A snippet of gene-regulating RNA may contribute to breast cancer metastasis

Scientists at Cold Spring Harbor Laboratory (CSHL) have discovered a fragment of gene-regulating RNA that can contribute to the proliferation of many breast cancers. In animal experiments, the researchers could reduce the growth of metastatic tumors with a molecule designed to target that RNA and promote its destruction. The same strategy, they say, could be used to develop a new breast cancer treatment for patients.

The study, led by CSHL Professor and Director of Research David Spector, was reported in the journal Nature Communication. In 2016, Spector and colleagues identified dozens of RNA molecules that were more common in breast cancer cells than in similar unregulated cells. They were all long, unencoded RNAs (lncRNAs) – RNA molecules that do not encode proteins and are thought to play various regulatory roles within cells. The current study examined how one of these, Mammary Tumor-Associated RNA 25 (MaTAR 25), influenced the behavior of breast cancer cells in mice.

Experiments by Kung-Chi Chang, a graduate student in Spector Laboratory, show that the molecule contributes to the progression of cancer in a number of ways – restoring cell growth as well as the ability to migrate and attack print. These effects may be due to changes in the activity of the tensin1 gene, which the team identified as one of the targets of MaTAR 25. Tensin1 helps bind an internal cell cytoskeleton to the matrix surrounding and so it is positioned to influence cell movement as well as the pathways that regulate growth.

To eliminate MaTAR 25, the researchers designed a small piece of nucleic acid that recognizes and binds to its sequence. Once bound, that molecule, called oligonucleotide antisense, triggers an enzyme inside cells to destroy the lncRNA. When the researchers inserted this molecule into the bloodstream of mice, it reached tumor cells and destroyed most of the MaTAR 25, with amazing effects.

When we performed histology on the tumors, we found that they were highly necrotic, resulting in high cell death after this RNA was reduced. And obviously, that’s an important finding, but just as well, if not more important, we found a significant reduction in metastasis to the lungs. So this, you know, really gave us some interesting data that this RNA molecule has the potential to be a therapeutic target. “

David L. Spector, Professor, Cold Ocean Laboratory

The Spector team found that elevated levels of a similar RNA called LINC01271 are associated with more aggressive infection in patients ’breast tumors. They are now investigating whether oligonucleotide antisense targeting LINC01271 can inhibit tumor growth and metastases in patient-derived breast cancer models.