Researchers have discovered the molecular switch that allows aggressive triple-negative breast cancer cells to grow the amoeba-like protrusions they need to crawl away from a primary tumor and metastasize throughout the body. These findings suggest a novel approach for developing agents to treat cancer once it has spread.
Triple-negative breast cancer has the worst outcome of all breast cancer subtypes because of its high rate of recurrence and metastatic spread. This is why the research team chose to examine the role of miRNAs in the spread of triple-negative breast cancer, which accounts for 15% to 25% of all breast tumors. The cancer is named triple-negative because its tumor cells do not display two hormone receptors (estrogen and progesterone) or HER2/neu growth factor, which each form the basis of current targeted breast cancer treatments.
Using genome-wide miRNA sequencing, Vivek Mittal, PhD, of Weill Cornell Medical College, and his research team found in human samples of triple-negative breast cancer that miR-708 was significantly down-regulated with its normal expression curtailed. In both laboratory cells and in animal studies, the researchers identified that the normal role of miR-708 is to suppress the protein neuronatin, which is located on the membrane of a cell’s endoplasmic reticulum–an organelle that stores calcium. Neuronatin helps control how much calcium leaves that organelle.
“It is calcium that provides legs to cancer cells to help them escape a tumor. So miR-708 acts as a suppressor of metastasis by keeping neuronatin in check,” Mittal said. “If miR-708 is itself suppressed, there is an increase in production of neuronatin proteins, which then allows more calcium to leave the endoplasmic reticulum and activate a cascade of genes that turn on migratory pathways leading to metastasis.”
Researchers found that delivering synthetic miR-708, carried by bubbles of fat, blocked metastatic outgrowth of triple-negative breast cancer cells in the lungs of mice. This makes miR-708 a promising therapeutic agent against metastatic breast cancer. The researchers also discovered that polycomb repressor complex proteins are responsible for silencing miR-708. These proteins remodel the way DNA is packaged in order to epigenetically silence genes. This study was published in Cancer Cell (2013; doi:10.1016/j.ccr.2012.11.019).
Mittal added that the findings suggest that pharmacological agents now being tested in lymphoma cancer cells may also help to restore miR-708 in triple-negative breast cancer. These drugs are designed to inhibit histone-lysine N-methyltransferase EZH2, the member of the polycomb group that directly silences miR-708.
“It is exciting that there are now drugs that can turn off the silencing of these critical genes. They could very well work for this aggressive breast cancer,” said Mittal. “Finding that there may be a way to shut down the spread of an aggressive breast cancer–which is the only way that triple-negative breast cancer can be controlled and lives spared–is very promising.”