Because the researchers knew that DACH1 is lost in such invasive breast cancers that carry poor prognoses, they investigated its potential role in the cancer cells' ability to migrate and invade, the prelude to metastasis. They focused on its effects on cancer-causing oncogenes, such as Ras and Myc.
In a series of experiments, the scientists, led by Dr. Pestell and first author Kongming Wu, Ph.D., assistant professor of Cancer Biology at Jefferson Medical College, looked at the effects of adding DACH1 to breast cells made cancerous by various oncogenes. When they added DACH1 to Ras-induced breast cancer cells, for example, they saw a greater than 75 percent reduction in cell migration. Cells turned cancerous by the oncogene ErbB2 showed a 50 percent drop in migration. Cells made cancerous by Myc also had 50 percent less migration.
The researchers performed a proteomic analysis, testing the expression of many proteins at once to see which might be regulated by DACH1. They found that IL-8 is a critical target of DACH1 that helps regulate breast cancer cell migration and metastasis. In mouse studies, they showed that DACH1 lowered the levels of IL-8 genetic material (mRNA) by approximately 90 percent in cancers caused by Ras.
According to Dr. Wu, the gene for IL-8 is also a known target of Ras, helping recruit the formation of new blood vessels to feed a developing cancer a process called angiogenesis. He notes that it's well known that tumors with high levels of IL-8 have a poorer clinical prognosis.
"The findings suggest an important role for IL-8 in blocking the progression of cancer and metastasis," says Dr. Wu. "Because IL
|Contact: Steve Benowitz|
Thomas Jefferson University