Aug. 1, 1998 Researchers at the University of Maryland School of Medicine have discovered a mechanism that creates mutations in the DNA of cancer cells. They also have identified a component of the protein machinery responsible for copying the cell’s DNA that is structurally different from the same protein in normal cells.
The protein in question is proliferating cell nuclear antigen (PCNA), a small protein found only in replicating cells. PCNA is essential for replication and repair of DNA, the biochemical instructions that tell cells when and how to reproduce. The scientists say that the altered form of PCNA potentially could serve as a marker for earlier and more accurate breast cancer diagnosis.
The Maryland researchers report their findings in the August 1 issue of the journal Cancer Research.
They describe for the first time a mechanism that contributes to the creation of mutations in the DNA of breast cancer cells. The combined effects of the defective replication machinery and the unique form of PCNA may make a more significant contribution to the development and progression of cancer than any single genetic mutation identified to date, they say.
In one study, first author Jennifer W. Sekowski, PhD, senior author Robert J. Hickey, PhD, and colleagues examined the ability of DNA replication machinery isolated from human breast cancer cells to correctly copy DNA. They found that 100 percent of cells from surgically removed breast tumors contained error-prone protein mechanisms that produced a high number of mutations during the DNA replication process. None of the non-cancerous human breast cells examined contained the faulty DNA replication machinery. "This study demonstrates for the first time that faulty cellular DNA replication machinery may significantly contribute to the accumulation of DNA mutations in breast cancer," says Hickey, a research associate professor of pharmacology and experimental therapeutics. Sekowski is a postdoctoral fellow working with Hickey.
In a second study, first author Pamela E. Bechtel, PhD, senior author Linda H. Malkas, PhD and colleagues examined the components of the faulty replication machinery in human breast cancer cells. They found a unique form of PCNA, structurally altered and not due to a genetic mutation. This novel form was found in 100 percent of surgically removed human breast tumors and was not detected in non-cancerous human breast cells.
"The novel form of PCNA that we have identified may prove to be a new signature for breast cancer," says Malkas. A unique form of PCNA could serve as a powerful new diagnostic marker for breast cancer, she adds.
Malkas is an associate professor of pharmacology and experimental therapeutics. Bechtel is a postdoctoral fellow in her lab.
Co-authors on the journal articles are Lauren Schnaper, Brian J. Long, Robert Freund, Ni Liu and Carla Rodriguez-Valenzuela, from the University of Maryland, the Greenebaum Cancer Center, and the Greater Baltimore Medical Center Comprehensive Breast Care Center.
The research was funded in part by the National Institutes of Health and the National Cancer Institute, Department of Defense Breast Cancer Fellowships, the U.S. Army Medical Research and Material Command, and the University of Maryland Greenebaum Cancer Center.
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