NYU School of Medicine researchers discovered that a molecular switch in messenger RNA is essential for locally advanced breast cancer progression.
For large tumors to progress, they must develop their own blood supply through tumor angiogenesis. Angiogenesis is often triggered as the expanding tumor cells move away from the existing blood supply and are deprived of oxygen, a condition known as hypoxia.
The ability of tumors to develop their own vasculature, limits their growth and is regulated at different levels of genetic control. The NYU team says that they found evidence demonstrating how an unorthodox second pathway in protein synthesis plays a role in controlling the translation of mRNAs for factors that orchestrate angiogenesis, the tumor response to hypoxia, and progression of tumors to form large locally advanced breast cancers.
The investigators report finding that two factors involved in protein synthesis, eukaryotic initiation factor 4E (eIF4E)-binding protein (4E-BP1) and eIF4G, are strongly overexpressed in the majority of human large, advanced breast tumors.
Using breast cancer cells and animal tumor models, the researchers observed that elevated levels of 4E-BP1 trigger hypoxia inhibition of conventional protein synthesis in tumor cells. Also, 4E-BP1 and eIF4G then increase the selective translation of specific mRNAs that promote tumor survival and angiogenesis, thereby functioning as a hypoxia controlled switch for tumor growth and survival.
The new study will be published in the November 9 issue of Molecular Cell.