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    Timing of Dietary Exposures on Risk of Reproductive Cancer

    Cover for Timing of Dietary Exposures on Risk of Reproductive Cancer
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    View/Open: Carney_georgetown_0076D_12683.pdf (14.MB)

    Creator
    Carney, Elissa
    Advisor
    Hilakivi-Clarke, Leena
    Sherman, Thomas
    Abstract
    TIMING OF DIETARY EXPOSURES ON RISK OF REPRODUCTIVE CANCER
     
    Elissa J. Carney, M.S.
     
    Thesis Advisor: Leena Hilakivi-Clarke, PhD.
     
    ABSTRACT
     
     
     
    The effect of dietary factors on breast cancer risk is largely determined by when during her life-time a woman is exposed to them. This dissertation encompasses three investigations of whether the timing of dietary exposures also determines their effect on reproductive tract cancers. Furthermore, the molecular mechanisms mediating the effects of dietary exposures during in utero, prepuberty, and adulthood on risk of endometrial or uterine cancer risk were investigated. First, I investigated whether prepubertal dietary intake of phytoestrogen genistein in soy foods alters ovarian cancer risk in 7, 12 dimethylbenz(a)anthracene (DMBA) treated mice which model women carriers of germline BRCA1 mutations. Prepubertal genistein diet reduced the incidence of granulosa cell tumors in Brca1+/- and wildtype mice. This effect was associated with reduced levels of estrogen receptor alpha, cell proliferation, and increased apoptosis. Second, I investigated whether lifetime or adult genistein intake can prevent tamoxifen-induced endometrial carcinogenesis in outbred Sprague Dawley rats. One third of tamoxifen treated rats developed premalignant endometrial lesions. Adult intake of genistein prevented lesions was associated with reduced ER-alpha levels and altered cytochrome P450 (CYP) signaling, suggesting a reduction in the formation of carcinogenic estrogen metabolites. The unfolded protein response was activated by tamoxifen in the uterus; however, genistein intake did not modify this response. Lastly, I investigated the effects of maternal exposure to obesity-inducing high fat diet or adipose-tissue derived adipokine leptin during pregnancy on offspring's risk of endometrial carcinogenesis in Pten+/- and wild type mice. Pten+/- mice exposed to leptin in utero had significantly higher risk of developing premalignant endometrial lesions than control mice, but this effect was not related to persistent changes in leptin signaling in the endometrium. Through these preclinical studies, I have demonstrated the significance of timing of dietary exposures on cancer risk in the female reproductive tract. I also have shown that the changes in cancer risk are associated with persistent alterations in the pathways that mediate cell proliferation and apoptosis. Findings obtained in these studies are translatable to preventing reproductive tract cancers in women by making dietary modifications involving consumption of soy foods.
     
    Description
    Ph.D.
    Permanent Link
    http://hdl.handle.net/10822/709844
    Date Published
    2014
    Subject
    Diet; Endometrial cancer; Genistein; Leptin; Ovarian cancer; Prevention; Nutrition; Biology; Nutrition; Biology;
    Type
    thesis
    Embargo Lift Date
    2015-02-15
    Publisher
    Georgetown University
    Extent
    193 leaves
    Collections
    • Graduate Theses and Dissertations - Physiology & Biophysics
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    • Cover for Timing of dietary exposures and tamoxifen resistance in rats

      Timing of dietary exposures and tamoxifen resistance in rats 

      Zhang, Xiyuan (Georgetown University, 2016)
      In the USA, one in eight women develop invasive breast cancer at some point of her life, and 70% of the cancers are estrogen receptor positive and thus are treated with antiestrogen therapy. However, half of the treated ...
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    Georgetown University Seal
    ©2009 - 2023 Georgetown University Library
    37th & O Streets NW
    Washington DC 20057-1174
    202.687.7385
    digitalscholarship@georgetown.edu
    Accessibility