Jefferson Researchers Show Antibody to Breast Cancer-Secreted Protein Blocks Metastasis
Scientists
at the Kimmel Cancer Center at Thomas Jefferson University in
Philadelphia have made a key discovery about the mechanism of breast
cancer metastasis, the process by which cancer spreads. Focusing on a
gene dubbed “Dachshund,” or DACH1, they are beginning to pinpoint new
therapeutic targets to halt the spread of cancer.
Reporting their findings in the Proceedings of the National Academy of Sciences,
researchers led by Richard Pestell, M.D., Ph.D., director of the Kimmel
Cancer Center at Jefferson and professor and chair of Cancer Biology at
Jefferson Medical College, showed that breast cancer cells secrete a
common inflammatory protein, IL-8. When the scientists blocked the
protein in mice with an antibody, they found that it completely halted
the spread of breast cancer to the lungs.
In addition, the team found that the DACH1 gene normally blocks the production of IL-8.
DACH1
is frequently lost or inactive in invasive breast cancer and can
prevent the migration and invasion of breast cancer cells. The finding
suggests that IL-8 is a potential target for new therapies to block
breast cancer spread.
“This
is a very important study by Dr. Pestell and his colleagues that
demonstrates that the protein dachshund blocks metastasis in a mouse
model and that this occurs through reduced production of the chemokine
IL-8,” says Max Wicha, M.D., director of the University of Michigan
Comprehensive Cancer Center in Ann Arbor. “Interestingly reduced
dachshund and increased IL-8 are associated with aggressive metastatic
breast cancer in women. Our laboratory has found that IL-8 regulates
breast cancer stem cells and that these cells mediate metastasis. Dr
Pestell’s work suggests that dachshund is a key regulator of this
process.”
DACH1
normally regulates eye development and development of other tissues,
playing a role in determining the fate of some types of cells. In
previous work, Dr. Pestell and his co-workers showed that DACH1 can
commandeer cancer-causing genes and return them to normal. The team
found evidence from more than 2,000 breast cancer patients that the
more the gene is expressed in breast cancer, the better the patient
did, enabling it to predict an individual’s prognosis.
Because
the researchers knew that DACH1 is lost in such invasive breast cancers
that carry poor prognoses, they investigated its potential role in the
cancer cells’ ability to migrate and invade, the prelude to metastasis.
They focused on its effects on cancer-causing oncogenes, such as Ras
and Myc.
In
a series of experiments, the scientists, led by Dr. Pestell and first
author Kongming Wu, Ph.D., assistant professor of Cancer Biology at
Jefferson Medical College, looked at the effects of adding DACH1 to
breast cells made cancerous by various oncogenes. When they added DACH1
to Ras-induced breast cancer cells, for example, they saw a greater
than 75 percent reduction in cell migration. Cells turned cancerous by
the oncogene ErbB2 showed a 50 percent drop in migration. Cells made
cancerous by Myc also had 50 percent less migration.
The
researchers performed a proteomic analysis, testing the expression of
many proteins at once to see which might be regulated by DACH1. They
found that IL-8 is a critical target of DACH1 that helps regulate
breast cancer cell migration and metastasis. In mouse studies, they
showed that DACH1 lowered the levels of IL-8 genetic material (mRNA) by
approximately 90 percent in cancers caused by Ras.
According
to Dr. Wu, the gene for IL-8 is also a known target of Ras, helping
recruit the formation of new blood vessels to feed a developing cancer
– a process called angiogenesis. He notes that it’s well known that
tumors with high levels of IL-8 have a poorer clinical prognosis.
“The
findings suggest an important role for IL-8 in blocking the progression
of cancer and metastasis,” says Dr. Wu. “Because IL-8 is a commonly
found protein, it’s possible to use this to block metastasis, perhaps
eventually as a target for gene therapy.”
Media Only Contact:
Steve Benowitz
Thomas Jefferson University Hospital
Phone: (215) 955-6300
Published: 7/8/2008