SIVARAMAN AND COLLEAGUES FIND CELL "SWITCH" IS "ON" IN BREAST CANCER: New Discovery Offers Hope

On April 2, 1997, Vimala S. Sivaraman, MD, clinical assistant professor of surgery, and colleagues at University Hospital and Medical Center announced the exciting new discovery of a key abnormality thought to trigger human breast cancer. Their findings—detailed in the featured article in the April issue of The Journal of Clinical Investigation (click here to see it)—could result in a fundamentally new approach to its diagnosis and treatment.

Specifically, the multidisciplinary team of researchers found that in patients with breast cancer, cancerous cells in the breast tissue have 5 to 20 times the amount of an enzyme called MAP kinase (mitogen-activated protein kinase) than in normal breast tissue cells.

In addition to Dr. Sivaraman, the research team includes Drs. Hsien-yu Wang (Physiology and Biophysics), Gerard Nuovo (Pathology), and Craig Malbon (Molecular Pharmacology) who directed the study.

Based on their findings, they conclude that elevated MAP kinase causes cells to proliferate, likely producing human breast cancer. By comparison, patients with benign fibrocystic breast disease or non-malignant fibroadenoma (fibrous tumor) show normal levels of MAP kinase, a level much lower than that found in patients with breast cancer.

The elevated level of MAP kinase in primary breast cancer was observed in lymph nodes of patients that went on to metastatic cancer.

Because abnormal cell growth is a major hallmark of cancer, scientists like the Stony Brook team are trying to understand the steps needed to convert a normal cell into a cancer cell that does not stop growing. The discovery made at Stony Brook sheds important new light on this cancer process.

It is not yet clear whether having excess amounts of MAP kinase is a cause, or a result, of cancer.

If the findings of the study reported by Dr. Sivaraman and colleagues are borne out, as expected, by independent research and evaluation, MAP kinase could become an important, easily-measured marker for detecting primary breast cancer. The elevated MAP kinase may be treatable by crafting a molecule to turn off the MAP kinase signal and delivering it to the cancerous cell.

MAP kinase is part of a growth-control pathway regulated by a gene called ras, which is known to often be damaged in cancer cells. The prediction has been that the MAP kinase pathway would be altered in tumor cells.

The new discovery concerning MAP kinase in breast cancer demonstrates the alteration in the ras pathway, and thus identifies a viable target for new approaches to treatment.

At present, there are drugs in the very early phases of development that can inhibit this pathway. If the MAP kinase finding can be shown to be related to many cancer cases, new drugs could be very rapidly developed.

Treatment using anti-sense DNA/RNA approaches to target molecules for suppression—now experimental—has been developed at Stony Brook and is currently in early clinical trials for other human diseases. Such treatment for breast cancer would be subject to much further study and eventual FDA review, an application process that could progress rapidly in the next few years.

Stony Brook's researchers have also developed a technique that allows small numbers of metastatic cells to be detected in a patient's lymph nodes. If cells expressing excess MAP kinase are found in lymph nodes, it is a sign that the tumor is very dangerous.

Biologist Dawn Willis, scientific program director of the American Cancer Society, in Atlanta, says that she sees the Stony Brook discovery "as offering a very good way to detect metastatic cells in lymph nodes and possibly elsewhere in the body."

Testing for such cancer cells, she added, might be "very important as a prognostic tool for metastatic breast cancer." In addition to spotting tumors that are very dangerous, such tests also could tell which are less threatening, and thus spare women from taking "very, very aggressive treatments that they may not need."