Proteins RhoA and ROCK1 Increase Risk of Invasive, Mobile Breast Cancer Cells

Biologists from the Johns Hopkins University have discovered a bit of shocking news. Low levels of oxygen present in many breast cancer tumors may transform cancerous cells from being rigid and stationary to mobile and invasive.

"High levels of RhoA and ROCK1 were known to worsen outcomes for breast cancer patients by endowing cancer cells with the ability to move, but the trigger for their production was a mystery," Gregg Semenza, M.D., Ph.D., the C. Michael Armstrong Professor of Medicine at the Johns Hopkins University School of Medicine and senior author of the article said, via a press release. "We now know that the production of these proteins increases dramatically when breast cancer cells are exposed to low oxygen conditions."

What exactly does "movement" mean for cancer cells? According to Semenza, here's how it works: Thin, parallel filaments that make up the cells allow them to contract and "grab" external surfaces that may pull them along to other areas of the body. For breast cancer patients in particular, researchers note that the proteins RhoA and ROCK1 are to blame for the formation of these structures.

For many suffering from cases of metastatic breast cancer, high levels of the proteins were discovered in the genes that code RhoA and ROCK1. Ultimately, these findings pushed Semenza and colleagues to find out reasons for why the proteins were so high in some cases. They found that oxygen plays a significant role in the production of the proteins and the severity of the cancer.

"As tumor cells multiply, the interior of the tumor begins to run out of oxygen because it isn't being fed by blood vessels," explains Semenza, via the release. "The lack of oxygen activates the hypoxia-inducible factors, which are master control proteins that switch on many genes that help cells adapt to the scarcity of oxygen." He explains that, while these responses are essential for life, hypoxia-inducible factors also turn on genes that help cancer cells escape from the oxygen-starved tumor by invading blood vessels, through which they spread to other parts of the body.

Daniele Gilkes, Ph.D., a postdoctoral fellow and lead author of the report, analyzed human metastatic breast cancer cells grown in low oxygen conditions from a laboratory. Findings showed that cells with lower levels of oxygen were typically more mobile than those exposed to normal levels. She also found a big increase of RhoA and ROCK1 protein levels in cells exposed to less oxygen.

In other words, study findings showed that women with high levels of both proteins (RhoA or ROCK 1) which usually presented themselves in environments where oxygen levels were low, were much more likely to die from breast cancer than those with low levels of the proteins or higher oxygen levels.

"We have successfully decreased the mobility of breast cancer cells in the lab by using genetic tricks to knock the hypoxia-inducible factors down," Gilkes concludes, via the release. "Now that we understand the mechanism at play, we hope that clinical trials will be performed to test whether drugs that inhibit hypoxia-inducible factors will have the double effect of blocking production of RhoA and ROCK1 and preventing metastases in women with breast cancer."

More information regarding the study can be found via the Proceedings of the National Academy of Sciences from Dec. 9.