The Stress and Cancer Link: 'Master-Switch' Stress Gene Enables Cancer's Spread

In an unexpected finding, scientists have linked the activation of a stress gene in immune-system cells to the spread of breast cancer to other parts of the body.

Researchers say the study suggests this gene, called ATF3, may be the crucial link between stress and cancer, including the major cause of cancer death – its spread, or metastasis. Previous public health studies have shown that stress is a risk factor for cancer.

Researchers already know that ATF3 is activated, or expressed, in response to stressful conditions in all types of cells. Under typical circumstances, turning on ATF3 can actually cause normal and benign cells to commit suicide if the cells decide that the stressors, such as irradiation and a lack of oxygen, have irrevocably damaged the cells.

This research suggests, however, that cancer cells somehow coax immune-system cells that have been recruited to the site of a tumor to express ATF3. Though it’s still unclear how, ATF3 promotes the immune cells to act erratically and give cancer an escape route from a tumor to other areas of the body.

“It’s like what Pogo said: ‘We have met the enemy, and he is us,’” said Tsonwin Hai, professor of molecular and cellular biochemistry at The Ohio State University and senior author of the study. “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.”

Hai and colleagues first linked the expression of the ATF3 gene in immune-system cells to worse outcomes among a sample of almost 300 breast-cancer patients. They followed with animal studies and found that mice lacking the ATF3 gene had less extensive metastasis of breast cancer to their lungs than did normal mice that could activate ATF3.

This stress gene could one day function as a drug target to combat cancer metastasis if additional studies bear out these results, Hai said. In the meantime, she said the results provide important insights into how cells in a tumor use their signaling power to coopt the rest of the body into aiding cancer’s survival and movement to distant organs.

The research is published in a recent issue of the Journal of Clinical Investigation.

Hai, a member in the Ohio State University Comprehensive Cancer Center, has studied ATF3 in cancer cells for years. When she had a chance to examine human samples from about 300 breast-cancer patients, she was stunned to find that the expression of ATF3 gene in certain immune-system cells was associated with worse cancer outcomes in this group of patients. ATF3 in cancer cells showed no such association.

To test that clinical data, she and colleagues conducted two rounds of studies in mice. The researchers first injected breast cancer cells into two groups: normal mice and mice that cannot express ATF3 in any cells. The cancer in normal mice metastasized to the lungs far more rapidly and extensively than did cancer in the mice lacking ATF3. In the second round of experiments, they used genetically altered mice that could not express ATF3 in a group of immune system cells called myeloid cells, and the results were similar.