Sylvester Comprehensive Cancer Center

UM Breast Cancer Researchers Win Department of Defense Grant to Expand Study

06.15.2009

Breast cancer researchers at Sylvester Comprehensive Cancer Center at the University of Miami Miller School of Medicine have been awarded a prestigious Department of Defense Synergistic Idea Award, one of just 12 such grants in the United States. The $725,000 research grant over two years will allow Lisa Baumbach, Ph.D., associate professor of pediatrics at the Miller School, and Mark Pegram, M.D., professor of medicine and associate director for clinical and translational research at the Braman Family Breast Cancer Institute at Sylvester, to expand their work examining the genetic differences found in African-American breast cancer patients.

This work is critical to understanding why African-American women suffer more devastating forms of breast cancer and have a higher death rate from the disease, and will lead to more effective prevention and treatment.

Recent discoveries by breast cancer researchers indicate that there may be distinct genetic differences in breast tissue between African-American, Caucasian and Hispanic patients. Baumbach and Pegram recently led a team that discovered hundreds of genetic differences among these ethnicities. The new grant will allow them to take those findings a step further, with an international collaboration on women of African descent.

In the earlier studies, Baumbach and Pegram worked with other scientists from UM, including Stefan Glück, M.D., professor of medicine and assistant director of the Sylvester Comprehensive Cancer Center/Clinical Trials, Merce Jorda, M.D., Ph.D., professor of clinical pathology, Carmen Gomez, M.D., associate professor of pathology at Sylvester, and Frederick Moffat, M.D., professor of surgery at Sylvester.

Using a pool of eight Caucasians, 10 African-Americans and 10 Hispanic women, the Miller School researchers looked at possible ethnic differences in gene expression in breast cancer. What they found was several hundred differences in the ways the genes were expressed in tumor tissue among the three ethnic groups. This may account for an increased incidence of a particularly aggressive form of the disease in African-American women.

That study compared normal breast tissue with cancerous breast tissue in patients with triple-negative breast cancer, an extremely aggressive form of breast cancer. The “triple-negative” form indicates that women are negative for the genes for estrogen receptor (ER), progesterone receptor (PR), and Her2/Neu, an epidermal growth factor receptor. This triple threat suggests a poor prognosis because this form of breast cancer is unresponsive to the most effective receptor-targeted therapies available today.

Breast cancer is the second leading cause of cancer death among African-American women, and carries a 20 percent higher mortality rate than it does for Caucasian women. Among scientists, it is widely acknowledged that African-American women, regardless of their age, are more likely to have triple-negative breast cancer. In addition, it is likely to occur at an earlier age, and have a higher proliferative fraction. All of this adds up to a worse prognosis. “There is a clear need,” says Baumbach, “for us to better understand the genetic differences in women of African ancestry so we can translate that into more effective guidelines and therapies.”

The preliminary findings led the UM team to identify ethnic specific gene expression patterns in African-American women. Using breast cancer tissue samples, they will now compare genome expression in African-Americans with naturalized African women, examining 50 women in each group. In addition, Baumbach and Pegram will analyze chromosomal alterations associated with gene expression differences.

DNA array studies will tell the scientists whether a part of the human genome is amplified or deleted. As they did in the original study, the scientists will use the Almac Breast Cancer DSA™ array research tool (developed by Almac Diagnostics Inc. of Research Triangle Park, N.C.) which is designed specifically to investigate gene expression in breast cancer. “A lot of genes in cancer are down-regulated,” explains Pegram, who says in some cases, the genes are even deleted.

If a gene is amplified and then over-expressed, scientists can potentially come up with a therapy to block that over-expression, just as they did in the case of HER-2. Pegram took part in that key research in the 1990s, which led to the development of Herceptin. Conversely, if a gene is under-expressed, scientists will then work to find methods to coax the gene to reactivate.

Pegram says breast cancer seems to be different in African-American women and scientists are working to find the biological basis. “We hope to identify the genes or molecular alterations that are causing these differences among ethnic groups,” says Pegram. Once that happens, “the goal is to identify a potential therapeutic target to personalize therapeutic approaches.”

Expanding the study for the Department of Defense grant has led to an international collaboration that includes Alan Ashworth, F.R.S., director of the Breakthrough Breast Cancer Research Center in London, who played a key role in identifying one of the major breast cancer risk genes (BRCA2), and will be analyzing the chromosomal alterations. Also joining the team is Rick Kittles, Ph.D., from the University of Chicago Medical School, who is internationally known for his work on genetic ancestry and genetic risk factors for prostate cancer in African-American men. He will conduct state-of-the art genetic studies to determine the African ancestry of the U.S. African-American patients in the study. In addition, Catherine R. Connor, a South Florida breast cancer activist, will review the progress of the project, relaying that information to the local African-American community, with the hope of encouraging future research participation.

Peter Bird, M.B.B.S., head of surgery at Kijabe Hospital in Kenya, will be providing tissue samples of 50 women of African descent. The other 50 samples will be African-American women whose formalin-fixed, paraffin-embedded (FFPE) tissue comes from Jackson Memorial Hospital, the Sylvester Comprehensive Cancer Center and the Miller School Department of Pathology.

Using FFPE samples has been difficult in the past because RNA taken from these samples is often degraded. However, as they did in the initial study, Baumbach and Pegram will be using new technology which enables researchers to obtain high-quality data from these tissue samples. The tissue studies are expected to begin by the end of June.

Baumbach calls the FFPE samples a “gold mine” of tissue resources that she hopes can expand their understanding of the disparity in breast cancer mortality. “Determining the exact genetic differences in breast tissue samples of certain ethnicities,” says Baumbach, “could have worldwide ramifications in terms of reducing the global burden of breast cancer by developing more effective preventions and treatments.”

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