Given the usefulness of knock-out mice, it would seem natural that researchers would try to breed a strain of mice lacking BRCA1. But when they first tried it in 1996, the results were disheartening. Embryos in which both copies of the gene were knocked out died before birth because a catastrophic number of DNA breaks quickly accumulated. Rodents lacking only one copy of the gene survived but were no more susceptible to tumors than were normal mice.
Three years ago, however, researchers at the National Institute of Diabetes and Digestive and Kidney Diseases at the NIH found a way out of this bind by placing the genetic equivalent of a time bomb in the BRCA1 gene. They buried short DNA strings, called Lox, inside the BRCA1 gene of mice. Like hidden charges, Lox cut and destroy the DNA around them when special, tissue-specific proteins prompt them. The Lox-laden rodents were healthy at birth and developed normally; when the females became adults, however, the Lox bomb detonated in the mammary gland, destroying the BRCA1 gene. Several months later, some of the female mice developed breast tumors similar to those seen in women.
"We found a lot of genetic and chromosomal changes in these tumors that helped us to figure out their origin," says Chu-Xia Deng, senior author of the study, which was published in Nature Genetics. The researchers discovered, for example, that a well-known tumor suppressor gene, called p53, is often mutated together with BRCA1 in mammary tumors. Deng says that other scientists are now interested in these animal models to test anticancer drugs in preclinical studies.
From Transgenic Mice to Treatments
More recently, a serendipitous discovery inspired a different solution for creating live animal models for breast cancer. Research groups at both Columbia University in New York City and at the Dana Farber Cancer Institute in Boston published results this month in Genes & Development. "We took the idea from a paper describing the case of a woman, affected by breast cancer, that had inherited a particular mutation in BRCA1," Argiris Efstratiadis, leader of the Columbia research group, explains.
Image: NATIONAL CANCER INSTITUTE
This mutation had not completely destroyed BRCA1 but resulted in a protein half as long and lacking some of its function. So instead of completely knocking out the BRCA1 gene, the scientists "knocked in" a carbon copy of this mutation to the mouse genome. Such genetically modified animals produced only the half-length protein, developed normally¿at least for some strains¿and after a period of latency, sometimes developed large breast tumors. What's more, BRCA1 was mutated in all tissues, so these mice¿unlike the BRCA1 knock-out mice¿also suffered from other cancers, including sarcomas, lymphomas and carcinomas.
"Although BRCA1 is usually referred as a breast cancer susceptibility gene, it is actually a [general] cancer susceptibility gene," Efstratiadis says. Indeed, several studies have shown that people with an altered BRCA1 have a small increased risk for developing a particular tumor of the peritoneum, or the tissue lining the stomach cavity. So, too, male carriers have a higher-than-normal risk of developing prostate cancer. As a result, these transgenic animals provide a promising model for studying the involvement of BRCA1 in other cancers.
Unfortunately, neither animal model so far mimics the most awful feature of breast cancer¿its extreme tendency to spread to other tissues, especially the bones. "Among the hundreds of transgenic mice that have been made to study tumors, I haven't yet seen a true good model for bone metastasis," Green says. But these rodents may help in the development of future high-tech methods in cancer management.