| January 31,
2001
Oncogene Spawns
Further Mutation in Breast Cancer Study
Penn Researchers Use Novel Mouse To Produce
Novel Results
(Philadelphia-PA) Like
a rabble-rouser, it appears that some errant genes can
be a bad influence on other genes, inciting a riot of
tumor growth. In an article in this month's Nature Medicine,
researchers at the University of Pennsylvania School
of Medicine describe how the human myelocytomatosis
(MYC) gene can select for spontaneous mutations in other
genes - leading to more tumor growth even after the
MYC gene is shut off. Their study has implications for
the search for therapeutics in cases of MYC-induced
breast cancer.
"MYC is an oncogene, a gene that has the potential
to cause cells to grow out of control, resulting in
tumor growth," said Lewis A. Chodosh, PhD, associate
professor in the Department of Molecular and Cellular
Engineering. "MYC-induced tumors tend to behave more
aggressively than other forms of breast cancers, and
we were looking to better understand why."
The researchers had primarily set out to study a larger
mystery: why women who give birth at a younger age are
less likely to develop breast cancer later in life.
Part of the difficulty was finding an animal model that
could mimic this phenomenon. A transgenic mouse, one
whose DNA included a cloned human gene, would over-express
the oncogene continually, not just later in life.
Instead, they created a strain of mice that would express
human MYC on demand. By mating transgenic MYC mice with
a strain of mice that would turn genes on in the presence
of an antibiotic, the researchers were able to create
mice whose MYC gene would turn on in the presence of
a particular antibiotic, doxycycline.
As a result, the researchers had a mouse whose MYC
gene could be turned on or off at will to simulate MYC-induced
breast cancer. The effort paid off well for the purposes
of research; MYC worked on in the mouse's mammary gland
with little or no expression in other tissues. What
they did not expect was that, while some tumors went
away when the MYC gene was turned off, half of the tumors
continued to flourish.
Surprisingly, the tumors that continued to grow all
harbored a spontaneous mutation in either Nras or Kras2
- members of the ras family of genes, another set of
genes with a tumor-causing reputation. Nearly all of
the tumors bearing normal ras genes stopped growing
when the researchers stopped administering the antibiotic.
Chodosh and his colleagues have demonstrated that, in
living creatures, MYC exacerbates tumor growth in breast
cancer by inducing a secondary pathway involving ras
mutations.
"Synergy is a nice trait to find among human endeavors,"
said Chodosh, "But synergy among oncogenes makes my
work a little more complex."
According to Chodosh, cancer is basically the progress
of uncontrolled cell reproduction. The mechanisms that
cells use to divide go out of control, which causes
the cells to multiply out of control. " As a cell divides
it makes a copy of its own DNA, one for each new cell.
The faster the reproduction, the more opportunities
to introduce error in the system - a mutation in a ras
gene in this case, " said Chodosh.
Currently, MYC is one of the genes that researchers
are looking as a target for new drugs to stop breast
cancer. The findings of Chodosh and his colleagues indicate,
however, that anti-MYC drugs may be an effective treatment
- but one that would not work to treat breast cancers
in which the ras oncogenes are already activated.
Other researchers involved in this study include: Celina
M. D'Cruz, Edward J. Gunther, Robert B. Boxer, Jennifer
L. Hartman, Louis Sintasath, Susan E. Moody, James D.
Cox, Seung I. Ha, George K. Belka, Alexander Golant,
of Penn, and Robert D. Cardiff of the University of
California, Davis.
The University of Pennsylvania Health System is distinguished
not only by its historical significance - first hospital
(1751), first medical school (1765), first university
teaching hospital (1874), first fully integrated academic
health system (1993) - but by its position as a major
player on the world stage of medicine in the 21st century.
Committed to a three-part mission of education, research,
and clinical excellence, UPHS has excelled in all three
areas. This year, the University of Pennsylvania School
of Medicine was ranked third among all U.S. medical
schools by U.S. News & World Report. Penn ranked second
among all American medical schools that received funds
from the National Institutes of Health, perhaps the
single most important barometer of research strength.
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