Natural Tumor Suppressor Identified

Researchers have identified a key step in the formation--and suppression--of esophageal tumors and possibly carcinomas of the breast, head, and neck. By examining human tissue samples, they discovered that Fbx4 (F-box only protein 4), a naturally occurring enzyme, plays a major role in halting production of another protein called cyclin D1, which is thought to contribute to the early stages of cancer development.

When mutations block production of Fbx4, cyclin D1 is not degraded, and consequently contributes to cancer's advance. Fbx4 acts like a barroom bouncer, stopping problems before it starts by breaking down cyclin D1 before it can affect the body, according to scientists from the University of Pennsylvania School of Medicine (Philadelphia, PA, USA).

"Cyclin D1 was identified nearly 20 years ago and after that, it became apparent that it was overexpressed in a high percentage of tumors,” stated J. Alan Diehl, Ph.D., associate professor of cancer biology at the University of Pennsylvania's Abramson Family Cancer Research Institute. "But its expression didn't correlate to mutations within cyclin D1, so we were looking for a protein that regulates accumulation. That's Fbx4.”

For this study, researchers screened 116 esophageal tumors and found 16 mutations. Their findings were published in the September 9, 2008, issue of the journal Cancer Cell. The actual mutations researchers discovered were located within a highly conserved region of Fbx4 that functions like an on switch. Mutations within that switch region suppress activation of Fbx4, which means it cannot trigger destruction of cyclin D1.

The results are significant in that they show how cyclin D1 becomes so prevalent in tumors. Before, it was thought that cyclin D1 was present because of a mutation somewhere in the DNA of a cell. Instead, this study demonstrates that cyclin D1 naturally occurs, but the body has created a natural defense mechanism that breaks it down before cancer develops. "When Fbx4 is inactivated, it permits the accumulation of its target, cyclin D1,” said Dr. Diehl.

While it remains important to determine the cause of the initial mutations, this study provides researchers with a better understanding of the early stages of cancer, which is critical to finding a way to reverse the process.

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University of Pennsylvania School of Medicine