Running a cancer roadblock

Research details how breast tumors thwart a protective piece of RNA

A small piece of RNA forms a big roadblock for breast cancer cells trying to spread away from the original tumor.

This scrap of genetic material, a microRNA dubbed miR-335, stops tumor cells from making key proteins that allow the cells to move around the body. Now, researchers at Rockefeller University and Memorial Sloan-Kettering Cancer Center, both in New York City, have found out how breast cancer cells get around the miR-335 roadblock. The microRNA also keeps cancer cells that do escape from establishing new tumors, the team reports in the Feb. 1 Genes & Development.

The findings are important for understanding the basic biology of how tumor cells migrate. Cancer’s spread, or metastasis, to other parts of the body is one of the main reasons cancer kills, says Khalid Sossey-Alaoui, a cancer biologist at the Cleveland Clinic’s Lerner Research Institute. So stopping tumor cells from spreading could be an important step in fighting the disease. “If we can get to this level, we could cure cancer,” Sossey-Alaoui says. “Seriously.”

Researchers already know a lot about how microRNAs help govern protein production within a cell and how interfering with that process can lead to cancer (SN: 8/28/10, p. 18), says Joshua Mendell, a molecular and cancer biologist at Johns Hopkins University in Baltimore. But much less is known about what exactly messes up the microRNAs, he says.

Breast cancer cells can get around miR-335 in two ways, according to the new research, led by Sohail Tavazoie. Aggressive tumor cells both chop out one copy of the miR-335 gene and use a chemical tag on the remaining copy to squelch the microRNA’s production, the researchers found. Invasive cancer cells “really try to turn off this microRNA any way they can,” says Tavazoie, a cancer biologist at Rockefeller University. 

Less aggressive tumors turn down production of the microRNA from both copies of the gene with the same type of chemical tag, known as methylated DNA, Tavazoie and his colleagues discovered. Tumor cells that don’t spread have two intact copies of the miR-335 gene that don’t bear the chemical marks.

Such methylation can be reversed with demethylating drugs, says Frank Slack, a cancer researcher at Yale. These drugs might reactivate miR-335 production and keep tumor cells from migrating, he says. Researchers are also experimenting with ways to directly restore missing microRNAs or to control the proteins regulated by microRNAs, but those approaches are not yet available for clinical use. “Reactivating the microRNA [gene] itself is probably the most expedient strategy in the short term,” Slack says.

Even if tumor cells do slip away from the original site, miR-335 stops the cells from initiating tumor growth elsewhere, the team found. But the microRNA doesn’t seem to affect cell growth once a tumor is established, which makes it different from other metastasis-suppressing microRNAs. The other microRNAs stop cancer’s spread mainly by interfering with the new tumor’s growth, says Dario Marchetti, a tumor biologist at Baylor College of Medicine in Houston. The new findings indicate that miR-335 could play an important role early in the body’s development by controlling where cells move in the embryo and start to grow, he says.

The function of miR-335 in controlling whether escaped cancer cells can form a new tumor may also be important in ovarian cancer. Women with ovarian cancer who later had a relapse were more likely to be missing a copy of miR-335 in their original tumors than women who did not relapse, the team found.

Tina Hesman Saey is the senior staff writer and reports on molecular biology. She has a Ph.D. in molecular genetics from Washington University in St. Louis and a master’s degree in science journalism from Boston University.

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