BRCA2 Mutations May Throw Wrench in DNA Repair

Women who have mutations in either of two genes, BRCA1 and BRCA2, have a dramatically increased risk of breast cancer. But researchers have had a hard time figuring out what role these two genes normally play--and why disrupting them has such a devastating effect. Now, results described in tomorrow's issue of Nature suggest that BRCA2 mutations could lead to cancer by interfering with cells' ability to repair damaged DNA. The findings imply that radiation could be especially effective in treating human breast cancers caused by similar mutations.

To find out what BRCA2 does normally, the team reporting the new results, which includes Allan Bradley of Baylor College of Medicine in Houston and Paul Hasty of Lexicon Genetics Inc. in The Woodlands, Texas, created "knockout" mice in which the gene was inactivated. They found that mouse embryos in which both BRCA2 copies were inactivated died early in development. This indicated that loss of the gene might somehow be halting cell growth.

Another clue came from studies in which the researchers showed that BRCA2's protein product associates with a protein called RAD51, a key component of the cell's DNA-repair machinery. This suggested that BRCA2 might itself be needed for DNA repair--an idea that received further support when the researchers exposed 3.5-day-old embryos to DNA-damaging ionizing radiation. Embryos with one or two intact BRCA2 copies survived, but those lacking both copies were totally destroyed.

Taken together, these findings suggest that BRCA2 mutations increase susceptibility to breast cancer by disrupting DNA repair and allowing cells to accumulate mutations, including those that foster cancer development. The embryos lacking functional BRCA2 genes probably stopped growing because molecular "checkpoints" in the developing embryo either halt the division of cells with damaged DNA, so that the damage can be repaired, or kill the cells outright.

Cancer gene experts are excited by these results. "This makes the idea that the BRCA genes are DNA-repair genes more believable," says Bert Vogelstein of Johns Hopkins University School of Medicine. And because mouse embryo cells with inactivated copies of BRCA2 are more sensitive to ionizing radiation than normal cells are, "it's a reasonable extrapolation" that breast cancers with mutated copies of the gene may be especially good candidates for radiation therapy.