Unraveling the role of the breast cancer gene.

Last October, an army of collaborating researchers from five North American medical institutions pinpointed the genetic flaw associated with some five percent of all breast cancers (SN: 9/24/94, p.197). Scientists around the world had hoped that this gene--a mutant form of BRCA1--would provide insight into the causes of most other breast cancers as well. Those hopes were dashed, however, when BRCA1 proved to be an unusually complex gene associated only with a small proportion of inherited forms of breast and ovarian cancers.

Now, work on the mouse equivalent of BRCA1 offers the first clues to the role played by the normal form of this gene. It appears to help control cell growth and maturation throughout the body, according to a report in the September Nature Genetics.

"We weren't really expecting [the BRCA1 gene] to be this broadly expressed," says Lewis A. Chodosh of the University of Pennsylvania School of Medicine in Philadelphia, an author of the new study. "It makes us think that BRCA1 is not just playing a role in the breast."

Women who inherit a flawed copy of the BRCA1 gene not only face an 85 percent chance of developing breast cancer at some point during their lives, but also experience a substantial increase in ovarian cancer risk. In recent months, researchers have also noted that people carrying a mutant copy of the gene experience more colon and prostate cancer. Although some researchers suggest normal BRCA1 may suppress tumors, no one knows how BRCA1 flaws might foster cancer.

To get an idea of just when the BRCA1 gene "turned on" and where it was expressed, the new study--conducted by researchers from Penn, the University of Michigan School of Medicine in Ann Arbor, and the National Center for Human Genome Research in Bethesda, Md.--studied embryonic, pubescent and adult mice. Surprisingly, the gene proved active in nearly all the immature tissues of very young embryos, but as the tissues matured, the embryos developed a specific pattern of BRCA1 expression which included the liver, lung, salivary gland and thymus.

In adult mice, the gene proved most active in the testes, which produce sperm, and in the thymus, which makes T cells, the immune system's laborers. While the breast, ovary, uterus and liver also expressed significant levels of the gene, BRCA1 appeared inactive in the kidney, heart and brain. This activity pattern suggests BRCA1 is most active in tissues that produce many developing cells, says Chodosh.

Because the breast develops largely after birth, the researchers investigated whether BRCA1 expression increased during times of breast development as a result of stimulation by the hormones estrogen and progesterone. And they indeed found substantial increases in BRCA1 activity during puberty, when mammary ducts are beginning to form, as well as during early pregnancy, when those ducts mature to express milk.

Remarkably, BRCA1 activity levels remained elevated long after pregnancy. Giving estrogen and progesterone in amounts typical of pregnancy also increased BRCA1 activity in mice that cannot produce those hormones. If hormones turn on BRCA1's tumor suppressing activity, "we could potentially use currently available [hormone-mimicking] drugs to protect against breast cancer," speculates Chodosh. However, he notes that work is still preliminary.

Myles Brown of the Dana Farber Cancer Institute in Boston says, "The work is an important first step, but only a first step, in understanding BRCA1."