Surgery (St Vincent's) - Theses

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    Biocellular aspects of high mammographic density as a risk factor for breast cancer
    Chew, Grace Li Ling ( 2016)
    High mammographic density (MD) is one of the strongest risk factors for breast cancer after high-risk mutations, with a 4-6 fold increased risk comparing the highest to lowest MD quartiles. MD is of great clinical relevance, given that the attributable risk of breast cancer (BC) due to high MD in the population may be as high as 30%, and the already widespread use of mammography for breast assessment. However, the biological basis for high MD and its associated cancer risk is poorly understood. A validated xenograft model where the dynamic effects of drug interventions and gene perturbations on human MD tissue can be investigated in the preclinical setting will be valuable. Prior to commencement of the PhD thesis, there were no animal models of human MD that could maintain the MD differential of tumour-free breast tissues. In the first published study, we developed a xenograft model of human MD, where matched high and low MD human tissues were precisely-sampled under stereotactic-guidance from fresh mastectomy tissues and maintained in separate vascularized biochambers in SCID mice. This study demonstrated that the high and low MD biochamber tissues retained their differential radiographic density and histologic features of the original human tissue. The high compared to low MD biochamber tissues were composed of increased stromal and decreased adipose percentage areas, reflecting the MD phenotype of the original human breast samples. The MD xenograft model was then extended to examine the changes in radiographic density and histology that occurred during murine pregnancy, lactation and postpartum involution states, and after exposure to exogenous endocrine treatment. These studies demonstrated the dynamic nature of the MD xenograft model, with decreased stromal and increased adipose tissue percentage areas observed in high MD biochamber tissues during murine lactation and postpartum involution, and also in Tamoxifen-treated compared to placebo-treated mice. High and low MD biochamber tissues had increased radiographic density with postpartum involution, and increased duration of implant. The radiographic density decreased in high MD biochamber tissues of Tamoxifen-treated compared to oestrogen-treated mice. As increased Cox-2 levels have been observed in breast tumours and stromal regions of high MD tissues, we investigated the expression of Cox-2 in the epithelial and stromal cells of matched high and low MD breast tissues. We demonstrated increased staining in both epithelial and stromal cells of high MD breast tissues. We then showed that the differential Cox-2 expression in high and low MD human breast tissues was maintained in murine biochambers, and was sensitive to hormonal supplementation. Collectively, this thesis indicates that the MD model will be valuable for investigating the mechanisms of how modifying factors, such as lifestyle behaviours and endocrine treatments like Tamoxifen, can reduce MD in cancer-free human breast tissues, and would be useful in research aiming to develop preventative therapies to reduce MD-related risk, such as Cox-2 inhibition.
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    Role of Epithelial Mesenchymal Plasticity associated cancer subpopulations in mammary tumourigenisis and chemoresistance
    Pinto, Cletus Anthony ( 2014)
    Tumour heterogeneity is a key characteristic of cancer and has significant implications relating to tumour response to chemotherapy as well as patient prognosis and potential relapse. It is increasingly accepted that tumours are clonal in origin, suggestive of a tumour arising from a deregulated or mutated cell. Cancer stem cells (CSC) possess/propagate these capabilities, and with appropriate intracellular triggers and/or signalling from extracellular environments, can ‘differentiate’ to initiate tumour formation. Additionally through epithelial mesenchymal plasticity (EMP), where cells gain and maintain characteristics of both epithelial and mesenchymal cell types, epithelial-derived tumour cells have been shown to ‘de-differentiate’ to acquire cancer stem attributes, which also imparts chemotherapy resistance. This new paradigm places EMP centrally in the process of tumour formation, propagation, progression and metastasis, as well as modulating drug response to current forms of chemotherapy. Furthermore, EMP and CSCs have been identified in cancers arising from different tissue types making them a possible generic therapeutic target in cancer biology. In this study, we expand on the relationship between tumour heterogeneity, EMP and CSC in BrCa through the identification and characterisation of epithelial and mesenchymal subpopulations within two BrCa cell lines. In addition, we demonstrate the plasticity that allows these cell populations to effectively regenerate the other cell populations with a particular emphasis on the CSC phenotype. Through a functional genomics screen, the importance of the mesenchymal phenotype in tumour initiation is demonstrated. Taken together, this study demonstrates that heterogeneity exists at a cell line level and this heterogeneity differs in different cellular systems. We also find evidence to suggest that BrCa cell lines can use multiple mechanisms to achieve an outcome such as tumour initiation or mammosphere formation, and subsequently emphasize the importance of phenotype specific drugs. This ideology of drug repurposing to identify phenotype specific drugs is explored through the use of the connectivity map database to identify new uses for previously established drugs to target these subpopulations find preliminary evidence for the role of HDACi to affect these EMP associated subpopulations in BrCa cell lines.