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CANCER RESEARCH:
New Model for Hereditary Breast Cancer

Michael Hagmann

Breast cancer strikes about one out of nine Western women in their lifetime and is second only to lung cancer as a cause of cancer deaths in women. For women who have mutations in BRCA1, one of two genes linked to the 5% or so of the cases that are hereditary, the disease is even more fearsome. They have a 70% chance of getting it. Now, researchers have an important new clue about how breast cancer develops, at least in these women.

The clue, in the form of an animal model for the disease, comes from the joint effort of two teams led by Chu-Xia Deng and Lothar Hennighausen at the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). In a paper in the May issue of Nature Genetics, the researchers report that they have inactivated, or knocked out, the BRCA1 gene in mice exclusively in the cells where breast cancer normally originates--the epithelial cells lining the milk ducts.

Previous efforts in which genetic tinkers knocked 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, while the other becomes inactivated later. But the animals with one inactivated copy did not get tumors at all, and those with two inactivated copies from the beginning died before birth. In contrast, the NIDDK team found that their animals do develop breast cancers, starting when they are about 10 months old. "This is quite exciting. 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.

In keeping with previous work indicating that BRCA1 is involved in repairing defective genes, Deng, Hennighausen, and their colleagues have found that breast cells lacking an active BRCA1 gene are prone to accumulating additional defects--most prominently the loss of the p53 tumor suppressor gene--that might be crucial contributors to cancer development. 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.

To knock out the gene specifically in breast tissue, Deng and Hennighausen engineered a so-called conditional mutant mouse strain. They first created mice with a genetic tag, called a loxP sequence, at two different spots within the BRCA1 gene. Then the team crossed the loxP mice with another transgenic strain carrying the gene for a molecular scissors, an enzyme called Cre recombinase. To make sure that the Cre gene is active only in the mammary epithelial cells, the researchers combined it with the regulatory DNA elements of a milk protein produced only in this tissue. The Cre recombinase recognizes the loxP sites and chops out the intervening part of the BRCA1 gene, inactivating it. Sure enough, some of the resulting mice developed breast cancer in at least one of their 10 mammary glands between 10 to 13 months of age.

Deng concedes that there are slight differences between his mice and women with BRCA1 mutations. Mice at 10 to 13 months of age are analogous to women in their 50s, while BRCA1-related breast cancers usually occur before menopause. Also, only 22% of the animals get the cancer, although Deng expects that more will as they age. Still, cancer biologist Bert Vogelstein of The Johns Hopkins University School of Medicine says that the animals provide the first "experimental system to figure out the way the BRCA1 gene works."

The NIDDK researchers began getting their first hints of how BRCA1 loss might lead to breast cancer when they looked at the milk ducts in mutant animals that were pregnant or lactating. "The mammary glands were smaller [in the mutants], and there is very sparse and sometimes abnormal branching" of the ducts, Deng says. At the same time the team observed extensive programmed cell death, or apoptosis, in the mammary tissue of mutant mice. "At first glance that looked quite inconsistent" with a gene abnormality that supposedly predisposes to the excessive cell proliferation of cancer, Deng says.

A peek at the chromosomes of tumor cells helped explain this apparent paradox, however. In cells lacking BRCA1, the entire genome seemed intrinsically unstable: There were extra copies of individual chromosomes, and some had large deletions or were fused to bits and pieces from other chromosomes. That makes sense, because previous studies had found a connection between BRCA1, as well as the other hereditary breast cancer gene, BRCA2, and the repair machinery for the chromosome breaks that lead to such instability.

Deng speculates that in the absence of BRCA1, cells accumulate enough DNA damage to trigger safeguards that cause them to stop dividing or even undergo apoptosis. That would explain the high cell-death rates seen in the mutant animals. However, the genetic instability also increases the mutation rates of crucial tumor-suppressor genes or cancer-promoting oncogenes--which may eventually overcome the growth controls and spur the development of tumors.

The Deng-Hennighausen team already has 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. They found that the mouse p53 gene 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 some 75%.

Hennighausen says he plans a variety of follow-up experiments with the mutant mice. For example, he wants to know whether the tumors spread as frequently as they do in human breast cancer patients and whether their growth is stimulated by the female hormone estrogen, as also happens in some human patients. If so, the animals would be good models for testing therapies.

Other researchers are also eager to get their hands on the long-awaited mice. Says Hennighausen, "We received several phone calls from people requesting the animals."


Summary of this Article
Similar articles found in:
SCIENCE Online
Search Medline for articles by:
Hagmann, M.
Alert me when:
new articles cite this article
Collections under which this article appears:
Genetics
Medicine/Diseases

Volume 284, Number 5415 Issue of 30 Apr 1999, pp. 723 - 725
1999 by The American Association for the Advancement of Science.


Copyright 1999 by the American Association for the Advancement of Science.