The findings are available online and will be published in the Jan. 18 issue of Proceedings of the National Academy of Sciences (PNAS).

Bruce has long been recognized as an inhibitor of apoptosis, but until now, its method of inhibition was not clear. Dr. Du analyzed Bruce mutant mice and found that Bruce regulates p53, a tumor suppressor gene, and the mitochondrial pathway of apoptosis.

Bruce's primary function resides upstream of mitochondria. Loss of function of Bruce increases the level of p53, making cells more sensitive to apoptosis. The transcriptional activity of p53 is responsible for the activation of genes including Pidd, Bax, and Bak. These in turn activate mitochondria, leading to apoptosis.

"The identification of Bruce as a regulator of p53 raises the possibility that therapeutic inactivation of Bruce activity could keep p53 levels high to combat certain tumors," said Dr. Du. "On the other hand, over expression of Bruce may help maintain cell survival in neurodegenerative diseases such as Alzheimer's disease." "Dr. Du's findings answer a fundamental question of apoptosis and have implications for a wide variety diseases," says Robb Krumlauf, Ph.D., Scientific Director of the Stowers Institute. "These findings are an example of the broad impact of basic research conducted at the Stowers Institute."

Dr. Du joined the Stowers Institute in 2001. She holds B.S. and M.S. degrees from Beijing Normal University, and a Ph.D. from Iowa State University. From 1998 to 2001, she was a Howard Hughes Medical Institute Postdoctoral Fellow with Dr. Xiaodong Wang at the University of Texas Southwestern Medical Center. She currently holds a secondary appointment as an Assistant Professor of Biochemistry and Molecular Biology at the University of Kansas School of Medicine.

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What results is a strong response against HER2/neu that incorporates all three arms of the immune system - B cell, T cell and natural killer cells - and which creates a long-lasting immune memory primed to attack breast cancer cells that are studded with HER2/neu proteins, he says.

In the experiments, three groups of seven mice were treated with three injections of a vaccine. The "control" arm received a VRP vaccine that contained an influenza protein, and the other two groups received one of two different doses of the VRP-neu vaccine. Researchers then implanted a HER2/neu-positive tumor into mammary tissue in the mice. All of the control mice developed breast cancer but only one mouse in each of the VRP-neu groups did. In short, 86 percent of mice that received the vaccine were protected against the cancer. The experiment was repeated numerous times with the same result, says Lachman.

Researchers also worked with mice that were genetically engineered to over-express HER2/neu. These mice normally develop breast cancer in all ten of their mammary glands by the time there are 120 days old. In this experiment, they vaccinated the mice three times with VRP-neu, and "not a single mouse developed a tumor," says Lachman.

Lachman suggests the vaccine might prove helpful in keeping human HER2/neu tumors from metastasizing, or spreading, but adds that this notion must be tested in human clinical trials.

Lachman believes that the vaccine will address two additional safety considerations "because it is built of RNA that cannot insert itself into the genome, and the possibility of autoimmunity to it appears to be low, because normal cells express very small amounts of the HER2/neu growth protein."

Contributors to the study are first author Xiaoyan Wang, M.D., Ph.D. and Jian-Ping Wang, M.D., Ph.D., both from M. D. Anderson; and Maureen Maughan, Ph.D., from AlphaVax, Inc.

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