Dr. Susan Love Research Foundation | Ending Breast Cancer

Researchers at the University of Michigan have discovered a gene that contributes to inflammatory breast cancer, the most aggressive form of the disease. The gene, RhoC GTPase, previously had been linked to cancer of the liver, skin, and pancreas. The findings, published in the October 15, 2000, issue of the journal Cancer Research, may ultimately lead to new forms of treatment for inflammatory breast cancer (IBC).

Women with IBC make up less than 6 percent of all the women diagnosed with breast cancer in the United States each year. IBC has a different phenotype than other breast cancers, which means it looks and acts differently than other forms of the disease. Most breast cancers are found when a woman or her healthcare provider finds a lump in her breast through self-exam, clinical breast exam, or mammography. In contrast, the first signs of IBC are usually visual: The breast becomes red, swollen, and warm, and looks infected. In some instances, the skin around the breast will begin to pucker or to develop ridges—somewhat like the skin of an orange—and the nipple will retract and lay flat against the breast. These signs and symptoms develop because cancer cells are blocking the lymph vessels in the skin of the breast.

IBC can spread rapidly from the breast to the lymph nodes and it quickly metastasizes, which is why it is harder to treat than other forms of the disease. Even with the best treatment—which typically involves chemotherapy, surgery, and radiation followed by tamoxifen—only 45 percent of women with IBC are alive and have no sign of the disease five years after their diagnosis.

Researchers became interested in a potential link between the RhoC GTPase gene and IBC when they found that 90 percent of the tumors in women with IBC "overexpressed"—made too many copies of—this gene. This finding was significant because the RhoC GTPase gene produces a protein that not only guides normal cells through their reproduction process but gives them the ability to move throughout the body, form clusters, settle in other locations, and form the blood vessels needed to feed themselves—the exact traits that cancer cells need to grow, spread, and invade quickly.

To test a possible link between the RhoC GTPase gene and breast cancer, researchers looked to see what would happen if they inserted the gene into normal breast cells. They found that the normal cells that received the gene formed more colonies and traveled farther than the breast cells that did not receive the gene. Next, they inserted cells with the gene and cells without the gene into two groups of mice. They found that 25 percent of the mice given the cells with the RhoC GTPase gene developed breast cancer but none of the mice that were given the cells without the gene did.

By substantiating a link between RhoC GTPase and breast cancer, researchers have created the opportunity for scientists to develop a drug that can treat IBC by shutting off the gene. This would not be the first time the discovery of a gene led to the creation of a drug to help fight breast cancer. After researchers discovered that about 30 percent of women have breast tumors that overexpress HER2 (also sometimes referred to as HER-2 or Her-2/neu or erb-b2), a gene that produces a protein that regulates cell growth, they went on to develop trastuzumab (brand name Herceptin). Herceptin is a member of the class of drugs called monoclonal antibodies, and by stopping the HER2 gene from overexpressing the HER2 protein, it slows the reproduction process of cancer cells. Herceptin is now regularly used—it is given intravenously once a week—to treat women with HER2-positive metastatic breast cancer.

Clearly, if a drug could act against RhoC GTPase the way Herceptin acts against HER2, it would be wonderful for women with IBC. It could also be beneficial for women with other forms of aggressive breast cancer if their tumors are also found to overexpress the RhoC GTPase gene. Creating such a drug undoubtedly will take years. But it would not even be possible without this recent discovery.