In breast cancer research, the gene Brca1 has received the lion's share of attention because mutations in that gene are responsible for about three percent of all cases of breast cancer. Researchers from the Howard Hughes Medical Institute (HHMI) at Baylor College of Medicine have identified a protein that works closely with Brca1 to initiate the repair of damaged DNA. They say that mutations in the gene that produces this Brca1 trigger protein may be responsible for more instances of breast cancer than Brca1 mutation.
The discovery of the trigger protein, which is made by a gene called ATM, suggests that malfunctions in Brca1 and ATM combined may account for nearly ten percent of all breast cancers. Both Brca1 and ATM are part of the cell's machinery for repairing genetic damage caused by radiation.
The discovery of ATM's role in triggering Brca1 was reported in the November 5, 1999, issue of Science by HHMI investigator Stephen Elledge and his colleagues in the biochemistry department at Baylor College of Medicine. Co-authors of the paper are David Cortez, Yi Wang and Jun Qin.
The ATM gene, which stands for "ataxia telangiectasia mutated," is named for the genetic disease in which people with two malfunctioning copies of the gene lose brain cells and control over muscles, have high cancer rates and increased sensitivity to radiation. The ATM protein is a "kinase," a type of enzyme that activates other proteins by adding a phosphate to them in a process called phosphorylation.
In their experiments, Elledge and his colleagues found that normal cells pulsed with gamma radiation contained phosphorylated Brca1; while irradiated cells from ataxia telangiectasia (AT) patients -- who do not have functional ATM genes -- did not. When the scientists inserted a functioning ATM gene into the cells of AT patients, the Brca1 protein did show phosphorylation.
Detailed studies of the Brca1 protein revealed that there are many sites on the molecule where phosphorylation can occur. When the scientists mutated the protein and blocked many of those sites, they found that the ATM protein could no longer control the Brca1 protein.
"We believe that these studies show that ATM is the sensor and the instructor for Brca1," said Elledge. "It tells Brca1 that there is a chromosome break due to radiation, and Brca1 is involved in orchestrating the repair process to fix the damage.
"Thus, we have now established a pathway that connects two major tumor suppressors involved in breast cancer."
Elledge emphasized that ATM and Brca1 are both middlemen in the DNA repair process and that further research will likely reveal that there are many more genes involved in the DNA repair pathway that may be important in breast cancer.
"Studies in yeast have shown that there are many other genes in this pathway," said Elledge. "We don't know all of the human genes yet, and it may be that we will end up with just one major pathway that accounts for a significant portion of all breast cancers."
ATM mutations may account for significantly more cases of breast cancer than the one to three percent attributed to Brca1 mutations, Elledge said.
"This work may provide a molecular explanation for other studies indicating that women who are heterozygous for ATM -- that is, they had one mutant form of the gene -- had a three- to four-fold higher predisposition to breast cancer."
Elledge and his colleagues also point out that studies in mice have shown that one mutant ATM gene rendered the animals more sensitive to genetic damage from radiation. Given that many women also possess one mutant ATM gene, the researchers write in the journal Science that their results "may have relevance to the issue of the relative benefits of broad x-ray screening for the early detection of breast cancer, a question to be resolved only by epidemiological studies."
According to Elledge, past studies also suggest that ATM is not a rare mutation. " If the published numbers are correct, there are one million women who are heterozygous for ATM, which means that it could actually account for a greater percentage of breast cancer than Brca1," Elledge said.
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