Abstract
Abstract Background: Social isolation is a potent psychosocial stressor and is associated with increase breast cancer mortality in human and animal studies. The effects of social isolation are unlikely to be mediated through an increase in stress hormone levels or macrophage-mediated immune responses, as these changes are transient and normalize during chronic social isolation. A recent study reported that an exposure to a persistent social isolation induced metabolic reprogramming in mammary gland adipocytes. We therefore tested whether the effects of social isolation on mammary cancer are potentiated in mice fed obesity-inducing high fat (HF) diet. Female C57BL/6 mice were group housed or isolated at weaning (3 weeks of age) and fed either AIN93G -based control or HF diet. Mammary tumors were induced by priming mammary glands with progestin (MPA) and then gavaging mice with DMBA weekly for 4 weeks. Results: Mice that were isolated and fed HF diet, became obese and developed insulin resistance. Mammary tumorigenesis was highest in socially-isolated obese mice, and also higher in group-housed, obese mice and isolated, normal weight mice, when compared to group-housed mice fed a control diet (p<0.001). Serum leptin levels were not affected by stress, but adiponectin levels were reduced in mice housed in social isolation (p=0.042), compared to group-housed mice. We found no evidence of inflammatory changes (expression of Tnf-α, Il1b or Il6, or macrophage number) in the mammary glands of the socially-isolated mice, and neither was the expression of tumor suppressor genes p16, p21 or Sirt1 altered by stress or diet. Since social isolation reduces mammary tumorigenesis in heterozygous p53 knockout mice, and p53 is known to respond to metabolic changes and to influence metabolic pathways, we studied whether its expression was altered by social stress. The results indicated that social isolation (p<0.001) (but not diet) significantly increased p53 mRNA expression. Apoptosis in Tunel assay was not altered, but cell proliferation, measured by Ki67 staining, was significantly increased in socially-isolated mice (p=0.002). The latter is consistent with a significant upregulation of cyclin D1 in the stressed mice (p<0.001). As the expression of Jnk1 (p=0.003) and Dram1 (p=0.003) were elevated in the mammary glands of stressed mice, p53-induced autophagy may have been increased. Finally, Mdm2 was upregulated in these mice (p=0.001), indicating that the negative feedback between this gene and p53 was disrupted by social isolation. All the observed changes were most apparent in HF fed, socially-isolated mice, but also seen in control diet fed mice exposed to social isolation stress. Conclusion: Our data suggest that HF-induced obesity potentiates the effects of social isolation on mammary carcinogenesis, and together, perhaps by a disruption of the Mdm2–p53 interaction and induction of genes that stimulate autophagy, increase mammary tumorigenesis in mice. Citation Format: Allison Sumis, Fabia O. Andrade, Leena A. Hilakivi-Clarke. Social isolation stress promotes obesity and mammary tumorigenesis and increases both Mdm2 and p53 expression and autophagy in the mammary gland. [abstract]. In: Proceedings of the Third AACR International Conference on Frontiers in Basic Cancer Research; Sep 18-22, 2013; National Harbor, MD. Philadelphia (PA): AACR; Cancer Res 2013;73(19 Suppl):Abstract nr B17.
Published Version
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