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    Social Isolation Stress, Obesity, and Breast Cancer Risk in Mice

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    View/Open: Sumis_georgetown_0076D_12678.pdf (2.3MB) Bookview

    Creator
    Sumis, Allison M.
    Advisor
    Hilakivi-Clarke, Leena
    Abstract
    Social isolation is a potent psychosocial stressor and is associated with obesity and increased breast cancer risk and mortality. In this thesis, I investigated the combined effects of social isolation stress and obesity on insulin resistance, mammary tumorigenesis, and the mechanisms involved.
     
    First, I studied the effects of social isolation stress in combination with an obesity inducing diet (OID) on mammary tumorigenesis induced by medroxyprogesterone acetate (MPA) and 7,12-dimethylbenz(a)anthracene (DMBA) in female C57BL/6 mice. Social isolation, with or without OID, increased food intake and body weight, and caused impaired insulin and glucose tolerance. Serum NPY levels were increased only in socially isolated OID fed mice, whilst adiponectin levels were reduced both by OID and social isolation. These changes may have contributed to insulin resistance. Mammary tumorigenesis was significantly higher in the socially isolated OID fed mice than in group-housed obese or control mice. Consistent with a previous study indicating that social isolation does not increase mammary tumorigenesis in p53 knockout mice, we found an increase in p53 mRNA expression in socially-isolated mice that exhibited increased mammary cancer risk. Apoptosis was not altered in these mice, but cell proliferation was significantly increased. Social isolation increased the expression of p53-induced autophagy-linked genes and other genes indicative of autophagy in the mammary gland. In summary, we found that obesity potentiates the effects of social isolation on mammary carcinogenesis, but primarily social isolation induced autophagy and cell proliferation but not apoptosis.
     
    Next, histone deacetylase inhibitor (HDACi) and DNA methyltransferase inhibitor (DNMTi) were administered in drinking water to group-housed or socially-isolated OID fed mice. Insulin resistance and body weight gain were reversed with these inhibitors. However, HDACi/DNMTi treatment did not reverse mammary tumorigenesis and neither did they reverse up-regulation of p53 or alter the expression of cell cycle and cell death genes. Taken together, these data suggest that insulin resistance in obese mice may result from epigenetically-induced changes and therefore DNMTi/HDACi drugs may be useful in preventing weight gain and improving insulin sensitivity, but the increase in mammary tumorigenesis in socially-isolated obese mice is not caused by an increase in DNMT and HDAC activity.
     
    Description
    Ph.D.
    Permanent Link
    http://hdl.handle.net/10822/709957
    Date Published
    2014
    Subject
    autophagy; breast cancer; epigenetics; insulin resistance; obesity; social isolation stress; Oncology; Oncology;
    Type
    thesis
    Embargo Lift Date
    2015-02-15
    Publisher
    Georgetown University
    Extent
    167 leaves
    Collections
    • Graduate Theses and Dissertations - Tumor Biology
    Metadata
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    Georgetown University Seal
    ©2009 - 2022 Georgetown University Library
    37th & O Streets NW
    Washington DC 20057-1174
    202.687.7385
    digitalscholarship@georgetown.edu
    Accessibility