Researchers have a new tool for studying how breast cancer develops in women whose genes give them a 70% chance of getting the disease. In the May Nature Genetics, researchers report that they have inactivated, or knocked out, the BRCA1 gene in mice exclusively in the cells where breast cancer normally takes root.
Previous efforts at knocking out one or both copies of the gene in all mouse tissues produced disappointing results. Women with BRCA1 mutations are born with one inactive copy of the BRCA1 gene, while the other gets turned off later. But the animals with one inactivated copy did not get tumors at all, and those with two inactivated copies from the start died before birth.
To knock out the gene only in breast tissue, teams led by Chu-Xia Deng and Lothar Hennighausen at the National Institute of Diabetes and Digestive and Kidney Diseases engineered a mutant mouse strain so that a molecular scissors would slice out the genetically tagged BRCA1 gene--but only in cells in the breast lining the milk ducts. Sure enough, after chopping out the BRCA1 gene in the breast tissue, some of the resulting mice developed breast cancer in at least one of their 10 mammary glands between 10 to 13 months of age.
The researchers also shed light on how BRCA1 tumors develop. They already have evidence connecting the BRCA1 defect to the loss of p53, the well-known tumor suppressor gene that is itself mutated in about 50% of all familial breast cancers. The mouse p53 gene, they found, is either totally silent or severely scrambled in two-thirds of the tumors in their BRCA1 knockouts. The researchers also found that inactivating one copy of the p53 gene in the BRCA1 mutants accelerated tumor formation in the animals and drastically increased the cancer incidence to about 75%.
"Such an animal model is invaluable for understanding the role of BRCA1 in familial breast cancer," says Andrew Futreal of Duke University Medical Center in Durham, North Carolina, a BRCA1 co-discoverer. What's more, Futreal says, the new animals could prove useful in evaluating new treatments or chemopreventive drugs that might delay or even block the onset of breast tumors.