The general thinking is that aneuploidy - a cell's possession of the wrong number of chromosomes, be they too many or too few - can cause cancer in and of itself. But Angelika Amon, professor of biology at the Massachusetts Institute of Technology, has a contrarian view.

"People think that if you have aneuploidy, you get an extra copy of an oncogene or you lose a copy of a tumor suppressor, and then you get cancer," she told BioWorld Today. "But I don't believe it's that simple."

Aneuploidy definitely contributes to cancer development; for cells, an extra chromosome "comes with a lot of baggage," Amon said. But for that baggage to translate into outright disease, "cancer cells have additional mechanisms to take advantage of the aneuploidy."

Amon shores up her opinions with data, published in the Aug. 17, issue of Science, on some counterintuitive effects of aneuploidy in yeast. Contrary to what one would expect for a cancer-causing genome change, aneuploidy slows down cell growth.

Amon and her colleagues at MIT and Princeton University generated yeast cells bearing an extra copy of one of a number of different chromosomes (they did not investigate cells lacking a chromosome because such cell lines are very difficult to maintain.) They first investigated the gene expression signatures of the aneuploid cells, and found that aneuploid cells shared a stess-like gene expression signature that was largely independent of which particular chromosome had been duplicated.

Aneuploid cells were growth delayed even under normal conditions, and very sensitive to conditions interfering with transcription, translation and protein folding: "that basically pretty much kills them - it's their Achilles Heel," Amon said.

The reason for the troubles of aneuploid cells is twofold, and bears some resemblance to the perils of overconsumption in general. Much like acquiring superfluous items entails first the financial stress of buying them and then the time sink of taking care of them, aneuploid cells first spend precious energy on their extra chromosome: over 90 percent of genes on the extra chromosomes were expressed.

But the resulting extra proteins, rather than being useful, are a menace to the cell. The cell, Amon said, "needs to deal with them and shield [itself] from the proteins that are hanging around," unable to form complexes with their usual partners because of their excess numbers.

Cells appears to protect themselves by degrading the proteins basically as soon as they are made. Despite being transcribed and translated, most of the proteins that Amon and her group checked were not present in unusually large quantities.

As a result, Amon said, aneuploid cells "are very specifically dependent on proteasome degradation for their survival" — a fact that may explain the clinical success of proteasome inhibitors like Millenium Pharmaceutical's Velcade (bortezomib).

Aside from possibly explaining the success of current drug treatments, the research also may point the way to new ones. Given that aneuploid cells share a gene expression signature that is independent of which particular chromosome is duplicated, "it should be possible to specifically go after them," possible by targeting the types of proteins, such as chaperones, that aneuploid cells are highly dependent on.

Currently, Amon and her team are working to check whether the effects of aneuploidy in mice mirror those they have observed in yeast. But Amon is optimistic that the findings will apply to mammals. "Maybe it's just because I'm a pompous yeast person," she said, with an anything but pompous laugh. "But I think time has shown that once you start looking at basic cellular processes, what is true in yeast is also true in mammalian cells."

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