIF4E is an established target for cancer therapy and clinical trials of the efficacy and safety of cancer therapeutics that target eIF4E have been carried out, again, with some success. However, it is clear that eIF4E expression may not equate to eIF4E activity, since eIF4E activity is additionally regulated by a family of binding proteins, the 4E-BPs, that bind to and inhibit eIF4E activity. Our hypothesis was that analysis of eIF4E activity in individual breast tumours, as opposed to eIF4E expression, gives improved prognostic, predictive and biological understanding of individual breast cancers, and overall insights into the mechanisms of breast carcinogenesis. In order to test this hypothesis we aimed to investigate eIF4E activity in breast carcinogenesis using a novel cross-disciplinary approach. First, we aimed to determine expression levels of eIF4E and its regulators in breast tumours, and to estimate the individual contributions of each factor to eIF4E activity by relating each expression level to cancer survival. This approach would allow us to build, in collaboration with mathematicians, an equation relating the levels of these factors together to estimate eIF4E activity.