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Gene May Hold Cancer Clues

By Robert Cooke. STAFF WRITER

By designing a mutant gene so it is only active in breast tissue, and then putting it into mice, scientists said yesterday they've uncovered vital new clues about breast cancer while creating a useful new animal for cancer research. The experiments, reported in the journal Nature Genetics, indicate that damaging the Brca-1 gene somehow makes the whole set of genes unstable, setting up the cancer process. And once the genome gets tipped off balance, they said, more mutations occur, eventually allowing tumor growth to begin. "This tells us that Brca-1's most important function is in maintaining genetic stability," said molecular biologist Chu-Xia Deng. And "the loss of Brca-1 increases the risk of mutations of all the other genes." The additional mutations that follow can erase the cell's ability to supervise its growth. Like a truck being driven with faulty controls, either the accelerator (an oncogene) or the brakes (a tumor suppressor gene) may be damaged, and either way the result is an emergency. In cancer, the emergency is runaway growth. Until now, said geneticist Lothar Hennigshausen, "no one had any idea how it [the Brca-1 gene] works." But now "we believe it is a gatekeeper that checks the genome to be sure it is intact. It's normally involved in the repair of mutations" that occur in other genes, including those that control growth. The Brca-1 gene was already known to be involved in breast cancer, but its role has been obscure. Brca-1 was isolated for study in 1994, tracked down because of its involvement in about half of the breast cancer cases known to be inherited. Women born with a mutant version of Brca-1 face an estimated 80 percent risk of eventually getting the disease. Deng, Hennigshausen and their colleagues at the National Institute of Diabetes, Digestive and Kidney Diseases in Bethesda, Md., also found that a vital gene often damaged after Brca-1 fails is the p53 gene, which is already a well-known tumor suppressor gene. Normally, p53's job is to intervene when things go haywire, and force sick cells to commit suicide, keeping them from growing and becoming cancerous. And without a suicide program, sick cells can survive and grow. Now that a mouse has been created with the Brca-1 mutation already in place, Hennigshausen added, researchers can begin to study other mutations which occur in turn in related genes, and how different mutation patterns alter a tumor's behavior. They can also use the mouse as a test bed for anti-cancer drugs. "We can test drugs very specifically on these mice," he said. And "we can also look to see how hormones affect cancer" in the search for useful treatments.

Copyright 1999, Newsday Inc.

Gene May Hold Cancer Clues., pp A32.