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New Pathway Provides More Clues About BRCA1 Role in Breast Cancer

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Duke Health News 919-660-1306

DURHAM, N.C. -- A breast cancer gene's newly discovered role
in repairing damaged DNA may help explain why women who inherit
a mutated copy of the gene are at increased risk for developing
both breast and ovarian cancer.

The discovery also could lead to more effective therapies
for women with and without mutated copies of the BRCA1 gene,
according to a study led by Duke University Medical Center
researchers.

"Since it was discovered in 1994, BRCA1 and its role in
preventing and causing cancer has been intensely studied, and
our research represents an important piece of the puzzle," said
Craig Bennett, Ph.D., a researcher in Duke's Department of
Surgery and lead investigator on this study. "This study has
identified an important mechanism by which BRCA1 comes into
play when DNA -- the basis for all cell function -- is damaged.
We have shown that this theory holds up not just in scientific
models but in human breast cancer cells as well."

The findings appear in the January 16, 2008 online edition
of the journal PLoS ONE. The study was funded by the United
States Department of Defense, the National Institutes of Health
and the Italian Association for Research on Cancer.

The researchers first looked at yeast to demonstrate that a
molecular pathway that is particularly susceptible to BRCA1
influence is also crucial to normal cell function.

"The BRCA1 pathway we discovered is directly involved with
the critical process of transcription, in which RNA acts as a
messenger between DNA and the making of proteins," Bennett
said.

DNA damage is a normal result of exposure to environmental
agents, such as carcinogens, and the response to this damage
can be influenced by other normal human processes such as aging
and hormonal changes, Bennett said. It's what happens to RNA
transcription after damage occurs in DNA that is
BRCA1-dependent.

"We found that BRCA1 acts together with transcription to
detect DNA damage and to signal the cell to repair itself,"
Bennett said. "When BRCA1 does not function correctly, as when
it is mutated, DNA damage remains un-repaired and cancer can
occur."

The researchers applied their findings in yeast to human
breast cancer cells, with the same results.

"The fact that we were able to duplicate our results in
human breast cancer cells is hugely important," said Bennett.
"Yeast is a wonderful model organism that has been used to make
significant discoveries in many areas of science and medicine,
including Parkinson's and Alzheimer's diseases, but the ability
to replicate results in human cells is key."

Bennett said the discovery will lay the groundwork for
further investigation of the role of BRCA1 and possibly lead to
new therapeutic strategies targeting the genes or protein
products within this pathway.

Women who have inherited a BRCA1 mutation have up to an 80
percent risk of developing breast cancer in their lifetime, and
they are also at risk for developing the disease at much
younger ages than women without the mutation, according to the
American Cancer Society. Their risk for developing ovarian
cancer is about 40 to 50 percent, compared to just over one
percent for the general population. The mutation is most often
found in women with Eastern European Jewish origin, but can be
found in women of any race.

"Someday we hope that this research will lead to the
development of more effective ways to treat both the women who
have inherited a mutated copy of the BRCA1 gene and those who
have not," Bennett said.

Other researchers involved in this study include Tammy
Westmoreland, Carmel Verrier, Carrie Blanchette, Tiffany Sabin,
Hemali Phatnani, Yuliya Mishina, Gudrun Huper, Alice Selim,
Ernest Madison, Dominique Bailey, Adebola Falae, John Olson,
Arno Greenleaf and Jeffrey Marks of Duke; and Alvaro Galli of
the Institute of Clinical Physiology in Pisa, Italy.

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