Researchers find new breast cancer gene may play role in estrogen-induced breast cancers
January 14, 2004 | For more information: George Stamatis 216-368-3635
 Researchers from the Case Western Reserve University School of Medicine have discovered a new breast cancer gene that may play a role in estrogen-induced breast cancers.
The lead researchers in this study, Monica M. Montano, Ph.D. and doctoral student Bryan M. Wittmann, in the Case department of pharmacology were searching for proteins that interact with the estrogen receptor when they discovered Estrogen Down-regulated Gene 1 (EDG1). EDG1 was found to suppress the normal function of estrogen receptors and inhibit breast cell growth, thereby possibly acting as a tumor suppressor.
The team's findings were published in a recent issue of "Cancer Research," the top cancer journal. The article, "Identification of a Novel Inhibitor of Breast Cell Growth That Is Down-Regulated by Estrogens and Decreased in Breast Tumors," was coauthored by Nancy Wang, M.D., a University Hospitals of Cleveland pathologist.
The study indicates that EDG1 levels are reduced by estrogens and show decreased expression in breast tumors. The link to estrogen is important because lifetime exposure to estrogen is a major risk factor for breast cancer. The growth of more than 95 percent of all breast cancers is initially dependent upon the presence and activation of an estrogen receptor. Montano and her team are suggesting that reduced levels of genes like EDG1 play a role in estrogen-induced breast cancer development.
"Despite the fact that the important role of estrogens in breast cancer has been known for a long time, the basis for estrogen's action in breast cancer is not well defined," Montano said. "Determining the answer to this question is one of the major goals of studies in my laboratory."
Wittmann analyzed the presence of EDG1 in breast tumor cells and compared it to the presence of the gene in normal breast cells in 43 patients. He found that EDG1 levels are significantly higher in normal breast cells as compared to breast tumor cells. He also found that tumor cells that express EDG1 are more likely to express the estrogen receptor. Tumors that are estrogen-receptor positive have a better prognosis, while breast cancer tumors that undergo high growth rates-and are less likely to express EDG1-have a worse prognosis.
"It's possible that by decreasing the levels of tumor suppressors like EDG1, estrogen is inducing breast tumor growth," Montano said. "Another possibility that we are investigating is that estrogen has DNA-damaging effects, thereby allowing for increased mutation rates."
More important, Montano said, is that EDG1 expression was found to be significantly lower in normal breast cells adjacent to Grade III tumors, which carry a worse prognosis, versus normal breast cells adjacent to Grade I and II tumors. She added that EDG1 could be used in the future as a diagnostic tool in determining breast cancer diagnosis.
"Since differences in EDG1 expression is reflected in normal breast cells adjacent to these tumors, there are implications with regards to genetic predisposition for a worse prognosis," Montano said, adding that possible future therapeutics could involve delivering EDG1 to tumor cells or increasing EDG1 expression in tumor cells through drugs. "If the absence of EDG1 predisposes one to tumors with worse prognosis, then earlier or more aggressive forms of treatment can be considered."
As a result of their findings, researchers generated genetically altered mice to verify what they observed in breast cells and human tissues. These mice also will help researchers further define the physiological role of EDG1, its role in other cancers, and the usefulness of treatments aimed at increasing EDG1 levels in breast cells.
The team has submitted a patent application for this gene, and results from their previous research were presented at a press conference during the 84th Annual Meeting of The Endocrine Society in 2002.
The EDG1 research is supported by a $1.45 million grant from the National Institutes of Health.
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