Elevated expression of eIF4E in confined early breast cancer lesions: Possible role of hypoxia

The translation-initiation factor eIF4E is rate-limiting for protein synthe sis, and its over-expression results in oncogenic transformation of mammali an cells. eIF4E facilitates the synthesis of several powerful tumor angioge nic factors (FGF-2 and VEGF) by selectively enhancing their translation, In breast carcinomas, eIF4E is commonly over-expressed, but the pathology whe re this elevation is initially manifested is presently unknown. To probe wh ether the elevation of eIF4E marks an early stage of cancer development, we focused our research on early cancerous lesions, We have analyzed 70 invas ive ductal carcinomas (IDCs), 78 ductal carcinomas in situ (DCIS), 51 benig n lesions and 4 model cell lines for elevated expression of eIF4E by severa l different methods: Northern/Western blots, immuno-histochemistry and in s itu RT-PCR, eIF4E expression was markedly increased in IDC and in islets of viable cells in the center of poorly vascularized DCIS, which are not easi ly identifiable by standard histological stains. We also show that expressi on of eIF4E is increased by hypoxia and, presumably, in hypoxic areas of th ese lesions, We propose that clonal expansion of cancer cells, permanently over-expressing eIF4E, gives them a critical advantage to survive hypoxia a nd marks the transition toward the vascular phase of cancer progression, He nce, eIF4E may be useful in stratifying DCIS lesions according to their mal ignant stage, (C) 1999 Wiley-Liss, Inc.