Abstract 1027: Autophagy as a mediator of increased mammary cancer risk in socially isolated mice

Social isolation in mice is a model of post-traumatic stress disorder (PTSD) which affects 12-20% of newly diagnosed breast cancer patients. Since social isolation increases the risk of breast and other cancers and increases overall and cancer-specific mortality, it is critical to determine the biological pathways that mediate the effects of social isolation on cancer to identify targets to prevent its adverse effects. Among the potential mechanisms is autophagy, which we have found previously to be induced in the mammary glands of socially isolated mice. Others have reported upregulation of p53 and Hk2 in socially isolated animals. Both are genes that induce autophagy. In our study, social isolation increased nuclear p53 levels, expression of the p53-regulated autophagy genes Dram1 and Mdm2 in the mammary glands of mice. Further, social isolation led to an increase in body weight, particularly when mice were fed a high fat diet, but the ability of social isolation to induce autophagy was independent of high fat diet. Here we investigated the effect of social isolation on mammary tumorigenesis in heterozygous Atg7 knockout mice. Social isolation was implemented by housing mice singly and feeding them a high fat diet from weaning onwards. Socially isolated wildtype C57BL6 mice exhibited upregulation of Atg7 and LC3II and downregulation of p62, indicative of increased autophagy that allows cancer cells to survive. Atg7+/- mice, in contrast, exhibited significantly lower LC3II and higher p62 levels compared with group-housed wildtype mice. We also found that socially isolated wildtype mice were at a significantly increased risk of developing estrogen receptor positive (ER+) mammary cancer induced by treating mice with 15 mg medroxyprogesterone acetate (MPA) and three doses of 1 mg 7,12-dimethylbetz(a)anthracene (DMBA) (given on weeks 7, 8 and 9). No increase in mammary tumorigenesis was seen in socially isolated Atg7+/- mice, compared with group-housed Atg7+/- mice. Our results confirm that social isolation induces autophagy and show that increased autophagy in socially isolated mice was causally linked to increased breast cancer risk. Since activation of survival autophagy is known to impair response to cancer treatments, including to chemotherapy and endocrine therapy, it is imperative to determine if cancer patients suffering from PTSD exhibit increased autophagy. Autophagy inhibitors, such as chloroquine, are currently being investigated in the clinic as