Sleeping Beauty Plays A Significant Role In Identifying Cancer Genes

The gene identification method was developed in genetically modified mice and utilized a piece of jumping DNA, called Sleeping Beauty. Jumping genes, or transposons, insert themselves into or between genes and can activate or inactivate a gene's normal function. Related transposons are natural to the genetic makeup of humans, animals and fish, but through millions of years of evolution, most transposons became inactive dead-ends. In 1997, in another study, University of Minnesota researchers took defunct, non-functioning jumping genes from fish and made the genes jump again. This research had reactivated the element in jumping genes from millions of years of evolutionary sleep, and hence the name Sleeping Beauty.

In the two current research studies, specially-designed Sleeping Beauty transposons were introduced into mouse DNA and made to jump around in the nucleus of mouse cells, including jumping into cancer-causing genes. By isolating and studying tumors that contained DNA strands of the Sleeping Beauty, researchers were able to efficiently find genes linked to cancer by seeing whether Sleeping Beauty turned them on or off -- in effect, uncovering the fingerprint of each tumor's cancer genes.

David Largaespada, Ph.D., associate professor and leader of the Genetic Mechanisms of Cancer Program, led the University of Minnesota Cancer Center research team. Their work focused on cancer gene discovery in solid tumors using transposon-based techniques.

"Current cancer gene identification methods, such as microarrays, give correlations typically of thousands of genes, and it's hard to know from the correlations which genes relate to cancer and which do not," says Largaespada. "By comparison, the jumping gene has attached itself to cancer genes in the tumors we studied and thereby allows us to focus in on smaller numbers of genes -- genes that we know are important to the genesis of tumors. The result is a quicker, more efficient and accurate identification of cancer-causing genes."

Nancy Jenkins, Ph.D., head of NCI's Molecular Genetics of Development and Neal Copeland, Ph.D. head of the Molecular Genetics of Oncogenesis in the Mouse Cancer Genetics program, led the NCI research team, which investigated the use of a highly mobile Sleeping Beauty transposon system to study lymphomas, a cancer that strikes the immune system.

Jenkins says that, "Although our discovery was made in laboratory mice, we believe that the technology used will reveal new insights into human cancer and could be translated for clinical use. Hopefully, this discovery will speed up the development of new drugs, and improve already-in-use-drugs, that target specific genes for treatment of various types of cancer, including lymphomas. The outcome of the new Sleeping Beauty method could be a major leap forward in understanding cancer's weak points and subsequently lead to thousands more cancer patients joining the ranks of survivors."

According to Largaespada, "About 300 human cancer-related genes have thus far been reported in the scientific literature. There may be as many as 1,000 or more cancer genes that still need to be identified."

Additionally, he says the Sleeping Beauty technology is capable of providing important information about the genes that current methods do not -- such as the specific combinations of mutant genes that can work together to cause cancer. "With this information, we will understand the development of tumors at the genetic level in much finer detail," he says. "This is important because no single kind of cancer is going to be cured by one drug; it is going to take a combination of drugs to attack the pathways that are required for cancer to start and grow."

The next step for Largaespada, Jenkins, Copeland and their colleagues will be to generate and analyze a large number of other tumors induced in mice using the Sleeping Beauty jumping gene. Largaespada and his team will focus on identifying genes causing prostate, lung and colorectal cancer; Jenkins and her team will study genes for tumors in the brain, melanoma, breast, leukemia and lymphoma.

Largaespada, Jenkins and Copeland acknowledge the difference between research in mice and actual use in humans, but Largaespada says, "We have proof of principle that we're on the right track. We know that some of the same genes that are mutated in cancer in mice using Sleeping Beauty are also mutated in the same form of cancer in humans. An example is the Notch-1 gene, which was found in a mouse with T cell leukemia induced by Sleeping Beauty and is mutated in about 50 percent of human with T cell leukemias. We believe the Sleeping Beauty method will allow us to identify many other such genes for other cancers."

For more information about the University of Minnesota Cancer Center, call the Cancer Information Service at 1-888-CANCER MN (1-888-226-2376).

For more information about cancer, visit the NCI Web site at http://www.cancer.gov or call NCI's Cancer Information Service at 1-800-4CANCER (1-800-422-6237).

The National Institutes of Health (NIH) -- The Nation's Medical Research Agency -- is comprised of 27 Institutes and Centers and is a component of the U. S. Department of Health and Human Services. It is the primary Federal agency for conducting and supporting basic, clinical, and translational medical research, and investigates the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit http://www.nih.gov.