Breast cancer susceptibility gene

November 30, 2000

Breast cancer is the most common cancer among women, and the second leading cause of mortality from cancer. The American Cancer Society estimates that in the US this year, over 182,000 women have been newly diagnosed with invasive breast cancer. Mutations in the so-called breast cancer susceptibility gene, BRCA1, account for 40-50% of early onset familial breast cancer cases and >75% of familial breast/ovarian cancer cases. Recently, scientists have discovered that the protein ATR is responsible for activating BRCA1 in response to UV light-induced DNA damage. As published in Genes & Development, this discovery provides the first evidence that ATR may be the newest breast cancer susceptibility gene.

Our genomes are under frequent attack by environmental carcinogens, metabolic byproducts and spontaneous mutations. On a daily basis we are exposed to UV light, which can introduce covalent bonds between adjacent bases in DNA, thereby altering the normal double-helical shape of DNA and blocking its replication. Whether or not this DNA damage is repaired properly is a primary determinant in the development of cancer. DNA damage repair involves a cascade of phosphorylating enzymes, or kinases, which regulate the action of specific repair proteins. BRCA1 is believed to be one of these repair proteins. In cells that have lost BRCA1 function, there are increased rates of mutation in response to DNA damage, and therefore a greater susceptibility to cancer.

Dr. Abraham and colleagues have discovered that after cells are exposed to UV light, the kinase ATR phosphorylates BRCA1 at six different sites. By up-regulating or down-regulating ATR expression levels, Dr. Abraham and colleagues were able to observe that BRCA1 phosphorylation increases or decreases, respectively. Phosphorylated BRCA1 relocalizes to distinct sites of DNA damage within the cell nucleus, and presumably aids in their repair. In addition to more clearly delineating the pathway of BRCA1 response to UV light-induced DNA damage, Dr. Abraham and colleagues have found that mutations which alter ATR expression or activity may increase one's susceptibility to the development of breast cancer.
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Cold Spring Harbor Laboratory

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