Dysregulation of ribosome biogenesis and translational capacity is associated with tumor progression of human breast cancer cells.

Abstract

Protein synthesis is a fundamental cell process and ribosomes - particularly through the ribosomal RNA that display ribozyme activity--are the main effectors of this process. Ribosome biogenesis is a very complex process involving transcriptional aswell as many post-transcriptional steps to produce functional ribosomes. It is now well demonstrated that ribosome production is enhanced in cancer cells and that ribosome biogenesis plays a crucial role in tumor progression. However, at present there is an important lack of data to determine whether the entire process of ribosome biogenesis and ribosome assembly is modified during tumor progression and what could be the potential impact on the dysregulation of translational control that is observed in cancer cells. In breast cancer cells displaying enhanced aggressivity, both in vitro and in vivo, we have analyzed the major steps of ribosome biogenesis and the translational capacity of the resulting ribosome. We show that increased tumorigenicity was associated with modifications of nucleolar morphology and profound quantitative and qualitative alterations in ribosomal biogenesis and function. Specifically cells with enhanced tumor aggressivity displayed increased synthesis of 45S pre-rRNA, with activation of an alternative preRNA synthetic pathway containing a 43S precursor and enhanced post-transcriptional methylation of specifc sites located in the 28S rRNA. While the global translational activity was not modified, IRES-initiated translation, notably that of p53 mRNA, was less efficient and the control of translational fidelity was importantly reduced in cells with increased aggressivity. These results suggest that acquisition of enhanced tumor aggressivity can be associated with profound qualitative alterations in ribosomal control, leading to reduced quality control of translation in cancer cells.