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Role of a
In Breast Cancer
By Michael Waldholz
The Wall Street Journal
(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
"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."