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dc.contributor.advisorDachs, Gabi
dc.contributor.advisorCurrie, Margaret
dc.contributor.advisorPhillips , Elisabeth
dc.contributor.authorMandani, Anishah Nanji Devji
dc.date.available2015-11-11T04:01:17Z
dc.date.copyright2015
dc.identifier.citationMandani, A. N. D. (2015). Development of a Metabolic Syndrome Mouse Model of Breast Cancer (Thesis, Bachelor of Biomedical Sciences with Honours). University of Otago. Retrieved from http://hdl.handle.net/10523/6059en
dc.identifier.urihttp://hdl.handle.net/10523/6059
dc.description.abstractMetabolic syndrome is a cluster of disorders, including obesity, atherosclerosis, inflammation and insulin resistance. It is associated with increased risk of various types of cancers including breast cancer. Obesity in particular is a risk factor for an aggressive tumour phenotype and reduced survival of patients with breast cancer. To understand the underlying mechanisms I aimed to develop and characterise a metabolic syndrome mouse with an orthotopic model of breast cancer. Apolipoprotein E (ApoE) is involved in the catabolism of triglycerides and cholesterol, and the ApoE knockout mouse model is prone to obesity and development of atherosclerosis. The double knockout ApoE/ArKO mouse displays all features of metabolic syndrome. At 6 months of age, wild type, ApoE and ApoE/ArKO C57BL/6 mice were inoculated with the murine breast cancer cell line E0771. Growth of tumours in the mammary fat pad and mouse weight were measured until tumours reached ethical endpoint. The hypoxia marker, pimonidazole, was injected 90min prior to euthanasia, and plasma, organs and tumours were harvested and weighed. Half of each tumour was formalin fixed and paraffin embedded for Immunohistochemical (IHC) analysis of cancer associated adipocytes (perilipin), proliferation (phosphohistone-H3), estrogen receptor status (ERα) and hypoxia (pimonidazole adducts). The other half was frozen and processed for tumour lysates, which were used to measure hypoxia inducible factor 1 (HIF-1α) by Western blotting, and adipokines, using an antibody array. Vascular endothelial growth factor (VEGF) and Insulin-like growth factor binding protein 5 (IGFBP5) concentrations were further analysed by an ELISA assay. HIF-1α levels in EO771 cells were analysed by subjecting the cells to hypoxic conditions. ApoE mice weighed more than wild type and ApoE/ArKO mice, and showed increased cellular proliferation. ApoE/ArKO mice had the least omental fat and the smallest tumours. IHC analysis showed that EO771 tumours in ApoE mice had the highest number of intratumoral, perilipin positive adipocytes (p<0.01), and tumours from ApoE/ArKO had the highest percentage of phosphohistone-H3 positive cells (p<0.05). All tumours stained negative for ER-α. Pimonidazole staining was prominent in all tumours, with secondary tumours staining strongly. From Western blot analysis, tumours grown in ApoE/ArKO mice had the highest level of HIF-1α, and HIF-1α levels were higher in secondary tumours compared to primary tumours (p<0.05). A range of adipokines was differentially expressed in tumours grown in the three different genetic backgrounds. VEGF concentrations were higher in primary tumours from ApoE/ArKO mice than ApoE and wild type mice. Primary tumours from ApoE/ArKO mice had significantly lower concentrations of IGFBP5 (p<0.01). My findings show that breast tumours grown in ApoE/ArKO mice have an aggressive tumour phenotype, with increased proliferation, tumour hypoxia and VEGF concentration. These models represent valuable tools for research that will bridge the gap between cell culture models and breast cancer patients.
dc.format.mimetypeapplication/pdf
dc.language.isoen
dc.publisherUniversity of Otago
dc.rightsAll items in OUR Archive are provided for private study and research purposes and are protected by copyright with all rights reserved unless otherwise indicated.
dc.subjectbreast cancer
dc.subjectmetabolic syndrome
dc.subjectmouse model
dc.titleDevelopment of a Metabolic Syndrome Mouse Model of Breast Cancer
dc.typeThesis
dc.date.updated2015-11-10T22:48:34Z
dc.language.rfc3066en
thesis.degree.disciplinePathology
thesis.degree.nameBachelor of Biomedical Sciences with Honours
thesis.degree.grantorUniversity of Otago
thesis.degree.levelHonours
otago.openaccessOpen
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