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The Interconnected Mysteries Of DNA Repair And Breast Cancer

December 01, 2014

The DNA in the nuclei of our cells gets tattered
every day from forces within, such as free radical damage,
and also from without, such as the sun’s UV rays. The
result is an estimated 20,000 DNA lesions per cell each day.
The body’s DNA repair system is superb at fixing these, but
no system is perfect. If defective DNA is left unmended, it
can cause cellular mutations that lead to cancer. Ryan B. Jensen, PhD, Assistant Professor of Therapeutic
Radiology and Pathology, is unraveling the connections
between DNA repair, breast cancer, and ovarian cancer.
His lab is looking for the instigating molecular events that
trigger mutations by tracing their origins to the BRCA2
(Breast Cancer Susceptibility) gene. It is well established
that women who inherit a mutation in BRCA2 are at
high risk of developing breast and ovarian cancer. Without
the BRCA2 mutation, for instance, women have a 12
percent chance of getting breast cancer; with the mutation,
the risk jumps to 90 percent over a patient’s lifetime.
What’s unclear is why BRCA2 mutations strike the
breast and ovaries. “No one has a clue why that is,” said Dr. Jensen, “why
it’s not the lungs or the brain. That’s a big mystery. My
lab is doing basic research to understand the biology of
what BRCA2 does, and what happens when it can’t do
its job. BRCA2 is a DNA repair protein that responds
to DNA double-strand breaks. These physical breaks in
the DNA helix are healed by BRCA2 through a complex
process called homologous recombination. But if the
breaks aren’t repaired properly, you get mutations in the
genes that drive the cancer process.” One reason for the mystery is that scientists didn’t
understand BRCA2 biochemistry. To study it would
require, for starters, purifying the protein coded for by the
BRCA2 gene. But the BRCA2 protein is large, unstable,
and fragile, all obstacles to purifying it. Dr. Jensen and his
colleagues worked on the problem for several years, and
in 2010 became the first to succeed at purifying the entire
BRCA2 protein. Using the same process, they are now
purifying mutant forms of BRCA2 taken from patients. That allowed the researchers to study the proteins
without all the interfering noise within cells. They put
the purified proteins—normal and mutant—into test
tubes or in vitro assays, mixed them with broken pieces
of DNA, and watched how they handled repair or failed
to. The goal is to pinpoint how and why something goes
wrong when BRCA2 is mutated, and why this defect leads
cells down the path towards tumorigenesis in the breast
or ovaries. In addition to the biochemical research, Dr. Jensen’s lab
is studying BRCA2 genetics. Using breast and ovarian
Radiobiology and Radiotherapy RESEARCH PROGRAM
cells isolated from human patients, they can then treat
the cells in tissue culture with various chemotherapy
drugs, and study the cellular response of the BRCA2
gene. Most of the drugs cause DNA damage. Dr. Jensen
wants to know what happens when BRCA2 is depleted
from a breast or ovarian cell. “Does it instantly become
genomically unstable? Does it die? If it doesn’t die, how
does it survive? Does it become a tumor cell? Those are
the genetic questions we’re trying to address.” Once Dr. Jensen and his colleagues have the biochemical
and genetic answers, drug-makers will have targets for new
therapies against breast and ovarian cancer. And perhaps
other cancers as well. “A failure in DNA repair,” explained Dr. Jensen, “ is
probably the driving force behind all mutations that
arise in cancer. DNA damage is an ever-present danger,
and if these DNA repair genes are not working properly,
you’re getting more genomic instability and mutations.
DNA repair genes are in charge of this process. If we can
understand that process, we can develop new therapeutic
avenues for treating cancer.” If we know that, a patient could come in and get
the sequencing done, and then get the drugs that are
most effective.”

Submitted by Emily Montemerlo on August 07, 2017