Exposure to social stress early in life may up breast cancer risk: Researchers

Local chemical signals released by fat cells in the mammary gland appear to provide a crucial link between exposure to unrelenting social stressors early in life, and the subsequent development of breast cancer, according to researchers from the University of Chicago.

Some forms of stress exposure may be associated with an increased risk of certain types of aggressive breast cancer. But the mechanisms linking the biology of social stress to cancer have been hard to identify.

To unravel that mechanism, the researchers looked for differences between mice raised in small groups and those that grow up in an isolated setting—an established model of chronic stress without social supports.

"We found that exposure to the stress of social isolation leads to reprogramming of genes in fat cells in the mammary glands. These fat cells then secrete substances that cause nearby pre-cancerous epithelial cells to proliferate more rapidly, accelerating the development of breast cancer. This local effect of fat cells in the breast was completely unanticipated," said study author Suzanne Conzen, MD, professor of medicine at the University of Chicago.

The researchers used a genetically altered mouse model of "triple-negative" breast cancer—a form of the disease that lacks receptors for estrogen, progesterone and HER2, three important treatment targets in humans. Triple-negative cancer, representing about 15 percent of all breast cancers, appears to occur disproportionately in younger women. In this mouse model, animals develop precancerous changes in mammary epithelial cells that later lead to cancer.

The mice tested—known as SV40-T antigen mice—all develop tumors by about 16 weeks of age. The researchers previously showed that female mice raised in isolation develop significantly larger, more aggressive, triple negative tumors, and wanted to understand the detailed biology underlying this observation.

Conzen worked closely with colleague Martha McClintock, PhD, professor of psychology at the University of Chicago, to carefully model chronic social stress exposure in female mice. In previous joint projects they showed that a measurable chronic stress response could reliably be induced in mice by raising them in isolation after weaning, rather than housing them in small groups.

In this study, Conzen also worked with colleague, Matthew Brady, PhD, associate professor of medicine and a specialist in fat cell biology, to decipher the effect of stress on the mammary fat.

The researchers looked for differences in gene expression in multiple tissues and circulating hormones between group-housed and isolated mice. To their surprise, there were no significant differences in circulating hormones.

They found a dramatic change, however, in fat cells located within mammary glands. Measurements of those cells taken at 15 weeks of age showed that social isolation stimulated significant increases in the expression of three genes—Hk2 (hexokinase), Acly (ATP citrate lyase) and Acaca (acetyl-CoA carboxykase).

Why is breast fat particularly sensitive to the effects of social isolation? Scientists don't yet understand how this response fits into the larger picture of the deleterious effects of stress on an organism, but "it will be an important avenue to pursue, particularly when so much human disease appears to be negatively impacted by social stressors, diet, and other factors causing metabolic derangement," Conzen said.

The researchers reported their finding in the July 2013 issue of the journal Cancer Prevention Research.