Small RNAs Can Prevent Spread Of Breast Cancer
Howard Hughes Medical Institute researchers have identified small pieces of ribonucleic acid (RNA) that suppress the spread of breast cancer to the lungs and bone. The new research shows that the most invasive and aggressive human breast cancer tumors are missing three critical microRNA molecules. When the researchers put those molecules back into human breast cancer tumors in mice, the tumors lost their ability to spread.
"The tiny RNAs prevent the spread of cancer by interfering with the expression of genes that give cancer cells the ability to proliferate and migrate," said senior author Joan Massague, a Howard Hughes Medical Institute researcher at Memorial Sloan-Kettering Cancer Center.
The researchers said their new research findings add to the growing number of cellular targets for drugs designed to prevent breast cancer metastasis. The scientists are also optimistic that their work could spur the development of new clinical tests to assess the likelihood that breast tumors will metastasize. Metastasis of breast cancer is the leading cause of death from the disease.
Metastasis occurs when cells from a primary tumor break off and invade another organ. It is the deadliest transformation that a cancer can undergo, and therefore researchers have been looking for specific genes that propel metastasis. If they can identify distinctive metastatic gene programs for different cancers, it may be possible to slow or halt metastases by targeting the proteins produced by those genes.
Massague, his postdoctoral fellow Sohail Tavazoie, and colleagues at Sloan-Kettering, published their findings in the January 10, 2008, issue of the journal Nature.
In the experiments reported in Nature, the researchers explored the role that microRNAs play in controlling the expression of genes that trigger the spread of breast cancer. MicroRNAs, which are no more than 20-22 nucleotides in length, play an important role in development, cancer, stress responses and viral infections. Unlike the large messenger RNA (mRNA) molecules that code for cellular proteins, the microRNAs regulate gene activity by repressing or enhancing the translation of mRNAs.
Messenger RNA molecules are the genetic templates for proteins. In constructing proteins, the mRNA template is transcribed from DNA genes and transported to the ribosomes - the cell's protein factories that are large complexes of protein and RNA. Given the importance of mRNA as an information-carrying molecule, the machinery that regulates mRNA levels and destroys faulty mRNA is critical in ensuring that errors in the genetic code are not passed on to proteins.
Massague and his colleagues have focused on identifying the driving forces behind the spread of breast cancer, and have, in previous work, identified distinct genetic signatures associated with metastasis to the bone and the lungs. They decided to explore the role of microRNAs in breast cancer shortly after other researchers published data showing that certain tumors, including breast cancers, had decreased levels of microRNA expression. These observations suggested to Massague and others that loss of the gene-suppressing molecules might well play a key role in the growth and spread of tumors.
To follow up on that hunch, Tavazoie and others in Massague's lab set their sights on identifying microRNAs that were suppressed only in aggressive, metastatic human breast cancers. They first analyzed cultured metastatic human breast cancer cells to create a genetic profile of the array of microRNAs produced by the cancerous cells. When they compared this microRNA profile to that from non-metastatic cancer cells, they found that a small subset of microRNAs was greatly reduced only in the metastatic cells.
They next found that when they restored normal levels of three of these microRNAs