Researchers say they have discovered a new molecular player in determining whether breast cancer cells will spread through the body: long strands of RNA known as lincRNAs that turn off tumor suppressor genes. The finding may lead to a test for predicting metastasis as well as drugs for preventing it.
Several factors influence whether cells will turn cancerous and later go mobile. Mutations in tumor suppressor genes such as p53 and BRCA1, play a role, as do "microRNAs" that silence critical genes.
Problems with lincRNAs appear to be another mechanism. Researchers first identified lincRNAs—short for large intervening noncoding RNAs—9 years ago. Often hundreds or thousands of times longer than microRNAs, which run about 22 nucleotides, some lincRNAs seem to influence gene expression by binding to enzymes that modify chromatin, the DNA-protein package that makes up chromosomes. The lincRNAs direct these chromatin-shaping enzymes to specific sites along the chromosomes, where they tack chemical groups onto genes, blocking them from being expressed. A lincRNA known as HOTAIR, for example, helps tell embryonic skin cells which genes to express depending on their location in the body.
Because some cancer genes had popped up in this skin cell work, cancer biologist Howard Chang of Stanford University began exploring whether HOTAIR and other lincRNAs might also play a role in cancer. His group and collaborators eventually homed in on HOTAIR in human breast cancer samples. Levels of HOTAIR were hundreds of times higher than normal in samples from metastatic breast cancer, the researchers found, and they were sometimes abnormally high in primary tumors as well. Looking at samples from 132 women with breast cancer followed for many years, the team also found that women with high HOTAIR levels in their primary tumor were three times more likely to develop metastatic cancer and die.
To find out more, Chang’s team used modified viruses to ramp up HOTAIR expression in breast cancer cells. When inserted into the tails of mice, these high-HOTAIR cells caused 10 times more metastatic tumors in the lungs than did unmodified cancer cells. HOTAIR apparently promotes metastasis by shutting off genes involved in keeping cells from moving. With these genes turned off, primary tumor cells can more easily invade the matrix of cells surrounding organs and form metastatic tumors, says Chang, whose team reports its findings in tomorrow's issue of Nature.
A test for HOTAIR levels could be used to predict which breast cancer patients will develop metastases, the authors suggest. And blocking HOTAIR or the enzymes it interacts with could be a way to prevent metastasis.
The broader message is that microRNAs are not the only kind of noncoding RNA that researchers should be paying attention to when it comes to how cancer spreads, says George Calin of the MD Anderson Cancer Center in Houston, Texas. "It opens up a new field of research."
Molecular geneticist Maarten van Lohuizen of the Netherlands Cancer Institute in Amsterdam agrees that the study is "important and provocative." But he notes that it raises many questions. For example, he wonders why HOTAIR would have such profound effects when it is just one of many lincRNAS present at high levels in metastatic tumors.