Unexpected links to Alzheimer's disease and Huntington's disease also seen; © Monkeybusiness Images/ panthermedia.net
Using an innovative tool that captures heretofore hidden ways that cells are regulated, scientists at Rockefeller University have identified a protein that makes breast cancer cells more likely to metastasize.
What's more, the protein appears to trigger cancer's spread in part by blocking two other proteins that are normally linked to neurodegeneration, a finding that suggests these two disease processes could have unexpected ties.
The study points to the possibility of new cancer therapies that target this "master regulator" that helps set metastasis in motion.
During the study, Sohail F. Tavazoie (Leon Hess Assistant Professor and head of the Vincent Meyer Laboratory of Systems Cancer Biology at Rockefeller) and his colleagues used technology previously developed to measure a new layer of regulation in cancer cells. In order to understand what triggers cells to become malignant, scientists often look at sequences of DNA, searching for genes which are turned on or off in cancerous cells. But in recent years, they've uncovered many new mechanisms that govern cell activity, including some that act on RNA, the genetic material that helps cells make proteins using instructions encoded in DNA.
The tool turns out, the shape of an RNA molecule matters. Specifically, some segments of messenger RNA form hairpin loops, which create sites for key proteins to bind to and regulate that RNA – telling the cell to destroy it, for instance. "These structural differences help determine RNA's fate, by exposing or hiding the binding sites for those key proteins," says Goodarzi.
So Goodarzi and Saeed Tavazoie developed a computer algorithm that scans samples of cancer cells and identifies patterns in the shapes and sequences of RNA. In the current study, the authors applied this algorithm to breast cancer cells. In cells prone to metastasis, for example, the scientists found certain RNA hairpin loops that were overrepresented in the sequences of RNAs targeted for destruction. They then identified a protein that binds to those hairpin sequences – TARBP2, known to play a role in the formation of small RNAs known as microRNAs. But here, it appears TARBP2 can also act as a "master regulator" of RNA itself, by binding to multiple sites and causing a suite of changes that lead to metastasis – including the destruction of the RNAs that carry those key binding sites. Indeed, they found that TARBP2 is overexpressed in cells prone to metastasizing, as well as in metastatic human breast tumors themselves.
To determine how TARBP2 carries out its effects, the researchers looked at which genes appear to be downregulated in metastatic cell lines, reasoning that TARBP2 may block these disease suppressors. They made two surprising discoveries – APP, a protein linked to Alzheimer's disease, and ZNF395, which is associated with Huntington's disease, are both downregulated by TARBP2. Cells prone to metastasis showed higher levels of TARBP2 and lower levels of APP and ZNF395; in cancer cells that tend not to spread throughout the body, the opposite was true.
In further experiments, they discovered that ZNF395 appears to decrease the expression of genes linked to cancer, while one segment of APP directly inhibits breast cancer's ability to metastasize.
The study raises hopes of new cancer therapies that target this "master regulator," TARBP2. "If we can understand the mechanism by which TARBP2 interacts with RNA, maybe in the future we could generate drugs that prevent it from sitting on RNA structures and shutting down the genes that suppress metastatic disease," says Tavazoie.
MEDICA.de; Source: Rockefeller University