A team of researchers at Princeton University and The Cancer Institute
of New Jersey has identified a long-sought gene that is fatefully
switched on in 30 to 40 percent of all breast cancer patients, spreading
the disease, resisting traditional chemotherapies and eventually leading
to death.
The gene, called "Metadherin" or MTDH, is located in a small region of
human chromosome 8 and appears to be crucial to cancer's spread or
metastasis because it helps tumor cells stick tightly to blood vessels
in distant organs. The gene also makes tumors more resistant to the
powerful chemotherapeutic agents normally used to wipe out the deadly
cells.
In identifying the genetic mechanism at play in the metastasis of
breast cancer, the scientists may have answered one of the biggest
mysteries in cancer research and paved the way for new drugs that could
thwart the gene's diabolical actions.
"Inhibiting this gene in breast cancer patients will simultaneously
achieve two important goals -- reduce the chance of recurrence and, at
the same, time decrease the risk of metastatic dissemination," said
Yibin Kang, an assistant professor of molecular biology at Princeton,
who led the research. "Clinically, these are the two major reasons why
breast cancer patients die from the disease."
The work is described in the Jan. 6 edition of Cancer Cell.
The discovery is important for several other reasons, according to
Michael Reiss, another author of the paper and director of the Breast
Cancer Research Program at The Cancer Institute of New Jersey, a part of
the University of Medicine and Dentistry of New Jersey-Robert Wood
Johnson Medical School.
"Not only has a new metastasis gene been identified, but this also is
one of a few such genes for which the exact mode of action has been
elucidated," said Reiss, also a professor of medicine, molecular
genetics and microbiology at UMDNJ-Robert Wood Johnson Medical School.
"That gives us a real shot at developing a drug that will inhibit
metastasis."
The multidisciplinary research strategy used by the team to pinpoint
the gene in breast cancer patients also could be used to find other
genes involved in the spread of other cancers, scientists said.
"The potential health implications of this study are significant," Kang
said.
The discovery is based on three years of work, using an approach that
combines the emerging science of integrative genomics with the classical
methods of clinical research and laboratory experiments.
"This paper is a great illustration of the way in which bioinformatics
can be synergistically combined with experimental work to produce
important results," said David Botstein, director of Princeton's
Lewis-Sigler Institute for Integrative Genomics.
>From the beginning, the scientists were looking for a way to understand
the dreaded process of metastasis, the term describing what happens when
cancer spreads to distant vital organs, such as the lungs, liver, brain
and even the bones.
As the scientists well understood, patients whose breast cancer can be
confined to the breast have the best chances at survival. The five-year
survival rates, as compiled by the National Cancer Institute, illustrate
the difference between localized and metastatic cancer: 98.1 percent of
patients with localized breast cancer survive five years after
diagnosis, as opposed to 27.1 percent for patients with cancer that has
traveled beyond the lymph nodes to bodily organs, according to the
federal agency's statistics.
In recent years, researchers have used advanced techniques such as DNA
microarray technology to try and identify genetic profiles of the so
called "poor prognosis" tumors -- those that are likely to come back
after the initial treatment and are most likely to spread beyond the
breast. Such studies, though useful in predicting outcomes, have
perplexingly offered up differing gene "signatures," making it difficult
to identify overlapping, functionally relevant genes that might be
important targets for therapeutic intervention.
The scientists in this study addressed this problem by using an
innovative computational biology approach. They re-analyzed massive
clinical breast cancer databases and found that study after study showed
one area in common -- a very small region in human chromosome 8 called
8q22. They found that this area of the chromosome is repeated many times
in the genomes of poor-prognosis breast tumors. Some chromosomes
contained as many as eight copies or "repeats" of the genetic segment.
Most normal DNA sequences contain only two copies of a given gene,
conveyed from the genomes of the male and female parents.
Next, the team studied breast tumor samples collected from patients at
The Cancer Institute of New Jersey. In doing so, the researchers were
able to validate the computational prediction, confirming that the
genetic sequence identified in the database was overproduced in the DNA
of the poor-prognosis tumor samples.
The researchers went on to discover that among a handful of genes in
the 8q22 region, MTDH is responsible for the aggressive behavior of
poor-prognosis tumors. They used recombinant DNA technology to enhance
the expression of individual genes in the region, one by one, in breast
tumor cells and tested their metastatic behavior in laboratory mice.
The scientists found that MTDH-overexpressing tumors are more likely to
metastasize to the lungs, other vital organs and bones. Importantly,
these tumors were also found to be more resistant to a wide range of
chemotherapeutic agents, including paclitaxel, cisplatin and adriamycin.
When researchers genetically altered the cancer cells to reduce the
expression of MTDH, these tumor cells become less able to metastasize
and more likely to be eliminated by chemotherapy agents.
"This is probably one of the first examples of a novel class of dual
functional breast cancer genes that cause both metastasis and
chemoresistance," Kang said.
Once the team had identified the specific gene, its scientists were
able to re-examine the tumor samples. "By analyzing 250 breast tumor
samples from patients, we found that this gene is amplified and
overexpressed in over 30 to 40 percent of breast cancer cases," Kang
said. "This indicates that new drugs against Metadherin may potentially
benefit a large population of breast cancer patients."
Gene expression is the translation of information encoded in a gene
into proteins that determine an organism's characteristics. Since only a
fraction of genes in a genome are expressed in a given cell, genes that
are turned "on" are viewed by scientists as a major signal that controls
the biology of both normal and malignant cells.
Breast cancer is caused by a malignant tumor that develops from cells
in the breast. The most common sign of breast cancer is a new lump or
mass in the breast. Scientists once thought that breast cancer spreads
first to nearby tissue and underarm lymph nodes before spreading to
other parts of the body. They now believe cancer cells may break away
from the primary tumor in the breast and begin to metastasize even when
the disease is in an early stage.
The team also found that the double menaces of MTDH may be involved in
the progression of other types of cancers, including prostate cancer.
The work was funded by a Department of Defense Era of Hope Scholar
Award and grants from the National Institutes of Health, the American
Cancer Society, the Susan G. Komen Foundation and the New Jersey
Commission on Cancer Research.
The Department of Defense awards, created in 2004, were designed to
provide substantial funds and support for exceptionally talented,
emerging breast cancer researchers -- individuals who had demonstrated
extraordinary creativity, vision and productivity, according to Capt. E.
Melissa Kaime, a physician who is director of the U.S. Army
Congressionally Directed Medical Research Programs.
"This award mechanism seeks the 'best and the brightest' early-career
researchers who will challenge current dogma and convention and who are
the future innovators of breast cancer research," Kaime said. "Era of
Hope Scholar Dr. Kang has already made exciting research achievements,
including his latest manuscript in Cancer Cell, and he is only halfway
into his five-year, $3.8 million award. The Breast Cancer Research
Program sees a promising and hopeful future with Era of Hope Scholars
like Dr. Kang dedicated to ending this disease."
Guohong Hu, a postdoctoral research associate in Princeton's Department
of Molecular Biology, is the first author on the paper. In addition to
Kang and Reiss, other authors include: Robert Chong, a 2007 Princeton
graduate who is now a research assistant in Princeton's Department of
Molecular Biology; Qifeng Yang, who was at UMDNJ-Robert Wood Johnson
Medical School and is now in the Department of Breast Surgery at Qilu
Hospital of Shandong University in China; Yong Wei, a postdoctoral
research associate in Princeton's Department of Molecular Biology;
Andres Blanco, a graduate student in Princeton's Department of Molecular
Biology; Feng Li, an associate research scholar in Princeton's
Department of Molecular Biology; Jessie Au, Distinguished University
Professor in the College of Pharmacy at Ohio State University; and Bruce
Haffty, professor and chair of the Department of Radiation Oncology at
UMDNJ-Robert Wood Johnson Medical School and chief of radiation oncology
at The Cancer Institute of New Jersey.
Source
Michele Fisher
Media Relations Specialist
Office of Communications
The Cancer Institute of New Jersey
195 Little Albany Street
New Brunswick, NJ 08903
umdnj.edu
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