eIF4E in human breast cancer and its role in regulating translation of splice variants of breast cancer genes

Abstract

In eukaryotes, most of mRNAs are translated by the scanning mechanism. The trimeric complex eIF4F (consisting of eukaryotic initiation factor eIF4E, eIF4G and eIF4A) binds to ribosomes and the 5’end of mRNA, unwinding the secondary structures for scanning. eIF4E is the least abundant initiation factor, and may therefore determine the rate of translation. Overexpression of eIF4E can cause malignant transformation of immortalized human cells. Anti-sense oligonucleotides of eIF4E partially reversed the malignant phenotypes, suggesting that overexpression of eIF4E is the direct cause of transformation. Two- to threefold higher eIF4E levels have been detected in breast cancer using immunohistochemistry. Aabout 10% of cellular mRNAs contain atypically long 5’UTR and many of these encode proto-oncogenes and growth factors. It is believed that these long 5’UTR sequences tend to form stable secondary structure, requiring higher levels or activities of eIF4F for their translation. Over 60% of human genes are alternatively spliced. These may produce variants with different degrees of secondary structure at their 5’-UTR. We hypothesized that the elevated eIF4E level in breast cancer cells allows more effective translation of breast cancer gene variants with extensive 5’UTR secondary structure. These changes in variants profile may be important for breast cancer development and progression. We first analyzed the expression levels of eIF4E in human breast cancer and non-tumor biopsies in tissue microarray. Our preliminary results showed that there was significantly higher eIF4E expression in tumor versus non-tumor and eIF4E expression was positively correlated to estrogen receptor (ER) expression (OR=4.4, p=0.006). Although eIF4E expression levels were independent of tumor grade and size, it was strongly associated with overall clinical ER and progesterone receptor status (OR=6.3, p=0.003 and OR=6.5, p=0.002). The differential translation of breast cancer gene splice variants in breast cancer cell lines is being analyzed and their correlation with the extent of secondary structure of their 5’UTRs will be determined.