Brunel University of London study finds protein widely used to stage breast cancer and other tumours actively prevents the chromosome chaos that drives cancer
A protein doctors routinely use to measure how aggressively tumours are growing may also help prevent the chromosome errors that drive cancer, new research by academics at Brunel University of London suggests. For decades, pathologists have measured Ki-67 across a range of cancers including breast cancer. Now that same protein appears to play an active part in preventing the chromosome damage that drives the disease. Ki-67 keeps the structural integrity of key regions of chromosomes called centromeres in tact during cell division, says the study published in the journal Developmental Cell.
The research, funded by the Wellcome Trust and the Biotechnology and Biological Sciences Research Council (BBSRC), was led by Professor Paola Vagnarelli at Brunel University of London in collaboration with scientists at the University of Edinburgh and the Technical University of Berlin.
“Doctors already measure Ki-67 to see how aggressive a cancer might be," said Professor Paola Vagnarelli, from the College of Health, Medicine and Life Sciences at Brunel, who led the research. "But our results suggest it is actually helping maintain genome stability. That means it may be more than a marker. It could potentially also be a therapeutic target."
The study examined three proteins that attach to chromosomes during cell division and help rebuild the molecular system that tells each new cell what kind of cell it is. Every human cell carries identical DNA. What makes a liver cell different from a brain cell is which genes are switched on and which are kept in sleep mode. When a cell divides, that entire system of switches must be reconfigured from scratch. These three proteins — Ki-67, Repo-Man and PNUTS — are central to that process.
Vagnarelli's team developed a method that individually removes each protein from a living cell precisely at the point of division. Older techniques could not isolate that moment cleanly. By combining this approach with large-scale genomic and proteomic analysis, the team built what they describe as one of the clearest pictures yet of how a newly divided cell rebuilds itself.
The findings show cells rely on each of the three proteins to reset themselves after division. When the team removed them one by one, the system quickly broke down. Without PNUTS, gene activity spiralled out of control and thousands of genes switched on at once. Without Repo-Man, cells escaped safety checkpoints. "What we didn't expect was how clean the separation was," said Prof Vagnarelli. "Each protein fails in its own specific way. There is no redundancy, no safety net. Which means there are three separate points at which this process can go wrong."
“When the system breaks down, cells can emerge with the wrong number of chromosomes. That condition, called aneuploidy, is seen in disorders such as Down syndrome and in many cancers. We also found that these chromosome errors can trigger inflammatory signals inside the cell.”
"These cells behave almost as if they are under attack," said Vagnarelli. "The immune response switches on because the genome is unstable. That link between chromosome imbalance and inflammation could help explain patterns we see in several diseases."
For cancer researchers, the combined findings point in a practical direction. Many tumours are driven by precisely the kinds of failures this study has mapped: chromosome instability, loss of gene regulation, cells dividing before they are ready. Understanding the normal machinery that prevents these errors may help researchers find ways to push cancer cells into making lethal mistakes.
"We now have a clearer map of the machinery that resets the cell after division," said Vagnarelli. "That knowledge gives us a starting point for thinking about new therapeutic approaches."