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Cancer gene BRCA1 operates genetic repair "machine" (7-28-99)

Scientists in San Antonio have discovered the machinery through which the BRCA1 breast cancer suppression gene does its protective work.

The lab findings from The University of Texas Health Science Center at San Antonio are reported in Friday's (the July 30) issue of Science and could affect how women with BRCA1-deficient tumors are cared for in the future.

In the paper, Wen-Hwa Lee, Ph.D., director of the university's Institute of Biotechnology (IBT), and his colleagues describe the molecular basis of a link between BRCA1 and the most important "DNA repair" machinery. DNA, or deoxyribonucleic acid, is the genetic blueprint found in the cells of all living things. Problems with the blueprint, such as breaks in the information, may result in conditions such as cancer. DNA repair refers to the healthy body's ongoing response to correcting DNA damage.

The IBT research also showed that human cells in which BRCA1 is defective are highly sensitive to DNA-damaging agents such as gamma radiation, and that restoration of a normal BRCA1 gene confers resistance against these agents.

"This work published in Science has broad implications for women who are concerned about breast cancer," said Dr. Lee, who also serves as professor and chairman of the Health Science Center's Department of Molecular Medicine. "Families harboring mutations in the BRCA1 gene may need to limit their radiation exposure because of a relative deficiency in repair."

BRCA1 is the first breast cancer gene commonly found to be defective in families with a prevalence of breast cancer. How BRCA1 malfunction leads to breast cancer is not understood. The study showed that the BRCA1 gene, by interacting with a DNA repair machinery complex composed of proteins called hRad50, hMre11 and p95, coordinates and facilitates the repair of DNA damaged by exposure to agents such as X-rays or gamma radiation.

"Dr. Lee and his team of outstanding investigators, through some very eloquent studies, have demonstrated that the normal BRCA-1 gene interacts with three proteins to repair DNA damage introduced by ionizing radiation (x-rays) and other drugs," said Charles A. Coltman Jr., M.D., chief executive officer of the Cancer Therapy & Research Center (CTRC) in San Antonio. "This represents a genetic mechanism that is critically important in maintaining the integrity of DNA. The mutated BRCA-1 gene fails to interact with these proteins and, thus, women who inherit this genetic abnormality are not able to repair such DNA damage.

"The implications of these data for women with this mutation are important in that exposure to x-rays should be minimized. Understanding this flawed mechanism represents a critical target to modify this genetic defect." Dr. Coltman is a professor of medicine at the Health Science Center and director of the San Antonio Cancer Institute, a partnership of the CTRC and the Health Science Center.

"It gives us more evidence of the functional importance of BRCA1 in the area of DNA repair," agreed Helen K. Chew, M.D., assistant professor of medicine in the Health Science Center's Division of Medical Oncology. "It doesn't translate into a direct benefit for patients right now, but it will help determine future clinical directions."

One in nine American women will be diagnosed with breast cancer. About 5 percent to 10 percent of cases involve BRCA1 deficiency. BRCA1 also is linked to familial ovarian cancers.

The paper, "Association of BRCA1 with the hRad50-hMre11-p95 Complex and the DNA Damage Response," describes experiments performed with various cell lines. Study authors are Qing Zhong (first author), Chi-Fen Chen; Shang Li; Yumay Chen, Ph.D.; Chuan-Cheng Wang; Jun Xiao; Phang-Lang Chen; Z. Dave Sharp, Ph.D., deputy director of the IBT; and Dr. Lee. All are from the Institute of Biotechnology.

"Now we know why this gene, when mutated, causes cancer," Dr. Lee said. "This work offers the hope and expectation that many radiation-resistant cancer cells can be sensitized for killing by the development of drugs that interrupt the interaction between BRCA1 and the DNA-repair machinery."

He likened the hRad50-hMre11-p95 complex of proteins to a car and BRCA1 to the operator. "We now know precisely how this car works, and that BRCA1 is the driver," Dr. Lee said. "When BRCA1 is not behind the steering wheel, the car cannot go anywhere."

Contact: Will Sansom