Stress: A Cause Of Breast Cancer?

By Peter Zafirides, M.D.

Ohio State University researchers say the study suggests a specific gene, called ATF3, may be the crucial link between stress and cancer, including metastasis – the major cause of cancer death. 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 trick immune-system cells that have been recruited to the site of a tumor to start expressing  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.

Our Body Turns Against Us

According to Dr. 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.

A Balancing Act

According to Dr. Hai, “If the body is in perfect balance, there isn’t much of a problem. When the body gets stressed, that changes the immune system. And the immune system is a double-edged sword,” she said.

In general, when cancer cells first appear, the immune system recognizes them as foreign and various immune cells travel to the site to attack them. Early on in cancer’s development, this process typically works.

But as cancer cells grow and thrive in a tumor, they send out certain molecular messengers to promote a chronic wound-healing response. Cancer cells, by acting like a wound that never heals, hijack this process to help themselves survive and spread.

Cancer’s Master Switch

“ATF3 induction in immune cells is one way this probably happens. We’re not saying it’s the only way,” Hai said. ATF3 is a master switch type of gene: Its gene product, the ATF3 protein, turns on and off other genes.

Though the work suggests a drug to dampen ATF3′s effect could lower the risk for metastasis, Hai noted that scientists don’t fully understand what the overall effects of that dampening would be.

“We have this gene for a reason. It’s a gene that helps us adapt to changes. So it’s a question of how and when to target ATF3,” she said.Hai plans to test whether these other kinds of stressors also affect the immune cells through ATF3 induction, changing them from attacking cancer cells to helping cancer cells.