Researchers have identified a pattern of gene activity in mice that may help to predict individual risk for breast cancer metastasis and survival in humans. A single gene, called bromodomain 4 (Brd4), regulates the expression of this pattern, also called a signature. The researchers found that one result of this Brd4 regulation is the suppression of tumor growth and metastasis in a mouse model of cancer. These findings, published by researchers at the National Cancer Institute (NCI) and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), parts of the National Institutes of Health, appear in the April 29, 2008, issue of the Proceedings of the National Academy of Sciences.

"Theses findings are exciting," said Kent W. Hunter, Ph.D., of NCI's Center for Cancer Research. "For the first time in mice, we have a candidate gene for what drives an entire gene signature. This should allow a better understanding of the mechanisms underlying cancer progression in humans."

Normal Brd4 activity is involved in important cell processes, including cell proliferation, cell cycle progression, and DNA replication. Defects in the processes related to Brd4 activity are well documented in breast cancer in humans. It is known that the Brd4 protein physically interacts with and regulates the activity of another important gene, called Sipa1, which reduces tumor invasiveness in mice.
The researchers began their search for the Brd4-induced gene signature by engineering highly metastatic mouse mammary tumor cells that expressed Brd4. They found that Brd4-expressing cells were less invasive and less mobile in laboratory experiments than non-Brd4-expressing cells, yet showed no change in their rate of growth.

Next, they implanted their metastatic Brd4-expressing cells into mice. For comparison, they engineered and implanted some of the same metastatic cells so that an unrelated control gene was expressed. After 4 weeks, the researchers found that Brd4-expressing metastatic cells seemed to suppress both tumor growth and metastasis. This group of mice had dramatically smaller tumors and had fewer metastatic tumors in their lungs compared to the mice in the control group. Overall, these findings appear to indicate that activation of Brd4 reduces tumor growth by influencing the response of tumor cells to signals from the microenvironment - the area immediately surrounding the tumor - that promote both tumor growth and metastasis.

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