A team of researchers at the National
Institutes of Health (NIH) has uncovered the role of two key genes
implicated in the development of inherited forms of breast cancer. In
the May issue of Nature Genetics, Xiaoling Xu, Chu-xia Deng, and
colleagues from the National Institute of Diabetes and Digestive and
Kidney Diseases (NIDDK) unveil a model of tumor formation that holds
great potential for studying breast cancer in women.
The animal model reveals new detail about how mutations in BRCA1 and
another gene, called p53, work in tandem to accelerate tumor formation
and growth. "This model may speed the process of future research on
breast cancer and its treatment," says Xu, lead author of the study.
Researchers at the National Human Genome Research Institute and the
National Cancer Institute also contributed to the project.
Scientists have known that mutations of BRCA1 are involved in the
development of these cancers but had not been able to identify
specifically how alterations in BRCA1 affected the timing and process of
tumor development. "We knew from previous work that the role of BRCA1 in
tumor formation was not straightforward," says Deng, a co-author of the
Recent work by the same team established that BRCA1 plays a critical
role in controlling when cells divide and how genetic material is
duplicated. In the Nature Genetics study, the researchers showed
that mutations in BRCA1 create an environment in which genes such as p53
mutate more readily. "Loss of BRCA1 creates the condition for p53 to
mutate," says Lothar Hennighausen, a mammary gland expert and NIDDK
co-author of the study. "P53 is believed to be the gatekeeper. Then when
you lose p53, the tumor grows," he adds. Half of human tumors have
mutated p53 genes.
Studying the relationship of mutations in BRCA1 and p53 was a complex
process that took over three years. First, to uncover the function of
BRCA1, the researchers bred mice to contain mutations in BRCA1 genes in
mammary gland tissues only, and only at specific points in development.
BRCA1 genes in these mice were unaltered in other cell tissues.
To accomplish this specific "knock-out" of genes, NIDDK's Kay-Uwe
Wagner, the second author of the study, applied a technique that uses
specially developed genes to act like molecular scissors that can
recognize, target, and cut out critical segments of genetic material.
The study of the resulting knockout mice allowed the NIDDK researchers
to build an accurate model of the mechanism by which BRCA1 mutations
lead to tumorigenesis.
When BRCA1 alone was deleted from mammary glands, 5 of 23 of the
experimental mice developed tumors over one year. The tumors showed
rearrangements of chromosomes where p53 is located. To focus on the role
of p53, the researchers then introduced a copy of a mutated p53 gene
into the mice. When the researchers introduced altered p53, 8 of 11 mice
formed tumors, a 90 percent increase. Tumors also grew faster--in 6
months instead of twelve--when the two mutations were present.
"We now have direct genetic evidence that p53 is involved in
BRCA1-associated tumorigenesis," says Xu, "but it is probably not the
only mutation involved. There may be some others, perhaps some that
activate oncogenes--the cancer genes that promote uncontrolled cell
"Animal models are vital to our understanding of human disease. This
model is the first that shows cancer development similar to the
development of breast cancer in women. It will be an important tool for
future work on tumors and their progression," says NIDDK Scientific
Director Allen Spiegel, M.D. The researchers believe that this model
provides a route for testing drugs to prevent tumor formation in humans,
as well as to test the role of environmental agents, such as radiation
or environmental estrogens in tumor growth.
An estimated 175,000 women will be diagnosed with breast cancer in
1999; about 43,000 will die. Mutations in the BRCA1 gene are found in 90
percent of women who have inherited both breast and ovarian cancer, and
in about 50 percent of women with inherited breast cancer alone.
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