Abstract LB-316: Social isolation alters abdominal and mammary adipocytes to potentially increase mammary tumorigenesis in mice

Abstract

Abstract Social isolation, characterized as withdrawal from interactions with others, is an equally powerful predictor of early all-cause mortality as smoking and high cholesterol. Social isolation has been consistently linked to increased breast cancer risk and mortality in animal studies and humans. Recent animal studies in our laboratory show that social isolation potentiates the effects of high fat (HF) diet on carcinogen- induced mammary cancer. Social isolation coupled with HF diet also magnified adverse metabolic effects associated with obesity, including insulin resistance. To investigate how these metabolic effects manifest, we measured and compared metabolic endpoints in abdominal and mammary gland adipose cells in 7- and 23-week-old female mice kept in social isolation for 4 or 20 weeks, respectively. Four groups of C56BL/6 mice were studied: control diet fed group housed mice (C-G), HF diet fed group housed mice (HF-G), control diet fed socially isolated mice (C-ISO) and HF diet fed socially isolated mice (HF-ISO). At 7 weeks of age, abdominal adipocytes of HF diet fed HF-G mice were significantly larger than in C-G control mice (C-G) (p = 0.012), indicating adipocyte hypertrophy, a hallmark of obesity. Adipocytes in HF-ISO were also enlarged, but not significantly. At 23 weeks of age, however, mammary adipocytes of HF-ISO mice were significantly reduced compared with C-G controls (p = 0.046) and HF-G group (p = 0.009). Abdominal adipocytes were reduced both in C-ISO (p<0.001) and HF-ISO (p = 0.002) compared with HF-G. Histological analysis indicated more pockets or areas of multi-locular adipocytes in the mammary adipocytes of socially isolated mice (both HF-ISO and C-ISO), suggesting the presence of beige adipocytes. Beige adipocytes are specialized white adipocytes that have an appearance and function similar to brown adipocytes that dissipate energy. An increase in beige adipocytes has been proposed to prevent and reverse weight gain and metabolic diseases, but it is not clear whether these cells affect the development of breast and other cancers. Immunohistochemical analysis for beige specific adipocyte markers in abdominal and mammary adipose tissue showed higher intensity staining for Ucp1 and Pgc1 in HF-G, HF-ISO and C-ISO, compared with C-G controls. In 7 week old mice, western blot analysis of mammary gland samples of these groups indicated more Ucp1 expression, albeit with no statistical significance. However, Bmp4, an activator of beige adipocytes, was downregulated in C-ISO (p = 0.015), HF-G (p = 0.020), and HF-ISO (p = 0.057) groups with C-G group, suggesting that if present, the beige adipocytes may not be active in socially isolated mice. Our findings suggest that social isolation may alter phenotype and function of abdominal and mammary adipocytes, and these changes could contribute to the increased breast cancer risk and mortality in socially isolated women and animal models. Citation Format: Madisa Macon, Allison Sumis, Wei Yu, Leena Hilakivi-Clarke. Social isolation alters abdominal and mammary adipocytes to potentially increase mammary tumorigenesis in mice. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-316.