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Cover for Timing of Dietary Exposures on Risk of Reproductive Cancer
dc.contributor.advisorHilakivi-Clarke, Leenaen
dc.contributor.advisorSherman, Thomasen
dc.creatoren
dc.date.accessioned2014-08-15T16:29:44Zen
dc.date.created2014en
dc.date.issueden
dc.date.submitted01/01/2014en
dc.identifier.otherAPT-BAG: georgetown.edu.10822_709844.tar;APT-ETAG: 80650ea6967d9dd0fe285809cd4bbc6a; APT-DATE: 2017-02-07_14:13:44en
dc.identifier.urien
dc.descriptionPh.D.en
dc.description.abstractTIMING OF DIETARY EXPOSURES ON RISK OF REPRODUCTIVE CANCERen
dc.description.abstractElissa J. Carney, M.S.en
dc.description.abstractThesis Advisor: Leena Hilakivi-Clarke, PhD.en
dc.description.abstractABSTRACTen
dc.description.abstracten
dc.description.abstractThe 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.en
dc.formatPDFen
dc.format.extent193 leavesen
dc.languageenen
dc.publisherGeorgetown Universityen
dc.sourceGeorgetown University-Graduate School of Arts & Sciencesen
dc.sourcePhysiology & Biophysicsen
dc.subjectDieten
dc.subjectEndometrial canceren
dc.subjectGenisteinen
dc.subjectLeptinen
dc.subjectOvarian canceren
dc.subjectPreventionen
dc.subject.lcshNutritionen
dc.subject.lcshBiologyen
dc.subject.otherNutritionen
dc.subject.otherBiologyen
dc.titleTiming of Dietary Exposures on Risk of Reproductive Canceren
dc.typethesisen
gu.embargo.lift-date2015-02-15en
gu.embargo.terms6-monthsen


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