Scientists Find Genetic Links For Deadly Type Of Breast Cancer

ANN ARBOR---Researchers at the University of Michigan Comprehensive Cancer Center have identified two genes that may control the development of inflammatory breast cancer---an aggressive, often lethal, form of the disease.

The discovery, published in the September 1999 issue of Clinical Cancer Research, is the first report of genetic markers associated with inflammatory breast cancer.

"Only six percent of the 180,000 women diagnosed with breast cancer each year have inflammatory breast cancer, but they have the least chance of survival," says Sofia D. Merajver, Ph.D., M.D., an associate professor of internal medicine in the U-M Medical School. Merajver directs the Breast and Ovarian Risk Evaluation Clinic at the U-M Comprehensive Cancer Center.

"Because this type of cancer gives no early warning signs and progresses so rapidly, the tumor is usually at an advanced stage by the time it is diagnosed," she says. "The mean five-year disease-free survival rate is less than 45 percent."

Unlike other types of cancer, inflammatory breast cancer is random and non-hereditary, so discovery of these genes will not help predict who is more likely to develop the disease, according to Merajver, who directed the U-M study. The most immediate benefit will be to physicians who must determine the most effective form of cancer treatment in new patients. The presence of both genetic markers in tumors from newly diagnosed women could be an indication for more aggressive treatment.

"Stage-matched inflammatory and non-inflammatory breast cancer cells look the same under a microscope," says Kenneth L. van Golen, Ph.D., a research fellow in the U-M Medical School, and first author on the study. "To understand why the clinical behavior is so different, we need to look for changes at the molecular level. Our goal is to understand how genetic abnormalities change normal breast tissue into a highly aggressive cancer."

Van Golen and his research team isolated 17 genes in mammary breast cell lines established from a woman with inflammatory breast cancer and two women who did not have cancer. Eight genes were found only in normal cells; nine were overexpressed or present in unusually large amounts in cancer cells. Once the genes were identified, the U-M team used DNA probes to search for matching genes in tissue from 29 inflammatory breast tumors and 19 stage-matched non-inflammatory breast tumors.

"It was a blind study," van Golen adds. "Neither I nor the two pathologists who confirmed our results independently knew whether a tumor specimen was inflammatory or non-inflammatory."

One of the 17 genes, which van Golen named LIBC for Lost in Inflammatory Breast Cancer, turned out to be a new tumor suppressor gene. LIBC was expressed in 79 percent of the non-inflammatory tumors in the study, but only 20 percent of the inflammatory breast cancers.

A second gene, called RhoC GTPase, had been identified previously by other researchers, but never related to breast cancer. Because it was overexpressed in 90 percent of the inflammatory breast cancer tumors, as opposed to only 38 percent of non-inflammatory tumors, van Golen and Merajver believe it is an oncogene---a gene that stimulates runaway growth in cancer cells.

The most surprising result of the study, according to van Golen, was that the loss of LIBC and the overexpression of RhoC occurred together in 91 percent of the inflammatory breast cancer tumors, but in none of the non-inflammatory tumors in the study. "A concordance rate of 91 percent is almost unheard of," van Golen says. "It is a strong indication that these genes interact to drastically change the behavior of normal mammary cells."

Merajver added that additional research with more patients will be needed to understand completely the functions of LIBC, RhoC and the other 15 genes identified in the study.

"Because changes in external appearance of the breast and at the microscopic level are so similar between non-inflammatory and inflammatory breast cancer, IBC tends to be a basket category," she says. "It takes strict criteria, accurate records and documentation from many clinical trials to tell the difference. We were fortunate to have access to records and specimens from many U-M Cancer Center patients with primary inflammatory breast cancer. Without them, this work would not have been possible."

The U-M study was supported with funding from the United States Army, the National Institutes of Health and the Susan G. Komen Breast Cancer Foundation.

Researchers from the University of Texas M.D. Anderson Cancer Center and the National Human Genome Research Institute collaborated in the study. Other members of the research team from the U-M include Seena Davies, a former U-M undergraduate student. Collaborators from the U-M Medical School include Zhi Fen Wu, M.D., research associate; Myla Strawderman, senior research associate; and Stephen P. Ethier, Ph.D, associate professor of radiation oncology.