New research provides details of how genetic mismanagement by RNA can lead to a human disease—in this case, breast cancer.
RNA, a twisty polymer once considered a mere molecular lackey, is now known to hold an executive position: controlling the activity of genes. The greater responsibility, however, means that if RNA bungles its job, the consequences can be dire. New research by HHMI Early Career Scientist Howard Chang and colleagues provides details of how genetic mismanagement by RNA can lead to a human disease—in this case, breast cancer.
The research, published in the April 15, 2010, issue of Nature, offers insights into how cancer progresses, and reveals a potential new marker that could be used to predict whether breast cancer is likely to spread to other parts of the body. Chang’s coauthors on the paper are from Stanford, Johns Hopkins School of Medicine, Academic Medical Center in the Netherlands, the Broad Institute, and Applied Biosystems.
You can think of lincRNA as an air traffic controller. When the controller goes wild, it misdirects the planes. In this case, HOTAIR sends PRC2 to inappropriate sites where it shuts down genes that normally prevent metastasis.
Howard Y. Chang
RNA's best-known role is carrying the genetic blueprints from DNA to the cell's protein-building factories. Some RNA molecules, however, bear no coded instructions for protein assembly, which suggests they may have other roles. Certain RNAs known as long noncoding RNAs (lincRNAs) are thought to possess key information about which genes get turned on and off, says Chang, who is at Stanford University School of Medicine. In earlier work, Chang's lab discovered that lincRNA can control not only genes that are adjacent to the DNA that encodes them, but also genes located some distance away—even on completely different chromosomes.
In the new work, the researchers found that lincRNA's wide-reaching influence can be a liability. They focused on a particular lincRNA called HOTAIR, which normally tells cells where they belong in the body. It does this by ensuring that only genes appropriate for a cell’s designated location are active. When HOTAIR is mistakenly turned on in breast cancer cells, the cells experience a sort of identity crisis and become equipped to exist somewhere other than in the breast.
"Turning on HOTAIR gives cancer cells the tool kit they need to move to another location and set up shop there," says Chang. This moving away and setting up shop—forming tumors that grow uncontrollably and replace normal tissue—is what oncologists refer to as metastasis, the process that makes cancer life-threatening.
Several years ago, Chang's lab developed a method for measuring the level of lincRNAs in cells. Using that technique, the researchers compared the concentration of lincRNAs in normal and cancerous breast tissue. "We collaborated with clinical colleagues who had saved patient samples from decades ago," says Chang. "From their records, we knew whether patients succumbed or did well."
When the researchers measured HOTAIR in the tissue samples, they found that patients with high levels of HOTAIR were about three times more likely to have metastases and die from breast cancer. Chang says this finding makes HOTAIR a powerful marker for predicting which patients are most likely to have cancer that will spread, possibly requiring more aggressive treatment.
To further investigate HOTAIR's role in cancer, Chang and colleagues altered the level of HOTAIR in several breast cancer cell lines and in mice. "When HOTAIR was made artificially high, we found that cells became very metastatic and could easily spread from the breast to the lung or other organs," he says.
The next big question was how to shut down HOTAIR's destructive effects. That became clear when the team's experiments showed that HOTAIR lincRNA works hand-in-hand with a group of enzymes called the Polycomb Repressive Complex 2 (PRC2).
"Polycombs normally shut genes down, but they don't know which genes to shut down. They need a guide—lincRNA—to show them where to go," Chang says. "You can think of lincRNA as an air traffic controller. When the controller goes wild, it misdirects the planes. In this case, HOTAIR sends PRC2 to inappropriate sites where it shuts down genes that normally prevent metastasis."
Stopping the aberrant, disease-causing activity may be possible, Chang says. "If you can shut down PRC2, the problems caused by excess HOTAIR can be largely alleviated." And it just so happens that the pharmaceutical industry already is working to develop inhibitors of PRC2.
"Our work is proof of principle, showing that you can pick out a subset of patients who should respond to such therapies," says Chang. And because lincRNA misdeeds may be involved in other diseases, the work may have even broader implications.
"Nothing we've found so far suggests that lincRNAs are involved only in breast cancer, and in fact there's quite a bit of evidence to suggest that they could be prevalent in other types of cancer and other diseases where a gene expression program is mistakenly turned on or off," Chang says.
In future work, Chang hopes to find out why HOTAIR is mistakenly turned on in breast cancer cells and to search for ways to target and eliminate cells that have high levels of HOTAIR.