Recent studies indicate a correlation between high expression of the POZ-ZF transcription factor Kaiso, and the aggressiveness of the triple negative breast cancer (TNBC) subtype. However, little is known about the biological roles of Kaiso in TNBC tumorigenesis and metastasis, which laid the foundation for this thesis. To elucidate Kaiso’s role in TNBC, we generated stable Kaiso depletion in two well-established TNBC cell lines – MDA-MB-231 and Hs578T – using RNA interference technology. Intriguingly, we observed that Kaiso depletion delayed the tumor onset of MDA-MB-231 but not Hs578T cells, and led to the reduced expression of the c-Myc oncoprotein in MDA-MB-231 but not Hs578T cells. We postulate that this reduction in c-Myc expression is partly responsible for the delayed tumor onset observed in MDA-MB-231 cells. Additionally, loss of Kaiso expression resulted in increased apoptosis of both MDA-MB-231 and Hs578T cells in vitro and in vivo, which was accompanied by reduced expression of the DNA repair protein BRCA1. Remarkably, bioinformatic analysis revealed that high Kaiso and BRCA1 mRNA expression correlates with the reduced survival rates of TNBC patients. Further characterization of the Kaiso-depleted cells revealed that loss of Kaiso expression strongly inhibited the metastatic abilities of MDA-MB-231 and Hs578T cells. Importantly, Kaiso depletion led to decreased TGFβ-receptor I and II (TGFβRI and II) expression that is essential for the activation of the TGFβ signaling cascade. Concomitantly, suppressing Kaiso led to reduced TGFβ signaling. As increased TGFβRI expression is independently associated with the poor prognostic outcome of breast tumors, and the TGFβ signaling pathway is highly involved in breast tumor metastasis, we hypothesize that Kaiso functions together with TGFβRI and the TGFβ signaling cascade to promote TNBC metastasis. An additional goal of this thesis was to investigate the role of Kaiso in the prevalence of TNBC in women of African ancestry (WAA) compared to Caucasian women – since increased Kaiso expression is implicated in the poor survival outcomes of breast cancer patients of African ancestry relative to their Caucasian counterparts. Using tissue microarray and immunohistochemical analyses, we revealed for the first time a high nuclear expression of Kaiso in TNBC tissues of WAA (Nigerian, Barbadian, African American) compared to TNBC tissues of Caucasian women. Collectively, these findings unveiled functional oncogenic roles for Kaiso in the tumorigenesis and metastasis of TNBC, and revealed a plausible link between high Kaiso expression, high African ancestry and the predisposition of young WAA to TNBC. / Thesis / Doctor of Philosophy (PhD)

Breast transillumination has received renewed interest as a noninvasive diagnostic method. However, it is still considered an experimental technique. Many aspects of the physics involved in transillumination have not yet been studied. In this project transillumination was simulated by experiments with a simple breast phantom of realistic dimensions. The light source used was a HeNe laser. From the experiments we found how the contrast of images of a spherical inhomogeneity (simulating a lesion e.g. tumor or cyst) depended on its size and position. The contrast was also measured as a function of the scattering and absorption coefficients of the inhomogeneity. The contrast of the image is shown to fit very well to the curve A(1-exp(-d(Σ^inh_eff – Σ_eff))), where a simple analytical model is developed, where A is identified to (1+B)^-1, B being a build-up factor depending on the surrounding medium and on the position of the inhomogeneity in the medium and d is identified as an effective optical diameter of the inhomogeneity. A three dimensional numerical diffusion program was developed to model the transillumination situation. It was found that diffusion theory gave accurate predictions of the contrast within the constraints of the mathematical model. The three dimensional diffusion approximation and its limitations are discussed in some detail. / Thesis / Master of Science (MSc)

This thesis explores the role of values in risk assessment for breast cancer. Why? First, breast cancer poses a serious health threat to women, yet currently has no known cause. This means the discussion of risk becomes central to this disease. Second, K.S. Shrader-Frechette has shown that values enter in at each stage of risk assessment. These stages are the choice of topics, methods, and evaluation. By using Shrader-Frechette's framework for analysis of such areas of breast cancer as mammography, prophylactic mastectomy, tamoxifen and the role of estrogen, research routes, and prevention, it can be shown that certain values dominate the risk assessment. These values are the technological imperative, individual causation of disease, and reductionism. This thesis argues that the dominance of these values has led to a narrow and biased view of breast cancer risk. This view leaves women with fewer legitimate choices for the management of breast cancer risk and in many ways excluded altogether from its risk discourse. As breast cancer advocacy groups have gained in strength, attention has been drawn to the fact that there are competing values which can be used in risk assessment for this disease. These competing values are a low-tech/high-preventative, holistic, care-oriented approach to disease. These values can provide a viable alternative assessment of risk in breast cancer. Furthermore, this alternative risk picture is more desirable than the current one, because it helps to redirect and widen the focus on risk in breast cancer and gives women a central role in its risk discourse. / Thesis / Master of Arts (MA)

The American Cancer Society predicted that 230,480 women would be diagnosed with, and 39,520 women would die from breast cancer (BC) in the United States in 2011. While the incidence of female BC has been decreasing, BC remains the second leading cause of cancer death among women in the United States. Cancer cachexia, the cancer-related loss of muscle, affects up to 25% of BC patients and is associated with poor prognosis and decreased quality of life. Alterations to the dystrophin glycoprotein complex (DGC), a transmembrane, multi-subunit protein complex with structural and signaling roles, have been reported in mammary tumors of BC patients and skeletal muscles of cachectic cancer patients. However, this complex is most frequently studied for its role in Duchenne muscular dystrophy (DMD), a severe, progressive muscle wasting disease. Despite the similar alterations reported in these diseases, it is unclear whether alterations in the DGC in one tissue can impact the progression of disease in another. Purpose: The purpose of the studies described in this dissertation was to identify differences in body composition, energy expenditure and plasma cytokine content between the C57BL/10ScSn-Dmdmdx/J (mdx) mouse model of DMD and C57BL/10ScSnJ (BL/10) control mice and to determine whether systemic alteration of the DGC (as observed in the mdx mouse) alters the growth of E0771 murine mammary tumors. Results: There were differences in body composition and plasma cytokine profiles between mdx and BL/10 mice. We also found that, relative to controls, the tumor–induced increase in cytokines that promote invasion and metastasis was not as severe in mdx mice. Conclusions: This study revealed several differences between mdx and BL/10 mice and provides support for the suggestion that the mdx mouse may not be an accurate model of DMD. In addition, the improved cytokine profile of tumor-bearing mdx mice suggests that the acute phase of DMD may be protective against BC invasion and metastasis. Further research should confirm this effect and determine whether alterations in the DGC of the mdx mouse are directly or indirectly responsible. / Ph. D.

This work demonstrates the ability of contactless dielectrophoresis (cDEP) for isolation of breast cancer cell stages. The ability to selectively concentrate breast tumor cells from a non-transformed or normal cell population is the key to successfully detecting tumors at an early stage of growth and treating transformed cells before they proliferate. Since all cell types have a unique molecular composition it is expected that their dielectrophoretic properties are also unique. DEP force is dependent on the frequency and magnitude of the applied field, as well as a particle's size and electric properties. Specifically, the Clausius-Mossotti factor in the DEP force equation determines a specific cell type's interaction with the electric field and the DEP force response. Cell properties affecting this parameter were investigated numerically and experimentally. MCF10A, MCF7, and MDA-MB231 human breast cancer cells were used to represent early, intermediate, and late staged breast cancer respectively. Experiments were conducted at 0.02ml/hr with applied voltages of 20Vrms, 25Vrms, 30Vrms, 35Vrms, 40Vrms and 50Vrms (n=8). Frequency measurements were recorded for the initial onset of DEP force and when 90% trapping was obtained. The trapping frequency ranges for each cell were distinct from one another with the least amount of overlap between the MCF10A cells and MDA-MB231cells. The MCF7 cell line had, on average, the smallest trapping region at each applied voltage, and fell in between the normal and late staged cells' trapping frequency ranges. Voltages of 20Vrms to 30Vrms were found the most efficient for cell isolation. / Master of Science

陳津利. / "2000年7月" / 論文 (哲學碩士)--香港中文大學, 2000. / 參考文獻 (leaves 138-151) / 附中英文摘要. / "2000 nian 7 yue" / Chen Jinli. / Lun wen (zhe xue shuo shi)--Xianggang Zhong wen da xue, 2000. / Can kao wen xian (leaves 138-151) / Fu Zhong Ying wen zhai yao. / Chapter 第一章 --- 緒論 --- p.1 / Chapter 第一節 --- 中國的乳腺癌患者 --- p.1 / Chapter 第二節 --- 中國內地的癌症自助團體 --- p.3 / Chapter 第三節 --- 硏究意義和主題 --- p.5 / Chapter 一、 --- 硏究意義 --- p.5 / Chapter 二、 --- 硏究主題 --- p.8 / Chapter 第二章 --- 文獻回顧 --- p.9 / Chapter 第一節 --- 乳腺癌和乳腺癌患者 --- p.9 / Chapter 一、 --- 乳腺癌和乳腺癌患者的定義 --- p.9 / Chapter 二、 --- 患者瀕死的心理反應 --- p.10 / Chapter 三、 --- 患者面臨的實際問題和情感需求 --- p.15 / Chapter 第二節 --- 支持的槪念和取向 --- p.21 / Chapter 一、 --- 社會支持的槪念 --- p.21 / Chapter 二、 --- 支持的類型 --- p.23 / Chapter 三、 --- 社會支持的功能 --- p.27 / Chapter 四、 --- 社會支持的測量和指標 --- p.31 / Chapter 第三節 --- 自助團體的定義及功能 --- p.36 / Chapter 一、 --- 自助團體的定義 --- p.36 / Chapter 二、 --- 自助團體作爲社會支持系統的組成部分 --- p.37 / Chapter 第三章 --- 硏究架構 --- p.46 / Chapter 第一節 --- 基本假設 --- p.46 / Chapter 第二節 --- 研究變量名詞的操作性定義 --- p.48 / Chapter 一、 --- 自助團體行爲認知 --- p.48 / Chapter 二、 --- 感受的情感支持 --- p.50 / Chapter 三、 --- 個人特徵 --- p.50 / Chapter 第四章 --- 硏究方法 --- p.51 / Chapter 第一節 --- 研究法的選擇 --- p.51 / Chapter 一、 --- 應用三角測量的思考 --- p.51 / Chapter 二、 --- 量化爲主、質性爲輔的主輔設計 --- p.51 / Chapter 三、 --- 同步三角測量法的采用 --- p.53 / Chapter 第二節 --- 問卷調查硏究設計 --- p.54 / Chapter 一、 --- 樣本策略_ --- p.54 / Chapter 二、 --- 測量工具 --- p.56 / Chapter 三、 --- 資料搜集方法 --- p.59 / Chapter 四、 --- 效度和信度 --- p.59 / Chapter 五、 --- 問卷調查的資料處理及數据分析 --- p.62 / Chapter 第三節 --- 質性硏究方案 --- p.63 / Chapter 一、 --- 硏究樣本及資料收集 --- p.63 / Chapter 二、 --- 資料分析 --- p.63 / Chapter 第四節 --- 硏究局限 --- p.65 / Chapter 第五章 --- 硏究結果 --- p.66 / Chapter 第一節 --- 中國乳腺癌患者的基本特徵 --- p.66 / Chapter 一、 --- 背景結構 --- p.66 / Chapter 二、 --- 身心狀況 --- p.72 / Chapter 三、 --- 病患情感特徵 --- p.77 / Chapter 第二節 --- 患者自助團體行爲認知 --- p.85 / Chapter 一、 --- 患者的自助團體活動參與程度(A1 ) --- p.85 / Chapter 二、 --- 患者的自助團體活動認知程度(A2 ) --- p.90 / Chapter 三、 --- 患者對自助團體的主觀認同(A3) --- p.91 / Chapter 四、 --- 個人基本特徵的作用 --- p.96 / Chapter 第三節 --- 患者自助團體中的情感支持感受(B) --- p.100 / Chapter 一、 --- 患者在自助團體中的情感支持感受 --- p.100 / Chapter 二、 --- 個人特徵對情感支持感受影響 --- p.108 / Chapter 第四節 --- 假設驗証：自助團體行爲認知與情感支持感受的 相關關係 --- p.114 / Chapter 一、 --- 活動參與程度(A1)與情感支持感受的相關關係 --- p.115 / Chapter 二、 --- 活動認知程度(A2)與情感支持感受的相關關係 --- p.119 / Chapter 三、 --- 主觀認同(A3)與情感支持感受的相關關係 --- p.120 / Chapter 四、 --- 個人基本特徵對行爲認知(A)與情感支持感受 關係的影響 --- p.122 / Chapter 五、 --- 小結 --- p.122 / Chapter 第六章 --- 結論、檢討及建議 --- p.123 / Chapter 第一節 --- 硏究結果討論 --- p.123 / Chapter 一、 --- 自助團體情感支持硏究結果與西方 研究的异同及討論 --- p.123 / Chapter 二、 --- 社會支持理論和槪念的适用性討論 --- p.127 / Chapter 第二節 --- 待5幵究或澄淸的議題 --- p.129 / Chapter 一、 --- 患者的情感問題： 乳腺癌是否破坏了患者的婚姻質量？ --- p.129 / Chapter 二、 --- 家庭的支持功能問題： 什么是對患者的“愛´ح ？ --- p.131 / Chapter 三、 --- 來自“大鍋飯´ح的資源： 制度安排帶給乳腺癌患者什么？ --- p.131 / Chapter 四、 --- 未接受乳房再造術： 經濟的？醫療的？制度的？觀念的？ --- p.132 / Chapter 五、 --- 關於自助團體的几點發現 --- p.132 / Chapter 第三節 --- 建議 --- p.134 / Chapter 一、 --- 政府部門與自助團體建立伙伴關係 --- p.134 / Chapter 二、 --- 加強對患者家庭的輔導，引進境外社會工 作理念和實務，開展針對性情感治療 --- p.134 / Chapter 三、 --- 營造新女性文化，關注自身生存質量 --- p.135 / Chapter 四、 --- 未來的硏究 --- p.136 / 參考書目 --- p.138 / 附錄 / 附錄一統計結果列表 --- p.152 / 附錄二 量表信度列表 --- p.173 / 附錄三調查問卷 --- p.177 / 附錄四訪談指引 --- p.185

There is considerable evidence that delays in diagnosing and treating breast cancer reduce long-term survival. The purpose of this study was to assess the waiting time between diagnosis and treatment for Alberta women with breast cancer and to examine the influence of age, cancer stage, Regional Health Authority (RHA), community size, and year of diagnosis on this time interval. The data were obtained from the Alberta Cancer Board. The information included approximately all Alberta women with breast cancer between 1997 and 2000. The overall median waiting time was 17 days. The mean and median delay increased by an average of two days each year. Only 43.8% of cases were treated within the recommended 14 days. The delay was significantly longer for women younger than 70, with stage 1 disease and from Northern RHAs. Efforts must be made to decrease delay and ensure that all women receive equal access to health services. / xii, 106 leaves : ill. ; 28 cm.

In the treatment of early stage breast cancer, both mastectomy and lumpectomy followed by radiation therapy have been recognized as having similar survival rates. Increasingly, women are being given the opportunity to choose which of these surgical treatment options they wish to pursue. Decisions tend to be made rather quickly, and some women may later regret their treatment choice. In this study, an instrument (Breast Cancer Treatment Inventory (BCTI)) was developed that identified five primary sources of influence that affect women's breast cancer treatment decisions: cosmetic outcome, preparedness, physician's choice, short-term effects, and long-term effects. Items were generated and refined by oncology professionals and breast cancer survivors, followed by a pilot study conducted with members of a breast cancer support group. The resulting 28-item scale was completed by 139 early stage breast cancer patients. A series of oblique factor analyses yielded a five-factor solution with reliabilities ranging from .66 - .87. Content validity was enhanced by involving oncology experts and women with breast cancer in the item generation procedures. Use of the BCTI may assist women through a methodical and effective decision-making process. The BCTI may also be appropriate for research studiesinvolving the process and prediction of treatment selection since it meets requirements for ease of administration, brevity, reliability, and validity. / Department of Counseling Psychology and Guidance Services

There is no abstract available for this dissertation. / Department of Counseling Psychology and Guidance Services

Breast cancer is a leading cause of cancer death in Africa. Hsp90 has been identified as a target for anti-cancer treatments as its inhibition results in the disruption and ubiquitin–proteasome degradation of activated oncoproteins. Currently, there are no US Food and Drug Administration approved Hsp90 inhibitor drugs and existing Hsp90 inhibitors such as geldanamycin and novobiocin are hepatotoxic and display a low affinity for Hsp90, respectively. Therefore, there is a need for the development of Hsp90 inhibitors with improved inhibitory properties. In this study twelve natural compounds bearing a quinone nucleus were screened and characterised for the modulation of Hsp90. The compounds analysed formed three series; the sargaquinoic acid (SQA), naphthoquinone, and pyrroloiminoquinone alkaloid series. Certain compounds exhibited half maximal inhibitory concentrations of between 3.32 μM and 12.4 μM, while others showed no antiproliferative activity at concentrations of up to 500 μM in the MDA-MB-231 breast adenocarcinoma cell line. Immunofluorescence and Western analyses indicated that the modulation of Hsp90 and partner proteins by SQA was more similar to that of novobiocin. Isothermal titration calorimetry analyses suggested that SQA interacted with Hsp90β with a low affinity, and saturation-transfer difference nuclear magnetic resonance confirmed that this interaction with Hsp90β occurred through the methyl moiety bound to 1, 4 benzoquinone of SQA. Pulldown assays indicated SQA disrupted the association between Hsp90 and Hop dose-dependently, more similarly to novobiocin. Immunofluorescence and Western analyses performed on naphthoquinone and pyrroloiminoquinone alkaloid compounds indicated modulation of Hsp90 and Hsp90 partner proteins by the compounds. Naphthoquinone compounds were prioritised for analysis for binding to Hsp90β over the pyrroloiminoquinone alkaloid compounds. Lapachol interacted with Hsp90β with a low affinity however; this interaction was thought to be too weak to disrupt the association of Hsp90 and Hop. The remaining naphthoquinone compounds showed no interaction with Hsp90β, thus allowing the determination of a preliminary structure-activity relationship for these compounds. To the best of our knowledge, this is the first study to describe a systematic subcellular analysis of the effects of geldanamycin and novobiocin in comparison to sargaquinoic acid and compounds of the naphthoquinone and pyrroloquinoline scaffold on Hsp90 and its partner proteins. / Microsoft� Word 2010 / Adobe Acrobat 9.54 Paper Capture Plug-in