Rampant cancer. Mice with only one working copy of tumor suppressor Mus81 have prostate (left) and muscle (right) cancers, among others.

Potent Tumor Suppressor Found

Tumor suppressor genes are sentries standing guard against cancer: Knock them out, and tumors can suddenly surface. Now, researchers studying mice have found one of the most powerful tumor suppressor genes yet--animals lacking it have a startling 50% chance of developing cancer.

Dozens of tumor suppressor genes have been identified, but most are poorly understood. Many, though, share one thing in common: The genes can't handle damage to their DNA, and when mutated, they make cancer more likely. Razqallah Hakem, a cancer biologist at the University of Toronto in Ontario, and his colleagues normally study a tumor suppressor called BRCA1, variants of which put women at high risk of breast and ovarian cancer. But recently, his attention was drawn to a more mysterious gene that hadn't been tied to cancer: Mus81. Yeast lacking Mus81 were hypersensitive to radiation and other agents that harm DNA; in one yeast species, the gene appeared to be a critical player in cell division.

Hakem's team wondered if Mus81, with its sensitivity to DNA damage, might have a cancer link. To find out, the scientists bred mice that lacked either one or both copies of the gene. Only half the animals with one good copy of Mus81, and a quarter of those with no copies, remained healthy and survived a year. Tumors, especially lymphomas, ran rampant through every one of the sick mice, the team reports in the 18 June issue of Science. These mice were more likely to get tumors than mice lacking almost any other tumor suppressor, except the widely studied P53 gene, Hakem says.

The work also casts doubt on a widely held theory about the function of Mus81. Yeast studies had suggested that Mus81 was critical for a specific stage in cell division that's essential for chromosome recombination during reproduction. To the researchers' surprise, however, the animals missing one or both copies of Mus81 were fertile and produced normal egg and sperm cells. Apparently, Mus81 works differently in mice.

"Mus81 really does play a critical role" in suppressing tumors, says Stephen West, a biochemist at Cancer Research UK in London. It's especially striking, he says, that mice with only one defective copy of Mus81 get cancer. Hakem says that came as a surprise to him, too. Although the good copy of Mus81 can still make protein, Hakem says, that's apparently not enough to stave off cancer.

Related sites
Hakem and colleagues' Science paper
Razqallah Hakem's home page
Background on some tumor suppressor genes

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