Apr. 14, 1999 PITTSBURGH, April 13 -- A research team at the University of Pittsburgh Cancer Institute and Magee-Womens Hospital has uncovered a pivotal role for problems with DNA repair in breast cancer, which could help explain why most early-stage breast cancers respond to available treatments and why advanced tumors thrive despite aggressive therapy. The report provides the first evidence that cells from early-stage breast cancers fail to repair DNA like normal cells through nucleotide excision repair (NER). The details will be reported at a scientific minisymposium on April 13 at the annual meeting of the American Association for Cancer Research in Philadelphia.
To begin, the research team looked at the level of mutations in a marker gene often used to indicate exposure to DNA-damaging agents. They found significantly elevated levels of mutations in this marker gene in newly diagnosed breast cancer patients compared with levels in controls, suggesting a problem with DNA repair in women with the disease. Next, they studied the activity of NER enzymes in various tissues from these women.
"We found that NER activity is substantially reduced in breast cancers taken from patients with ductal carcinoma in situ, stage I or stage II cancers," explained Jean Latimer, Ph.D., assistant professor of obstetrics, gynecology and reproductive sciences at the University of Pittsburgh and investigator at the Magee-Womens Research Institute. "We found a reduction in NER activity in every breast cancer patient tissue we examined but in no control breast tissue samples taken from women undergoing routine breast reduction surgery," she added.
About 30 different NER proteins are necessary to detect and repair injuries from ultraviolet radiation, x-rays and chemical toxins. Like linemen who inspect each railroad tie along a set of tracks before a train passes over them, NER enzymes inspect each nucleotide of a DNA helix for any damage before another set of enzymes encounters this genetic material and replicates it prior to cell division. In making their repairs, NER enzymes cut a large swatch of the helix around a mistake and replace the damaged DNA with the correct sequence of nucleotides.
For its studies, the team looked at breast tissues from 30 early-stage breast cancer patients and 12 controls. In 85 percent of the patients, the investigators also found that non-cancerous cells surrounding a breast tumor had poor NER activity, suggesting that a breakdown in this safety mechanism may initiate the cancer in most women affected by the disease.
Dr. Latimer's results could explain why chemotherapy and radiation therapy are so effective against early-stage breast cancer. "Standard chemotherapy drugs like 5-fluoruracil and cyclophosphamide and radiation therapy all work by damaging DNA. If a breast tumor has a poor capacity to repair this damage, it will die," remarked Dr. Latimer.
Variations in NER activity among the breast cancer patients studied also suggest that therapies could be custom tailored, according to Dr. Latimer. "If a breast cancer biopsy indicates better, though still abnormal levels of NER activity, it's possible that the patient may not respond optimally to chemotherapy or radiation therapy. In this case, a clinician might want to use biological therapies, which do not operate by damaging DNA directly."
Unfortunately, according to Dr. Latimer, later-stage breast cancers appear to regain NER activity. "In our preliminary studies of breast cancer samples from women with advanced disease, we are finding normal NER activity." The reason, suggested Dr. Latimer, may be a redundancy in the NER system.
"Advanced-stage tumors may compensate for the lack of one NER enzyme by increasing the production of another NER enzyme that performs the same function," Dr. Latimer said. "In this way, the tumor can effectively repair treatment-related DNA damage."
To accomplish its work, Dr. Latimer's team used fresh tissues taken within five hours of surgery and grown in culture. A patent is currently pending on this culture method, which is the only one available to grow normal breast tissue for up to three months.
Dr. Latimer's study co-author and collaborator, Stephen Grant, Ph.D., assistant professor of environmental and occupational health at the University of Pittsburgh's Graduate School of Public Health, performed the research to detect marker gene mutations in the breast cancer patients the team evaluated.
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