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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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