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Science:
Research Shows
Role of a Gene
In Breast Cancer

By Michael Waldholz

04/30/1999
The Wall Street Journal
Page B1
(Copyright (c) 1999, Dow Jones & Company, Inc.)

Cracking four frustrating years of experiments, government researchers say they have finally bred a strain of mice that indicates how a previously identified gene causes breast cancer.

Developing the first animal model to study the disease is the latest in a controversial, two-decade hunt for the breast-cancer gene. Within months of the 1994 discovery of the gene, called BRCA1, researchers began marketing a test that, for the first time, revealed to women in certain families whether they had inherited a higher-than-usual risk of developing breast, and ovarian, cancer.

Researchers still had no idea how the gene transformed healthy cells into cancer and, therefore, no idea how to stop it. But over the years, some women who learned they carried BRCA1 nonetheless took the drastic step of undergoing pre-- emptive surgery to have their healthy breasts and ovaries removed.

Meanwhile, more than a dozen teams of scientists around the world continued struggling to identify BRCA1's role in cancer. That knowledge, researchers hope, will someday lead to nonsurgical ways to prevent the disease and new pharmaceutical treatments to fight it.

From that quest a breakthrough has surfaced in a small laboratory at the gigantic government research complex in Bethesda, Md. Led by Chu-Xia Deng, a Harvard-trained investigator at the National Institute of Diabetes, Digestive and Kidney Diseases, scientists say that they have bred a strain of mice that develop breast cancer as a direct result of inheriting a mutation in a mouse form of BRCA1.

By examining the disease in the mice, Dr. Deng's team has produced strong evidence that inheriting a defective form of BRCA1 doesn't, in and of itself, cause cancer. Rather, the scientists argue, BRCA1 is actually a so-called "caretaker gene" whose role within a cell is to protect the integrity of other genes.

When BRCA1 is damaged, other genes under its protection can go awry, allowing normal cells to divide without check, eventually becoming a tumor.

"Finally we have an animal model to study the disease, to study how to prevent the gene from causing cancer, and how to create drugs that can block that process," says Wen Hwa Lee, a cancer-gene scientist at University of Texas Health Sciences Center in San Antonio,

Dr. Lee, who himself has spent the past five years studying the biochemical mechanism by which BRCA1 mutations lead to cancer, says his lab just created a similar strain of mice. "But Deng beat us," he says. More importantly, however, Dr. Lee says his research, and experiments he hopes to publish soon, confirm that BRCA1's role in human biology is far more important than its involvement in cancer.

"The gene is one of the few genes so far identified as 'caretaker' because they keep other genes from becoming damaged during normal cell division," Dr. Lee says. "We want to find [drugs] that can mimic this protective mechanism. It's really fantastic, because we now have a very clear direction for future research."

Precisely how and when the advance, if ever, will lead to new therapies isn't clear. Drug-making scientists these days are embracing the notion that uncovering the genetic basis of a disease will eventually lead to more effective and safer medicines. But the journey from gene discovery to the creation of a marketable medicine will likely take many years.

Dr. Deng, whose new research is being published today in the journal Nature Genetics, says he is already being barraged with requests from other scientists for samples of the cancer cells from the mice. It's a gratifying turn of events for the 43-year-old biologist who failed at several previous lengthy efforts to breed a BRCA1-mutated mouse.

Because mice and humans inherit two copies of every gene, one from each parent, the researchers struggled to produce mice that inherit the damaged gene, and develop disease, in a way similar to humans. When the scientists bred mice with both gene copies mutated, the mice died in gestation, suggesting the gene was crucial to fetal development. But when the scientists produced mice with only one damaged copy, the mice were born healthy and didn't develop cancer.

Finally, Dr. Deng and his lab found a way to produce mice in which only mammary cells contained one damaged gene. Only when scientists then damaged the other BRCA1 copy in breast cells did some tumors form. By tracing the gene's activity in these mice, scientists found that only in cells with two mutated copies did other unrelated genes suddenly became destabilized -- that is, damaged and ineffective. Among the genes altered in this way was one called p53 that scientists know plays a critical role in keeping cells from growing into tumors.

"Breast cancer takes so long to form in many of these women because this process -- of first damaging both copies of BRCA1 and then damaging other genes -- can take years to occur within a cell," Dr. Deng says. "Our job now is to figure out how to keep that from happening at all."






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