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This dissertation, Sirtuin 6 Expression in Breast Cancer by Yuk-tim, Chiu, 趙玉甜, was obtained from The University of Hong Kong (Pokfulam, Hong Kong) and is being sold pursuant to Creative Commons: Attribution 3.0 Hong Kong License. The content of this dissertation has not been altered in any way. We have altered the formatting in order to facilitate the ease of printing and reading of the dissertation. All rights not granted by the above license are retained by the author. Abstract: Sirtuins (Silent Information Regulator Two (SIR2) protein) are NAD-dependent protein deacetylases, originally discovered in yeast. Sirtuins play a critical role in the regulation of different cellular processes involving aging, chromatin silencing and cellular differentiation. SIRT6 is a member of Sirtuins and plays a role in regulation of DNA repair and suppression of genomic instability. Many studies have shown SIRT6 to be associated with diseases of aging, including cancer. The finding by our collaborator that SIRT6 expression was found in chemotherapy-resistant breast cancer cell lines stimulated this study which aims to explore the role of SIRT6 expression as a prognostic marker in breast cancer. One hundred and eighteen breast cancer samples in tissue microarray blocks were examined for SIRT6 expression by immunohistochemistry. As SIRT6 expression is predominantly located in the nucleus but with a small fraction in cytoplasm, the calculation of nuclear or cytoplasmic localization scores were divided by total localization scores to increase accuracy. The nuclear localization scores represent the SIRT6 expression in breast cancer. Statistical analysis was performed using SPSS software. SIRT6 overexpression in the nucleus was significantly associated with poorer overall survivals (p=0.018) while low cytoplasmic expression of SIRT6 was also associated with poorer overall survivals (p=0.014). There was no relationship between SIRT6 expression and disease-specific survivals. By multivariate analysis, SIRT6 expression was an independent predicator of poorer overall survivals. These results suggest that SIRT6 overexpression induces apoptosis in cancer cells through deacetylation of transcription factor p65. SIRT6 interacts with and deacetylates p65 to activate nuclear factor kappa B gene linked to cancer. Also high levels of SIRT6 were associated with resistance to paclitaxel and epirubicin inMCF-7 breast cancer cell lines. This provides evidence that Sirt6 is an important prognostic marker and therapeutic target for breast cancer. DOI: 10.5353/th_b4854125 Subjects: SirtuinsBreast - Cancer - Genetic aspects

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