Cancer gene found vital to mouse embryos.

Like no other bit of DNA, the gene behind breast cancer inspired a worldwide quest. After victoriously nabbing it, however, scientists found themselves confronting the laborious task of determining what role this gene, BRCA1, normally plays and how mutations in it lead to cancer.

Now, a newly developed strain of mice genetically engineered to be defective in BRCA1 is beginning to offer some clues. It seems the gene may play a vital role in nervous system development.

"With this mouse, we have a potentially powerful model system" for studying BRCA1, says project leader Beverly Koller of the University of North Carolina at Chapel Hill Medical School. "And, for the mouse, BRCA1 is essential. Without it, they die before birth."

After a group of Utah researchers announced that they had found BRCA1 (SN: 9/24/94, p. 197), three other groups identified a total of 22 mutations in the gene. Any one of these mutations confers an 85 percent lifetime risk of breast cancer (SN: 12/3/94, p. 372).

The mutations have one thing in common. They stop cells from making a functional BRCA1 protein.

Everyone inherits a copy of BRCA1 from each parent. A single normal copy of BRCA1 is enough to put the brakes on abnormal cellular growth. But if the normal copy is damaged, cancer can arise.

Koller and her colleagues attempted to make a mouse that begins life with two defective copies of the gene. The team first created mice that carried a mutation in one copy of BRCA1, then bred those mice in order to produce some offspring with mutations in both copies.

The matings failed to create any of the desired BRCA1 knockout mice. Koller and her team hypothesized that the mouse embryos had died before birth. As the researchers report in the February Nature Genetics, they found that many of the knockout embryos had a spine that didn't seal completely or no brain. In addition, cells in the embryos had overgrown and failed to mature. The embryos died after 10 to 13 days, about halfway through normal gestation. Because certain breast and nerve cells mature from the same type of embryonic cells, Koller suggests that the BRCA1 protein may help both cell types mature. These findings may not be directly applicable to humans. Scottish researchers described in the June 15, 1995 Nature a breast cancer patient with a normal nervous system who inherited two mutant BRCA1 genes. Koller points out, however, that the second mutation may have arisen in the individual's lifetime and that researchers need to identify other such patients.

The mouse development "offers an important tool for studying the function of BRCA1," says Barbara L. Weber of the University of Pennsylvania in

Philadelphia. Koller notes that the mice with single mutations are still too young to have developed tumors. If they do, Weber points out, they would provide a model for developing breast cancer treatments and preventive measures.