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dc.contributor.advisorKerin, Michael J.
dc.contributor.authorHeneghan, Helen M
dc.description.abstractThe two greatest health concerns worldwide at present are cancer and obesity; both of which continue to rise in incidence and are associated with high morbidity and mortality. Understanding the aetiology and mechanisms of these diseases is critical in order to develop clear and effective strategies for improving global health. Mi(cro)RNAs are a recently discovered class of short, non-coding, endogenous RNA molecules, only 18-25 nucleotides long. These small, ubiquitous molecules have been shown to play critical regulatory roles in a wide range of cellular processes. Aberrant miRNA expression has been observed in various pathological events including carcinogenesis, and in the aetiology of obesity and metabolic disorders. Furthermore, miRNAs have emerged as an exciting new class of disease biomarkers. The purpose of this study was to investigate the expression and dysregulation of miRNAs in two common diseases; breast cancer and obesity, with particular emphasis on exploring the potential of miRNAs as novel noninvasive biomarkers. An early goal of this study was to define a protocol for optimal analysis of miRNA expression in human blood samples. This was achieved through RQ-PCR quantification of specific miRNA sequences, in total RNA isolated from whole blood using a modified copurification technique. Using this approach, it was established that cancer-specific miRNAs were dysregulated in the circulation of breast cancer patients compared to controls. Specifically, miR-195 and let-7a were significantly increased in breast cancer patients (19.25 and 11.20 fold respectively), and levels correlated with tumour miRNA expression, tumour burden and other clinicopathological variables including hormone receptor and lymph node status. In addition, elevated systemic miR-195 was observed to be specific to breast cancer patients. In combination with let-7a and miR-155, this panel of 3 circulating miRNAs could discriminate breast cancers from controls with a remarkably high sensitivity of 94%. A further novel finding from this work was the discovery that an inherited variation in the let-7 binding site in the KRAS oncogene conferred increased susceptibility to breast cancer, particularly the 'triple negative' subtype, in premenopausal women (OR 4.78, CI 1.71 - 13.38, p=0.015). Finally, results from this work demonstrate that metabolic miRNAs are dysregulated in obese adipose tissue and also have potential to serve as novel non-invasive biomarkers for obesity and related metabolic conditions. Although elucidating their mechanisms of action is still in its infancy, the discovery of miRNAs has uncovered a new and exciting repertoire of molecular factors upstream of gene expression, with great potential for new developments in current diagnostic and therapeutic strategies in the management of common diseases. If the current momentum in miRNA translational research can be maintained, this has the potential to transform current practice to the ideal of individualized care for patients in the near future.en_US
dc.subjectBreast Canceren_US
dc.titleAnalysis of MiRNA Expression and Biomarker Potential in Common Diseases: Breast Cancer and Obesityen_US
dc.contributor.funderHealth Research Board (HRB) Irelanden_US
dc.local.noteMicroRNAs (miRNAs) are regulatory genetic elements which are expressed in an organ-specific manner. Their expression is frequently abnormal in many diseases including breast cancer and obesity. This thesis involved developing a method of quantifying miRNAs in blood, and identifying certain miRNAs which reflected the presence of these common diseases. Circulating miRNAs were found to reflect certain features of disease, such as breast cancer stage or likely response to certain treatments (e.g. surgery) This work highlights their potential for use in routine clinical blood tests to more accurately gauge a patient¿s disease burden and response to therapy.en_US

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