A key step in the formation - and
suppression - of oesophageal cancers and perhaps carcinomas of the breast,
head, and neck has been identified by researchers from the University of
Pennsylvania School of Medicine.
By studying human tissue samples, they
found that Fbx4, a naturally occurring enzyme, plays a key role in stopping
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 broken down, and subsequently contributes to cancer's advance.
Fbx4 acts like a bouncer, stopping trouble before it starts by breaking down
Cyclin D1 before it can affect the body.
"Cyclin D1 was identified nearly 20 years
ago and after that, it became apparent that it was overexpressed in a high
percentage of tumors," says J. Alan Diehl, PhD, 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 a
recent issue of Cancer Cell.
The actual mutations researchers found are
located within a highly conserved region of Fbx4 that functions like an on
switch. Mutations within that switch region inhibit activation of Fbx4, which
means it can't trigger destruction of Cyclin D1.
The results are important 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 shows that Cyclin D1 naturally occurs, but our bodies have
created a natural defense mechanism that breaks it down before cancer develops.
"When Fbx4 is inactivated, it permits the
accumulation of its target, CyclinD1," says Diehl.
While it remains important to define the
cause of the initial mutations, this study provides researchers with a better
understanding of the early stages of cancer which is crucial to finding a way
to reverse the process.