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BRCA1
Mutation Linked to Breast Cancer Stem Cells
Newswise — A new study may
explain why women with a mutation in the
BRCA1 gene face up to an 85 percent lifetime
risk of breast cancer.
Researchers from the University of Michigan
Comprehensive Cancer Center found that BRCA1
plays a role in regulating breast stem
cells, the small number of cells that might
develop into cancers.
The study, in mice and in
human breast cancer cells, found that BRCA1
is involved in the stem cells
differentiating into other breast tissue
cells. When BRCA1 is missing, the stem cells
accumulate unregulated and develop into
cancer.
“Our data suggest that an
important reason women with BRCA1 mutations
get breast cancer is that BRCA1 is directly
involved in the regulation of normal breast
stem cells. In these women, loss of BRCA1
function results in the proliferation of
breast stem cells.
“Since we believe that
breast cancer may originate in these cells,
this explains why these women have such a
high incidence of breast cancer,” said
senior study author Max S. Wicha, M.D.,
Distinguished Professor of Oncology and
director of the U-M Comprehensive Cancer
Center.
The study, published
online this week in the Proceedings of the
National Academy of Sciences, provides
strong support for the hypothesis that a
small number of cells, called cancer stem
cells, are responsible for fueling a tumor’s
growth.
Wicha’s lab was part of the team that first
identified stem cells in human breast cancer
in 2003.
BRCA1 is one of two genes,
that when mutated confers a high risk of
breast and ovarian cancer.
Previous research has
shown that BRCA1 is involved in DNA repair,
but it has been unclear why women with this
gene mutation have such a high risk of
breast cancer, up to 85 percent lifetime
risk compared to 16 percent in the general
population.
The cancers which develop in these women are
generally a more aggressive form called
“triple negative type,” because they do not
express hormones or proteins, including
estrogen, that can be targeted with
therapies.
In the current study using
both mice and human breast cells,
researchers found that BRCA1 regulated the
development of the
estrogen-receptor-negative stem cells into
estrogen-receptor-positive cells.
When BRCA1 is missing,
genetically unstable stem cells accumulate
and then may develop into breast cancers.
Researchers detected
clusters of expanded stem cells in breast
tissue isolated from women carrying BRCA1
mutations, and found that women with these
expanded stem cells had a particularly high
chance of developing breast cancer.
“If larger studies confirm these findings,
it could potentially lead to a test to
identify BRCA1 carriers at particularly high
risk of developing breast cancer. This might
help them and their physicians make a more
informed decision about preventative
measures such as prophylactic mastectomy,”
Wicha says.
BRCA1 mutations are the
most common cause of hereditary breast
cancer, which account for approximately 10
percent of the 180,000 breast cancers
diagnosed in the United States this year.
For information about breast cancer, call
the U-M Cancer AnswerLine at 800-865-1125.
To learn more about cancer
stem cells, visit
http://www.mcancer.org.
In addition to Wicha,
study authors were U-M research investigator
Suling Liu; U-M research fellow Christophe
Ginestier; Emmanuelle Charafe-Jauffret,
M.D., Ph.D., from the Centre de Recherche en
Cancerologie de Marseille in France; U-M
research assistant Hailey Foco; Celina Kleer,
M.D., Harold A. Oberman Collegiate Professor
of Pathology and associate professor of
pathology at U-M; Sofia Merajver, M.D.,
Ph.D., professor of internal medicine at
U-M; and Gabriel Dontu, M.D., Ph.D.,
research assistant professor of internal
medicine at U-M.
The University of Michigan
has filed for patents covering these and
related technologies, and, through its
Office of Technology Transfer, is currently
looking for commercialization partners to
help bring the technology to market.
Much of the work is being
commercialized through OncoMed, a University
of Michigan startup company in which Max
Wicha and other U-M inventors hold a
financial interest.
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