California Pacific Currents 2001
Research into the Precursors of Breast Cancer Cells Yields New Treatment Strategies
Shanaz H. Dairkee, PhD
If you're a woman diagnosed with a small cancerous breast tumor, you will most likely have a lumpectomy, and possibly radiation or chemotherapy. After this standard treatment, you will probably walk away from cancer for good. This scenario holds true for about 75 percent of women in this situation. The remainder, however, will have a recurrence, possibly within five years. And once there is a recurrence, patients may need more aggressive treatment, and they face a decreased chance of survival.
Why some women experience recurrence and others do not is not completely known. Although no evidence of cancer may have been found in the lymph nodes or the normal tissue surrounding the tumor, perhaps a few malignant cells somehow got into the bloodstream. Or maybe, as suggested by new research at the California Pacific Medical Center, some cells in the “normal” tissue immediately surrounding the tumor harbored a genetic abnormality similar to that found in the tumor itself. And perhaps, over time, successive generations of those cells took on the characteristics of the tumor and became malignant. If so, a new tumor would form—in short, a recurrence.
Precursors to Cancer
Geneticist and breast cancer researcher Shanaz H. Dairkee, PhD, of the California Pacific Medical Center Research Institute, has a theory about those so-called normal cells with genetic abnormalities. She thinks they're precursors of their neighboring tumor cells. “The tumor cells progress much more rapidly and have many other changes,” she says, “but they both have the same basic genetic deletion, which is not found in the rest of the normal-looking tissue in that breast.”
Dr. Dairkee's theory of cancer cell precursors is a direct outgrowth of her research. “Understanding the very early stages of breast cancer is the major focus of my research. My goal is to design model systems that reflect the early stages of malignant progression in the hope that they suggest strategies for early intervention, not only for women who already have breast cancer but to prevent cancer in those who are healthy,” she says. Her work with model systems, especially genetic analysis of breast cancer cells in culture (i.e., in a test tube or Petri dish), is yielding intriguing clues to the natural history of this disease. But getting the cancer cells to live and proliferate outside the body in culture was a major hurdle.
Novel Approaches Pay Off
Although malignant cells are known for their uncontrolled growth, Dairkee and her research group found that they often wouldn't grow in culture. “For a long time, that puzzled us,” she says. Through creative strategies funded by the National Institutes of Health, which included novel approaches such as simulating the tumor microenvironment in culture, she and her group successfully overcame this obstacle.
Future plans include immortalizing these samples with telomerase, an enzyme produced by our cells to regulate normal growth. Using genetic engineering techniques, the Dairkee lab will try to “upregulate” telomerase production in tumor cultures to produce an unlimited supply of cells for analysis.
The Promise of Molecular Analysis
Now armed with viable model systems for breast cancer, Dairkee subjects them to detailed molecular analysis and also compares them with normal, healthy breast cells. One approach has been to expose the normal cells to carcinogens known to cause breast cancer in animal models. She observes the cells over successive generations to see what genetic changes occur and if those changes reflect genetic alterations found in breast cancer cells. It was through studies like these, for example, that she detected those normal-looking precursor cells that mirror genetic anomalies found in nearby malignant breast cells.
To test the hypothesis that these cells are precursors to cancer, she did a small retrospective study in collaboration with clinicians from the University of California at San Francisco (UCSF), with input from radiation oncologist Mark Rounsaville, MD, and biostatistician Dan Moore, PhD, of the California Pacific Medical Center. Excised tissue from 100 breast cancer patients who had had a lumpectomy was genetically analyzed. It was found that those patients with evidence of precursor cells were three to four times more likely to have a recurrence than those without. On the strength of this evidence, Dairkee and pathologist Michael D. Lagios, MD, medical director of the Breast Cancer Consultation Service at St. Mary's Medical Center in San Francisco, will soon begin a larger study. Sponsored by the California Breast Cancer Research Program, the study will evaluate the prevalence of precursor cells in patients with noninvasive and invasive breast cancer. The goal is to define the area of breast tissue that should be excised so that it includes any precancerous cells in adjacent tissue. It will also identify patients at low risk for recurrence because they lack precursor cells. The overall effect of the study will be to improve breast cancer treatment.
A Rich Testing Ground
Dairkee's model systems are also providing information about which drugs work in different types of breast cancer and which do not. These systems are a rich testing ground for new potential treatments. “If I take a population of breast cancer cells and put an anticancer drug on them, like tamoxifen, it is going to kill a great many cells. However, it is the cells that survive that I want to profile.” Because they were not killed by the drug, the cells are resistant, and any patient with similarly mutated cells will not be cured by the drug. The answer may be to try another drug in the model. The molecular characteristics of the cultured cancer cells may also suggest new approaches for drug development that target specific mutations. Says Dairkee, “These are examples of the constant interchange between laboratory studies and clinical applications that keep us excited about the research we do.”
Where do Dairkee and her colleagues see cancer diagnostics and treatment heading? “To individualized therapy based on the unique characteristics of the patient's tumor. These characteristics are most likely a reflection of the combined influence of the person's heredity and environment,” she says. “A deeper understanding of the biology and pathology of cancer will continue to reveal these connections, and new emerging technologies will expedite this process tremendously.”
Precancerous changes in some women may appear as early as puberty, but because the mutated cells grow very slowly, they may go undetected for many years. Uncovering aberrant genetic signs early on, long before a tumor arises, and treating the patient with therapies known to counteract or even correct the particular defect will go a long way toward preventing and controlling breast cancer—most probably in our time.