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. / published_or_final_version / Pathology / Master / Master of Medical Sciences

Breast cancer is the most frequent malignancy in women. Recent studies have proposed that sirtuin 1 (SIRT1) may play a certain role in the tumorgenesis and disease progression of cancer. Therefore, in this study, we demonstrate the localization of SIRT1 in the breast cancer cells by immunohistochemistry method and try to correlate the expression level of SIRT1 with various clinical-pathological parameters as well as the survival time of breast cancer patients. One hundred and eighteen breast cancer cases, arrayed as dual‐cores, were studied in the tissue microarray blocks for their SIRT1 nuclear and cytoplasmic stain. The expression of SIRT1 is found in over 95% of the tumor samples. Although the active functioning site of SIRT1 is known to be mainly the nucleus, both nuclear and cytoplasmic localization score are assessed separately for SIRT1 expression for more accurate statistically analysis. By bi‐variate Pearson correlation analysis, high nuclear localization of SIRT1 is significantly correlated with low tumor grade (p=0.006) and ER (p=0.001) and PR positive status (p=0.044). Moreover, the cytoplasmic localization score of SIRT1 shows positive correlation with tumor grade (p=0.010). The relationship of SIRT1 expression and survival time of breast cancer patient was studied by Kaplan‐Meier analysis. Despite a marginal fail in obtaining a statistically significant result, the trend in survival curve clearly indicated that nuclear localization of SIRT1 is associated with a poorer overall survival (p=0.052). Although the pathway of how SIRT1 affects the survival of breast cancer patient is still unknown, many studies suggested that it is largely due to the deacetylated inactivation of p53 tumor suppressor protein by SIRT1. In conclusion, we propose that nuclear localization of SIRT1 can be a potential prognostic factor of breast cancer patients. / published_or_final_version / Pathology / Master / Master of Medical Sciences

Background Breast cancer prevalence is increasing in most countries. Not only the threat of death and impact of breast cancer treatment, but also the participation roles during treatment decision making can be substantial, leading to psychological distress and poor quality of life. Previous studies have explored patients’ participation preference, the extent of participation congruence and related factors, revealing that women suffering from breast cancer may benefit from participation in treatment decision making whilst participation incongruity could be potentially detrimental for women with breast cancer. Objectives This study aimed to systematically review the literature and summarize the extent of breast cancer patients’ participation preference, participation congruence, and related factors. Methods Multiple searches for key words were conducted through electronic sources, including PubMed, PsycINFO, and Medline via Ovid databases for all relevant English language literature. Studies were selected basing on specific inclusion/exclusion criteria. The STROBE checklist was applied for reporting quality assessment. Results A total of 778 studies were identified. Twelve eligible studies were included in this review. Twelve factors relating to breast cancer women’s participation congruence in treatment decision making were identified as follows: age, nature of preferred role of treatment decision making, educational level, time related issues, language/ethnicity, marital status, information and recommendations of treatment, offering treatment options, physician characteristics, type of therapy or cancer program, stage of breast cancer, and surgeon volume. Conclusions Three themes (i.e. patient oriented, physician-patient interaction, and medical provision) of intervention points towards patient participation congruence were synthesized and discussed, and they were useful for improving the quality of existing breast cancer treatment decision making by addressing patient’s perceived participation congruence. / published_or_final_version / Public Health / Master / Master of Public Health

Despite the medical advancements, the woman breast cancer incidence rates keep rising in the past few decades. Scientists have proposed the increased exposure to endocrine disrupting chemicals as a possible factor for the rises. Zearalenone (ZEA) and aflatoxin B1 (AFB1) are common mycotoxins that are present in cereal crops worldwide. ZEA has long been recognized as a xenoestrogen, while the endocrine disrupting effects of AFB1 on steroidogenesis have been identified recently. Due to the co-occurrence and the endocrine disrupting potentials of ZEA and AFB1, the hypothesis of this project was proposed as exposure to low doses of ZEA and AFB1 might affect the growth of hormonal dependent breast cancer. In order to address the hypothesis, the aim of the first study was to examine the ultimate effects on growth and cell cycle progression in breast cancer MCF-7 cell line, following low dose exposure to ZEA and AFB1 individually and in combination. The effects on viability, cell growth, DNA synthesis, cell cycle progression and cyclin gene expressions were determined. Significant interactions were detected for their effects on viability and DNA synthesis. While ZEA promoted growth, DNA synthesis and cell cycle progression in MCF-7 cells, AFB1 was cytotoxic and counteracted the effects of ZEA. This study confirmed the growth promoting properties of ZEA, and is the first to report the combined effects of ZEA and AFB1 on breast cancer cell growth, suggesting endocrine-disrupting mycotoxins that co-occur in human food can interact and modulate the effects of each other on human health. The second study aimed to reveal the modulation of breast cancer genes and the underlying pathways that were directly affected by ZEA and AFB1. By using a real time reverse transcription polymerase chain reaction array, it was shown that ZEA was capable of altering the expressions of a large number of breast cancer related genes, whereas AFB1 had minimal effects on the breast cancer gene expressions. With the use of specific inhibitors, estrogen receptor α, G protein-coupled estrogen receptor 1, and mitogen-activated protein kinases (MAPKs) were found to be responsible for ZEA’s effects on cell growth and myelocytomatosis oncogene activation; while MAPK pathways might be involved in the cytotoxic effects by AFB1. Further confirmation is necessary for linking the activations of estrogen receptors and MAPKs to breast cancer cell growth by ZEA and AFB1. The last study aimed at assessing the impacts of ZEA and AFB1 on steroidogenic and steroid metabolic enzymes in MCF-7 cells, which might result in hormonal imbalance and undesirable breast cancer cell growth. By evaluating the mRNA expressions, it was found that ZEA significantly modulated the expressions of all the steroidogenic and steroid metabolic enzymes tested while AFB1 altered the expression of cytochrome P450 (CYP) 1A1 and CYP 1B1. Coexposure of MCF-7 cells to the two mycotoxins revealed that AFB1 antagonized the effects of ZEA on expression of CYP 1A1, CYP 3A4 and CYP 1B1. Further research into the alternations of enzyme levels and activities by ZEA and AFB1 is necessary before a solid conclusion can be made. / published_or_final_version / Biological Sciences / Doctoral / Doctor of Philosophy

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published_or_final_version / Medical Sciences / Master / Master of Medical Sciences

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No description available.

Using the biopsychosocial model and the Epigenetic principle, this study looked into younger women's experiences of the psychosocial impact of breast cancer at diagnosis, treatment and beyond the breast cancer experience. Case study methodology was employed and five women between the ages of 20 and 40 were interviewed on their experiences using the semi-structured approach to interviewing. The knowledge gained was analysed thematically. Results of the study revealed that breast cancer posed major psychosocial challenges for these young women as they attempted to negotiate the illness experience with the activities developmentally appropriate to their life stage. Developmentally relevant challenges were expressed in the areas of work, childrearing and partner-relationships and it was evident that spirituality and positive social support networks such as friendships and church groups played a significant role in helping individuals cope with the process, and emerge from it with an increased value for life. / Thesis (M.A.)-University of KwaZulu-Natal, 2007.