Metastases are responsible for over 90% of cancer deaths. In the upcoming issue of G&D, Dr. Robert Weinberg (MIT) and colleagues lend molecular insight into how microRNAs suppress tumor metastasis.

Scott Valastyan, lead author on the study, describes it as presenting “detailed mechanistic insight regarding the process of tumor metastasis, and identifies several key regulators of this process that might prove to be interesting diagnostic and/or therapeutic targets in breast cancer.”

Dr. Weinberg’s group previously showed that the human microRNA, miR-31, suppresses breast cancer metastasis and that its expression is associated with patient outcome. miR-31 regulates the expression of almost 200 genes. However, in this new paper, the authors identify that re-introduction of three miR-31 targets is sufficient to completely reverse miR-31’s influence on metastasis.

The researchers characterized both the individual and overlapping contributions that each of these three miR-31 effectors makes to the metastatic process. While three distinct steps are affected by this cohort of miR-31 targets (namely local invasion, early post-intravasation events and metastatic colonization), of particular interest was the finding that two of the three effectors regulate metastatic colonization - the final and rate-limiting step of metastasis.

Scott Valastyan emphasizes that “Our finding that miR-31, integrin-alpha5, and radixin affect the process of metastatic colonization may be of particular interest in light of the fact that colonization efficiency is strongly associated with patient survival outcome in many human tumor types - including breast cancer”.

Source:
Heather Cosel-Pieper

Cold Spring Harbor Laboratory

A low cellular level of a tiny fragment of RNA appears to increase the spread of breast cancer in mouse models of the disease, according to researchers at Whitehead Institute for Biomedical Research.

Measuring levels of this so-called microRNA, which is also associated with metastatic breast cancer in humans, may more accurately predict the likelihood of metastasis (which accounts for 90% of cancer-related deaths) and ultimately help determine patient prognoses.

In the study, whose results are reported in the June 12 issue of Cell, Scott Valastyan, a graduate student in Whitehead Member Robert Weinberg’s laboratory, screened patient breast cancer samples for microRNAs with potential roles in metastasis. MicroRNAs are single strands of RNA about 21-23 nucleotides long. Within a cell, a single microRNA can fine-tune the expression of dozens of genes simultaneously. This capability could be particularly important in metastasis, a multi-step process that could be influenced by a single microRNA at several points.

The screened samples were classified as either metastatic cancer or non-metastatic cancer. After analysis, the microRNA miR-31 stood out because of its inverse correlation with metastasis. In samples where a patient’s original tumor had not metastasized, the cancer cells retained high levels of the microRNA. But where the tumor had metastasized, the cancer cells came to possess lower levels of miR-31.

The functional role of miR-31 in metastasis regulation was then confirmed in mice. When Valastyan removed miR-31 from normally non-aggressive breast cancer cells and implanted those cells into mice, the cells formed highly aggressive tumors. Mice injected with the cancer cells lacking miR-31 had 6 to 10 times more cancer cells that metastasized to their lungs than did their counterparts implanted with unmodified cancer cells.

To see how increasing miR-31 levels could affect metastasis, Valastyan introduced miR-31 into breast cancer cells that readily metastasize. After injecting these altered cells into mice, the mice had four to 40 times fewer metastases than mice injected with the unaltered cells.

Valastyan says that quantifying miR-31 levels in a patient’s cancer cells could one day support a more accurate prognosis. Currently, breast cancers are divided into three major categories, two of which are typically associated with poor prognoses.

“This microRNA seems to be quite unique, in that it seems to provide some prognostic utility across these existing subclassifications [of cancers],” says Valastyan. A better-defined prognosis could help patients determine whether they might benefit from poorly tolerated cancer therapies.

In addition, miR-31 could be a useful target for cancer therapy. Weinberg, who is also a professor of biology at MIT, is cautiously optimistic. “At present, it’s quite difficult to inhibit the action or promote the actions of a microRNA in a whole organism,” he says, “but in the future, microRNAs like this one might prove to be very important in altering the clinical progression of a tumor or causing it to revert to a more benign state.”

This research was supported by the National Institutes of Health (NIH), MIT Ludwig Center for Molecular Oncology, U.S. Department of Defense (DoD), Breast Cancer Research Foundation, Harvard Breast Cancer Specialized Program of Research Excellence (SPORE), and a DoD Breast Cancer Research Program (BCRP) Idea Award.

Robert Weinberg’s primary affiliation is with Whitehead Institute for Biomedical Research, where his laboratory is located and all his research is conducted. He is also a professor of biology at Massachusetts Institute of Technology.

Full Citation:

“A Pleiotropically Acting microRNA, miR-31, Inhibits Breast Cancer Metastasis”
Cell, June 12, 2009
Scott Valastyan (1,2), Ferenc Reinhardt (1), Nathan Benaich (1,3), Diana Calogrias (4), Attila M. Szász (4), Zhigang C. Wang (5,6), Jane E. Brock (4), Andrea L. Richardson (4), and Robert A. Weinberg (1,2,7).

References

1.Whitehead Institute, 9 Cambridge Center, Cambridge, MA 02142, USA
2. Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
3. Department of Biology, Williams College, Williamstown, MA 01267, USA
4. Department of Pathology, Brigham and Women’s Hospital, Boston, MA 02115, USA
5. Department of Surgery, Brigham and Women’s Hospital, Boston, MA 02115, USA
6. Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115, USA
7. MIT Ludwig Center for Molecular Oncology, Cambridge, MA 02139, USA

Source
Whitehead Institute for Biomedical Research