Yeast cells point to human cancer gene.

On the road to cancer, cells seem to lose the ability to count. When a normal cell divides, it painstakingly creates a pair of cells having the same number of chromosomes. Tumor cells often have extra or missing chromosomes, a condition known as aneuploidy.

Aided by clues from yeast cells, scientists have now found that specific mutations in human cancer cells may permit this chromosomal chaos to occur. The development of aneuploidy, researchers suspect, advances tumor formation by eliminating tumor suppressor genes or by increasing the number of growth-promoting genes.

Cancer investigators predict that more mutations abetting aneuploidy will emerge in the next few years and that their discovery may suggest new strategies for combating tumors.

"This is the first step through the door, which is going to be flung open wide in the near future," says Stephen J. Elledge of the Baylor College of Medicine in Houston.

That initial step was taken by scientists from the Howard Hughes Medical Institute at Johns Hopkins Medical Institutions in Baltimore and at Case Western Reserve University in Cleveland.

Some of those investigators had previously discovered that genes vital to the repair of damaged DNA in yeast have human counterparts that are mutated in some forms of cancer. Consequently, they decided to study whether several mutant strains of yeast might help explain the aneuploidy that occurs so frequently in human cancer cells.

Those yeast strains have similar trouble segregating chromosomes among dividing cells. This abnormality stems from the strains' inability to respond to problems in cell division, such as the misassembly of the spindle, a network of filaments that lets dividing cells partition their chromosomes properly.

In recent years, scientists have identified the mutated genes responsible for these yeast strains. The human copy of one such yeast gene, BUB1, is mutated in 2 out of 19 colorectal cancer cell lines examined, report Hopkins' Bert Vogelstein and his colleagues in the March 19 Nature.

The investigators do not have direct proof that mutations in the human BUB1 lead to aneuploidy, although they do have evidence that the mutant gene enables human cells to proceed with aspects of cell division after being treated with drugs that disrupt spindle assembly. Cells without the mutant gene halt the process completely, says Vogelstein.

The researchers have found a second human gene related to BUB1, and they are examining whether it -- or human versions of the other yeast genes that cause chromosomal instability -- is mutated in cancers.

Understanding how cells detect and respond to chromosomal problems while dividing and how mutations allow cancer cells to ignore those problems may eventually suggest new ways to kill tumor cells without harming healthy cells, says Vogelstein.

Other scientists note that this cancer study once again highlights how the study of simple organisms such as yeast can provide insight into human biology and illness.

"The mechanism by which aneuploidy might arise in tumor cells was never clear," says Terry L. Orr-Weaver of the Whitehead Institute for Biomedical Research in Cambridge, Mass. "Obviously, there's real value in sorting out the basic biology in model organisms first."