Scientists at Oregon Health Sciences University in collaboration with a team from the University of California at Santa Cruz have discovered that abnormal expression of a tumor suppressor gene is implicated in breast cancer. Their work appears in the July 22, 1997 issue of the Proceedings of the National Academy of Sciences and details the action of a gene called WT1, which had been previously linked to kidney cancer in children.
"The WT1 gene normally prevents cell division by inhibiting the synthesis of growth factors that themselves trigger cell growth," explains Charles T. Roberts, Ph.D., professor of pediatrics at Oregon Health Sciences University and a senior author on the paper. "Loss of WT1 function in the kidney causes Wilms tumor, the most common childhood abdominal cancer. We reasoned that malfunction of this gene in the breast may also cause tumors. Because scientists have long suspected that certain growth factors play a role in breast tumor growth and WT1 regulates these same growth factors, we studied the activity of the WT1 gene in normal human breast tissue as compared to a large sample of breast cancers." Roberts and his colleagues Gary B. Silberstein, Ph.D., and Charles W. Daniel, Ph.D., of UC Santa Cruz discovered that the WT1 gene is active in normal breast tissue. Nearly 70 percent of breast cancer samples, on the other hand, showed altered WT1 gene activity. "Abnormal expressi! ! on of the WT1 gene may be one of the earliest steps in the development of breast tumors because it is seen in carcinoma 'in situ,' the very beginning stage of breast cancer," says Roberts.
While some breast tumors grow rapidly and are highly resistant to treatment, others can be either successfully treated or contained for decades. Surgery, chemotherapy, radiation and bone marrow transplantation are currently among the physician's arsenal of weapons. Adding to this arsenal, sophisticated future treatments are expected to use gene therapy to restore functional tumor suppressor genes and will depend on the discovery of promising therapeutic targets such as the WT1 gene.
"The story is complex," explains Roberts, "because it has been difficult to find a single molecular or genetic defect that is common to all of the various different forms of breast tumors. Finding abnormal WT1 activity in several types of breast cancer suggests that defects in WT1 action may underlie many forms of breast cancer."
In the complex microworld of the cell, the culprit gene or molecule underlying a disease may be influenced by surrounding molecular events. For example, while the absence of a functional WT1 gene is frequently seen in breast tumors, WT1 is curiously present in a highly malignant subset of advanced breast tumors. "These are called estrogen receptor-negative tumors," explains Roberts, "and though WT1 is present in these tumor cells, it may be dysfunctional. This may be because another well known tumor suppressor gene called p53 is found in these advanced tumors and p53 is known to interact with WT1 and may interfere with its normal function."
"Linking a dysfunctional WT1 tumor suppressor gene, which is present in a high proportion of breast cancers, with the potential over expression of growth factors that have the capacity to stimulate tumors, provides an exciting new pathway for the development of therapies to treat breast cancer," says Philip F. Smith, Ph.D., director of the neuroendocrinology program at the National Institute of Diabetes and Digestive and Kidney Diseases, which funded the research. "The role of hormones and growth factors in the development of breast cancer is a priority area of the NIDDK, and this discovery reinforces the importance of support for fundamental research into cell growth in opening new avenues to attack breast cancer and other hormone-responsive cancers."
Pinpointing the role of abnormal WT1 gene action in the development of breast tumors paves the way for designing strategies directed at restoring the function of the gene in various forms of breast cancer. The previously discovered breast cancer genes known as BRCA I and II play a role in hereditary forms of the disease, which comprise only 5 to 10 percent of all breast cancer cases. "The possible relationship between changes in the WT1 gene and mutations in the BRCA genes remains to be discovered," explains Roberts, who also serves as the director of research at Doernbecher Pediatric Research Laboratories located at OHSU.