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Breast Cancer Gene Dons New Hat

10 July 2000 8:00 pm
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A gene that can cause breast and ovarian cancers when it's mutated also seems to play a key role in the development of T cells, the soldiers of the immune system, according to a study in this month's Nature Immunology. The findings don't explain how the gene, BRCA1, contributes to cancer, but they shed new light on how T cells ripen.

Mutations in BRCA1 have been implicated in about 5% of breast and ovarian cancers. Researchers think the BRCA1 gene normally plays a crucial role in DNA repair. Some suspected the gene might also be important in T cells--which fight infections of bacteria, viruses, and parasites--because those cells produce large amounts of the BRCA1 protein and because DNA repair is a natural part of a T cell's journey to maturity. To produce a wide variety of different T cells that can tackle any invader, the DNA encoding the cells' receptors is reshuffled during maturation, which means DNA strands need to be broken and glued together again.

To find out how important BRCA1 is to the immune system, a team led by molecular biologist Razqallah Hakem of the University of Toronto created mice that lacked the protein in their T cells. As a result, they had 90% fewer T cells than a control group. Their T cell population was also very young, suggesting the cells hadn't completed their maturation process, and was less responsive to various stimuli. The scientists found that p53, a protein that responds to DNA damage by either shutting down cell division or causing the cell to commit suicide, was apparently involved in their demise. The knockout mice had high p53 levels in their T cells, whereas the protein was undetectable in the control group.

But a follow-up experiment surprised researchers. It showed that the T cells didn't succumb as a result of DNA reshuffling gone awry. After knocking out BRCA1 and also the gene for p53--thus preventing the cells from killing themselves--the researchers found that the animals produced normal amounts of T cells. In addition, the sites where their receptor DNA was broken and repaired were intact.

Although BRCA1 must be critical to T cell development, it may not be crucial for repairing DNA during the reshuffling of receptor genes, says Doug Green, an apoptosis researcher at the La Jolla Institute for Allergy and Immunology in San Diego, California. "Most of us assumed that this was the major source of DNA damage in these cells," he says. The next step, says Green, is to figure out BRCA1's role in the development of cancer.

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