Image: NATIONAL CANCER INSTITUTE ONE IN EIGHTwomen, the National Cancer Institute estimates, will develop breast cancer during her lifetime.

Few bits of DNA have as bad a reputation as BRCA1 and BRCA2, the breast cancer susceptibility genes. Women with inherited alterations in either one are at a high risk of developing breast and/or ovarian cancer, and these mutations are responsible for 30 to 80 percent of all hereditary forms of the diseases. Genetic testing can detect cancer-predisposing mutations, but a positive result gives only an estimated risk. It cannot reveal when¿if ever¿cancer might develop.

For this reason, the BRCA genes have become synonymous with Damocles¿ sword, hanging over the lives of women with family histories of breast cancer. The disease burden is impressive: a report from the National Cancer Institute (NCI) estimates that about one in eight women in the U.S. (approximately 13 percent) will develop the disease during her lifetime.

Mutations in the BRCA genes are responsible for only a small fraction of these cases. But for researchers, they represent one of the few handles they can grab at to study the molecular pathways behind breast cancer. Thus, the BRCA genes are among most molecular oncologist's top-10 favorite subjects. A glance at the medical literature reveals that BRCA1 alone¿the better studied of the two genes¿has been the subject of more than 2,000 papers published in peer-reviewed journals to date.

From this work, scientists have learned that the protein BRCA1 encodes normally helps guard DNA against damage from free radicals, radiation and chemicals. Such damage can jeopardize genetic information and alter the normal function of cancer-related genes, eventually leading to the appearance of tumors. Whereas some cellular machinery actually kills off cells that have accumulated too much damage, the BRCA1 protein seems to act like a plumber, fixing breaks as they occur along the genome.

A study in the May issue of the Proceedings of the National Academy of Sciences confirmed this idea, showing that the BRCA1 protein physically binds to damaged DNA and then recruits other molecules to assemble the equivalent of a DNA-repair kit. Scientists further demonstrated that the absence of the BRCA1 protein does not directly cause cancer but makes cells more susceptible to mutations that in turn can lead to malignant transformations.

Much of this knowledge, though, comes from studies done in test tubes and cells. In the body, cancer is a multistep process: many changes, driven by consecutive genetic alterations, must take place before a dutiful cell can escape the redundant mechanisms in control of its growth; others disruptions are required to foul the immune system's surveillance and lay new blood vessels to feed tumor cells. As a result, scientists desperately need living models to explore the process of cancer development in its full complexity.

Making Living Models

Genetic engineering has allowed scientists to make their own living models for studying a host of diseases. In many cases, they create strains of animals (usually mice) in which they "knock out" a single gene, destroying its function. Also, they can introduce mutations at specific sites to reproduce those behind human diseases. Hundreds of strains of so-called knock-out rodents exist today and represent the ultimate tool for studying cancer.

"In these animals you can study the molecular signaling pathway and the other genes involved in cancer progression," says Jeff Green, a researcher at the National Cancer Institute in Bethesda, Md. "You can observe the effect of different factors, such as hormones, on the tumor growth, and you can cross animals carrying different mutations to see their effect combined."

Image: NATIONAL CANCER INSTITUTE

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