IBT scientists find link between ATM, BRCA1 genes
Geneticists at the Health Science Center have uncovered an important connection between ATM and BRCA1two genes that when mutated are linked to cancer development. The finding, published in the July 13 issue of Nature, marks another important step in development of potential anti-cancer therapies.
The ATM gene is mutated in a rare genetic disorder called ataxia telangiectasia (AT). Characteristics include weakened immunity, stunted growth, neuronal degeneration and a one-hundred-fold increase in the incidences of cancers such as leukemia and lymphoma. Women who are from families of AT patients and who carry only one good copy of the ATM gene have a three- to fourfold increased risk of breast cancer, said Dr. Nicholas S.Y. Ting, postdoctoral fellow in the Department of Molecular Medicine and co-author of the Nature article.
BRCA1-related mutations are responsible for 2 percent to 5 percent of all cases of breast cancer, Dr. Ting said. Loss of normal function of ATM and BRCA1 combined may account for nearly 10 percent of all cases.
Researchers in the laboratory of Dr. Wen-Hwa Lee, professor and chairman of molecular medicine and director of the Health Science Center's Institute of Biotechnology (IBT), examined cell lines derived from AT patients and cancer patients. "The results of our studies have provided one potential molecular and biological explanation of how the loss of normal ATM function could lead to increased risk of breast cancer," Dr. Ting said.
The ability of genes to repair themselves in response to molecular "injury" or "insult" is a key factor in whether or not a person will develop cancer. Mutations that affect normal ATM and BRCA1 function can result in impaired repair response, which ultimately may lead to tumor formation, Dr. Ting said.
The UTHSC team found that the ATM protein (ATM gene product) interacts with a protein called CtIP, which binds or locks itself to the BRCA1 protein and impairs its normal function. ATM is able to release CtIP from BRCA1, allowing BRCA1 to participate in the production of another key protein, GADD45, which is important for genetic repair.
"Current strategies for identifying women at risk for breast cancer include identifying mutations in the BRCA1 and BRCA2 genes," Dr. Ting said. "Mutations to these genes have been associated with 50 percent of all cases of inherited breast cancers. It may also be beneficial to screen women for mutations of the ATM gene as a risk factor for breast cancer."
The Nature paper is titled "Functional Link of BRCA1 and Ataxia Telangiectasia Gene Product in DNA Damage Response." Co-authors from the IBT are Dr. Lee, the corresponding author; Dr. Ting; Dr. Eva Y.-H.P. Lee; Dr. Phang-Lang Chen; graduate students Shang Li and Lei Zheng; and Drs. Yael Ziv and Yosef Shiloh of the Department of Human Genetics and Molecular Medicine at Tel Aviv University.
The San Antonio researchers obtained the AT patient cell lines from the Israeli researchers, who were the first to identify the AT gene.
Grants from the National Institutes of Health funded the study, along with pre-doctoral training grants and a post-doctoral fellowship from the U.S. Department of Defense Breast Cancer Research Program.