Silencing the BRCA1 gene spells trouble.

Since 1994, scientists have known that having a mutated version of the BRCA1 gene greatly heightens a person's risk of breast cancer. Healthy BRCA1 encodes a cancer-suppressing protein that aids in DNA repair. Scientists have noted a scarcity of the protein in women who have breast cancer but don't have a family history of the disease or the BRCA1 mutation.

Researchers now report that some of these breast cancer patients nevertheless have an incapacitated BRCA1. Although the gene itself remains intact, a nearby stretch of DNA that switches on the gene has become impaired. The culprit is hypermethylation, a state in which too many methyl groups--hydrocarbon fragments--latch onto a specific DNA region. In some breast cancer patients, hypermethylation disables the control, or promoter, region for BRCA1 and silences the gene such that it can't direct production of its protein.

Cells routinely coat DNA with methyl groups, and the shifting patterns of methylation seem to regulate genes. In the new study, hypermethylation prevents necessary proteins from binding to BRCA1's promoter, thus shutting it down, says study coauthor James G. Herman, a medical oncologist at Johns Hopkins Medical Institutions in Baltimore.

Working with scientists in Spain and the Netherlands, Herman and his U.S. colleagues found hypermethylation of this promoter region in 11 of 84 randomly examined breast tumors that occurred in women with no family history of breast cancer. After expanding the search, the team detected DNA hypermethylation in 33 of 184 breast tumors sampled. Some of the women were chosen for this larger group, also without a known hereditary basis for the cancer, because they had types of breast cancer often seen in BRCA1-mutation carriers.

Hypermethylation showed up in 14 of 23 medullary and mucinous breast cancers, two uncommon malignancies that show up with unusually high frequency in patients with the mutations, the team reports in the April 5 JOURNAL OF THE NATIONAL CANCER INSTITUTE.

"They picked up [hyper]methylations where you'd expect to find them," says William D. Foulkes, a cancer geneticist at McGill University in Montreal. "This study is the first to really suggest there might be something going on with hypermethylation of BRCA1" in breast cancer.

While the cause of hypermethylation isn't known, the study "puts BRCA1 back into the focus of clinical oncologists and cancer geneticists," says Foulkes. "These findings add weight to the suggestion that a lack of BRCA1 protein may have important consequences in nonhereditary breast cancer."