How Do the Metabolic Effects of Chronic Stress Influence Breast Cancer Biology

摘要

In the C3(1)/SV40 T-antigen (Tag) FVB/N mouse model of human estrogen and progesterone receptor-negative breast cancer, the stress response elicited by social isolation is associated with increased expression of metabolic genes in the mammary gland. To further understand accelerated tumor growth associated with social isolation, we separated mammary gland adipocytes from ductal epithelium and stroma and then analyzed individual fractions for changes in metabolic gene expression and function. The increased expression of the key metabolic genes Acaca, Hk2 and Acly was found to be significantly elevated in the adipocytes of the mammary gland, and surprisingly, was not significantly increased in visceral adipose depots of socially isolated female mice. Increased metabolic gene expression in the mammary gland of socially isolated mice coincided with increased glucose metabolism, lipid synthesis, and leptin expression. Furthermore, culture media from isolated versus group-housed mouse mammary adipose tissue resulted in relatively increased proliferation of mammary cancer cells. These results suggest that exposure to chronic social isolation results in metabolic changes in mammary gland adipocytes that contribute to increased growth of adjacent epithelial cell tumors. We propose a model in which environmental stress affects estrogen-independent mammary tumor growth, at least in part, through changes in mammary adipocyte biology.