A new study from the US published in the Journal of Clinical Investigation finds that activation of a master gene called ATF3 that is important for helping cells adapt to stress may be involved in helping breast, and possibly other cancers spread to other parts of the body (metastasis).

With the vast majority of all cancer suffering and death associated with metastasis, researchers are keen to learn more about what causes it. The American Cancer Society says metastasis is the single most significant challenge to management of cancer.

Previous studies have shown that stress is a risk factor for cancer, and for example, that psychological stress is linked to breast cancer aggressiveness.

And researchers already know that ATF3 is activated when all types of cells experience stressful conditions that threaten their ability to maintain a constant internal environment (homeostasis).

Under normal circumstances, triggering ATF3 protects the body from harm by causing normal cells to commit suicide if there is a risk they have become permanently damaged by the stressful conditions (eg lack of oxygen or irradiation).

When cancer cells first arise, the immune system recognizes them as foreign agents and enlists immune cells to attack them. In the early stages of cancer development this works. But then things go wrong: one reason is cancer cells start to send signals to immune cells that cause them to misbehave in a way that helps the tumor grow.

In the new study, researchers at Ohio State University show that cancer cells are able to switch on ATF3 in immune cells that have been summoned to tumor sites. The result is ATF3 then causes the immune cells to malfunction and allow cancer cells to escape from the tumor and spread to other parts of the body.

Senior author Tsonwin Hai, a professor of molecular and cellular biochemistry at Ohio, says:

“If your body does not help cancer cells, they cannot spread as far. So really, the rest of the cells in the body help cancer cells to move, to set up shop at distant sites. And one of the unifying themes here is stress.”

In previous work, Prof Hai and her team found expression of ATF3 was linked to poorer outcomes in 300 breast cancer patients.

When they examined tumor samples from those patients they were stunned to find expression of ATF3 in certain immune cells was tied to poorer outcomes whereas ATF3 in cancer cells showed no such link.

In the new study, the researchers investigated those clinical results further by conducting two experiments in mice.

They first injected breast cancer cells in normal mice and in mice that could not express ATF3 in any cells.

The breast cancer in normal mice spread to the lungs much faster and more extensively than it did in the mice lacking ATF3.

In the second experiment, the team repeated what they did in the first experiment, except that instead of mice that could not express ATF3 in any cells, they used mice that had been genetically engineered to lack ATF3 only in a group of immune system cells called myeloid cells.

The results of the second experiment were similar to those of the first experiment, leading Prof Hai and her team to write:

“In conclusion, we identified ATF3 as a regulator in myeloid cells that enhances breast cancer metastasis and has predictive value for clinical outcomes.”

If further studies confirm these findings, the team believe the stress gene could one day be a target for drugs that fight cancer spread.

In the meantime, Prof Hai says, they help us better understand how tumor cells hijack the body’s own resources to promote cancer survival and spread.

There are lots of ways to switch on ATF3 in cells, as well as the signals sent by cancer cells, a high-fat diet, radiation, chemotherapy, UV damage and even chronic behavioral stress, are others.

The team now plans to investigate further how these and other stressors affect immune cells through switching on ATF3, changing them from attacking cancer cells to helping cancer cells.

Written by Catharine Paddock PhD