Social stress connected to triple-negative breast cancer via fat cells

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 to the subsequent development of breast cancer, according to new research.

Some forms of stress exposure may be associated with an increased risk of certain types of aggressive breast cancer. The researchers looked for differences between mice raised in small groups and those that grow up in an isolated setting, which is an established model of chronic stress without social supports. Their study was published in Cancer Prevention Research (2013; doi:10.1158/1940-6207.CAPR-12-0458).

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

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% 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. All the mice used develop tumors by approximately age 16 weeks.

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 age 15 weeks showed that social isolation stimulated significant increases in the expression of three genes—Hk2 (hexokinase), Acly (ATP citrate lyase) and Acaca (acetyl-CoA carboxykase).

All three are crucial to the uptake and metabolism of glucose, the primary source of cellular energy. Glucose uptake in the mammary fat cells of stressed mice was approximately twice as much as in the mammary fat cells of unstressed mice, indicating a significant increase in metabolic activity.

These cells use glucose to synthesize lipids—fatty substances often used to convey biological signals. Increased fat cell metabolism was associated with increased local secretion of substances such as leptin, an important chemical messenger produced by fat cells. Leptin can stimulate proliferation of epithelial cells within the mammary gland. Although leptin levels in the blood stream did not change, fat cells from isolated mice churned out three times as much leptin as the same cells from group-raised mice.

When premalignant epithelial cells from the tumors were exposed to the substances secreted by mammary-gland fat from isolated mice, they began to proliferate more rapidly, suggesting that the isolated animals' fat could secrete substances that boost tumor growth.
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