Oncolytic viruses (OV) are a promising alternative cancer therapy due to their specificity and lack of debilitating side effects, such as those which typically accompany conventional therapeutics such as chemotherapy and radiation. Bovine herpesvirus type 1 (BHV-1) is an alphaherpesvirus with the ability to infect and kill multiple human tumor cell types. In comparison to other species-specific viruses, for which deficiencies in type I interferon signalling pathways dictates cellular sensitivity to infection, mutations in KRAS were found to correlate with high levels of BHV-1 replication. Interestingly, BHV-1 is able to induce cellular cytotoxicity in the absence of a productive infection. In contrast to current breast cancer (BC) treatments, which are largely based on receptor expression status, BHV-1 is able to infect and kill BC cells and breast cancer initiating cells (BCICs) from luminal and basal subtypes. Furthermore, BHV-1-infected BC cells are significantly diminished in their capacity to form tumors in vivo, suggesting that BHV-1 reduces the tumor forming capacity of BCICs. Combination therapy involving OVs has been used to exploit differences in the mechanism of tumor cell death elicited by individual treatments. Treatment with epigenetic modifiers such as 5-Azacytidine (5-Aza), a DNA methyltransferase inhibitor, has been shown to increase the antitumor activity of OVs. Our data indicates that 5-Aza strongly synergises with BHV-1, increasing virus replication and cytotoxicity in vitro. In vivo, BHV-1 monotherapy did not significantly impact tumor growth or survival of CR bearing subcutaneous breast tumors; however, combination therapy with 5-Aza significantly decreased the number of secondary lesions compared to BHV-1 monotherapy. Overall, the data presented in this dissertation indicate that BHV-1 is a promising broad spectrum OV with a unique mechanism of tumor cell targeting, and the ability to infect and kill tumor cells independent of a productive infection. / Thesis / Doctor of Philosophy (Medical Science)

Background: There is uncertainty about the lifetime risk of contralateral breast cancer (CBC) in a woman who is diagnosed with early stage breast cancer. Studies report a wide range of rates of CBC between 2% and 35%. Objectives: (i) To determine the risk of CBC in women with early stage breast cancer, and (ii) to evaluate the risk of CBC in women who undergo adjuvant systemic treatment and adjuvant radiation treatment. Methods: PubMed, Ovid MEDLINE, EMBASE, Healthstar, Cochrane Central Register for Controlled Trials were searched. Studies were included if participants had: unilateral invasive breast carcinoma; 5 years of median follow-up; a minimum of 100 participants. Randomized controlled trials were included for the meta-analysis. A random-effects meta-analysis was used to estimate the pooled rate of CBC. Results: 4571 articles were extracted out of which 22 randomized controlled trials were included in the final meta-analysis. The overall pooled rate of CBC was 0.36% per year, (95% CI, 0.32% - 0.41%). The rate of CBC in studies without adjuvant systemic treatment was higher than the rate without such treatment, 0.56% per year (95% CI, 0.40% to 0.77%) versus 0.35% per year (95% CI, 0.31% to 0.40%). The rate of CBC in studies with adjuvant radiation treatment was 0.26% per year (95% CI, 0.18% to 0.39%) which is similar to the rate in studies with radiation. Conclusions: The rate of CBC in women with early stage breast cancer is relatively low. This is important for breast cancer patients who are considering contralateral prophylactic mastectomy. / Thesis / Master of Science (MS) / The rate of contralateral breast cancer in women with early stage breast cancer is uncertain. In order to determine this rate, a systematic review and meta analysis was conducted. The rate of contralateral breast cancer in women with early stage breast cancer was found to be 0.36% per year. This rate appears to be constant for up to 10 years after the original breast cancer diagnosis. This data is important for women with breast cancer and their healthcare teams in order to make decisions about bilateral mastectomy.

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Background Preclinical data suggests that metformin may have anti-cancer effects to reduce breast cancer incidence and improve cancer prognosis. However, the current evidence in observational studies is inconclusive. A systematic review and meta-analysis was conducted to assess the effect of metformin on the incidence and mortality of breast cancer in diabetic patients. Methods A comprehensive literature search was performed on Medline (Pubmed), EMBASE, and the Cochrane library from inception to November 2016 with no language restrictions. Outcomes were incidence of breast cancer and all-cause mortality. Risk of bias and overall quality of evidence was assessed using the Newcastle Ottawa Scale and GRADE respectively. A meta-analysis was performed using the most adjusted odds ratios (ORs) or hazard ratios (HRs) and 95% confidence intervals (95% CI) as effect measures. Results A total of 12 observational studies were included for breast cancer incidence and 11 studies for all-cause mortality. No significant association was found between metformin exposure and incidence of breast cancer (OR: 0.93, 95% CI: 0.85-1.03, I2 = 35%). A 45% risk reduction was observed for all-cause mortality (HR: 0.55, 95%CI: 0.44-0.70, I2=81%). Presence of publication bias is strongly suspected for both outcomes. Conclusion The use of metformin in standard cancer therapy may improve overall survival of diabetic patients with breast cancer. No effect of metformin on the incidence of breast cancer was observed. Interpretation of results is limited by the observational nature of the studies and methodological biases. Clinical trials are warranted to determine the role of metformin in breast cancer risk reduction and prognosis. / Thesis / Master of Health Sciences (MSc)

Breast Cancer (BC) is the leading cause of cancer related deaths among women worldwide. Its etiology includes inactivation of tumor suppressors. In line with this notion, our laboratory has recently reported that CYB5D2 possesses tumor suppressing activities in cervical cancer; evidence also suggests CYB5D2 as a novel tumor suppressor of BC. I thus hypothesize that CYB5D2 mitigates cell propagation in vitro. To examine this possibility, I transiently expressed CYB5D2 in two typical BC subtype cell lines, HCC 1954 (HER2+) and MCF7 (Luminal A). Remarkably, cell population was diminished over a period of at least five days post-transfection when compared to empty vector (EV). To characterize CYB5D2-derived inhibition of BC cell proliferation, I generated a Tet-On inducible system in both cell lines in which CYB5D2 expression is induced upon addition of doxycycline. As expected, induction of CYB5D2 led to a decline of cell propagation and colony formation based on cell proliferation and colony formation assays respectively. Moreover, knockdown of CYB5D2 via lentivirus-based shCYB5D2 transfection in HCC 1954 and MCF7 cells resulted in an incline of cell propagation and colony formation when compared to the shCTRL (control) line. To examine possible apoptotic mechanism of tumor suppressor, we performed TUNEL assay analysis in cell lines expressing CYB5D2. Both HCC 1954 and MCF7 obtained similar results exhibiting evidence of apoptotic cells when compared to their respective controls. Interestingly, upon CYB5D2 expression HCC 1954 also displayed evidence of halting G1 phase progression when performing cell cycle analysis, suggesting a promising alternate tumor suppressing mechanism. Lastly, to corroborate with previous observations of an existing molecular interaction between CYB5D2 and tumor suppressor Phosphatase and tensin homolog (PTEN) we performed a Co-Immunoprecipitation (Co-Ip) assay. As expected, endogenous CYB5D2 and PTEN lysate from HCC 1954 and MCF7 were demonstrated to interact on a molecular level. These observations support the notion that CYB5D2 elicits tumor-suppressing activities in both Her2+ and Luminal A breast cancer cell lines. It is important to note that we detected a greater tumor suppressing impact of CYB5D2 in HCC 1954 when compared to MCF7 suggesting a potential mechanism to favour HER2+ status. Additional research in determining potential tumor-suppressing pathway of CYB5D2 in BC is encouraged as we established promising insight of novel tumor suppressor. / Thesis / Master of Health Sciences (MSc)

Breast cancer is the second leading cause of cancer-related death in women worldwide. Despite more frequent and efficient screening measures, subtype-specific treatments, and overall improved patient outcomes, metastasis remains difficult to treat and accounts for 90% of breast cancer patient deaths. While the role of intercellular communication in metastasis, either among cancer cells, or between cancer cells and the tumor microenvironment is well established, additional research on specific molecular and cellular mechanisms underlying these interactions is necessary to develop novel therapeutic strategies. One mechanism that facilitates metastasis is epithelial-mesenchymal transition (EMT), which can be induced in cancer cells following the secretion of growth factors by tumor-associated macrophages (TAMs). During EMT, epithelial cells lose their cell-cell junctions, resulting in an alteration of intercellular communication. One of the junctions lost during EMT is gap junctions composed of connexin43 (Cx43), however, this is paired with an increase in expression of cytoplasmic Cx43 which binds microtubules. To elucidate the role of cytoplasmic Cx43 during EMT and breast cancer metastasis, we utilize a Cx43 mutant that has reduced binding with microtubules. We demonstrate disruption of the interaction between Cx43 and microtubules decreases mesenchymal marker expression and cell migration in vitro during EMT, and reduces breast cancer metastasis to the lungs in vivo, identifying a novel non-junctional tumorigenic role for Cx43 in metastasis and a potential therapeutic target in the treatment of breast cancer. / Doctor of Philosophy / Cancer, which is caused by the uncontrolled growth of abnormal cells, remains one of the top causes for death worldwide. Breast cancer, in particular, is the second leading cause of cancer deaths in women in the United States. With advances in screening and improved/subtype specific treatments, patient outcomes have significantly improved for localized tumors. However, the spread of cancer from the primary tumor to a distal part of the body, called metastasis, remains difficult to treat and accounts for approximately 90% of cancer-related deaths. One mechanism known to facilitate metastasis is a cellular process called epithelial-mesenchymal transition (EMT). During EMT, epithelial cells lose their cell-cell junctions and apical-basal polarity, and gain mesenchymal characteristics, becoming more motile and invasive. These characteristics facilitate the invasion of cancer cells into tissue surrounding the primary tumor as well as entry into the bloodstream and exit at a distal site, subsequently forming a secondary tumor (metastasis). In tumors, EMT is often induced through communication between cancer cells and cancer-promoting immune cells such as tumor-associated macrophages. One of the cell-cell junctions lost during EMT are connexin43 gap junctions, which are channels that facilitate the transfer of small molecules between cells, promoting communication. We utilize mammalian cell lines and a mouse breast cancer model to investigate the role of connexin43 in EMT and breast cancer metastasis. This work provides information that can be used to develop new therapeutics and strategies for the treatment or prevention of breast cancer metastasis.

Breast cancer is the most common cancer and the second most common cause of cancer death in women. In 2008 there were 182,460 women diagnosed with breast cancer, and 40,480 women died of this disease. Breast cancer can be prevented by medical (tamoxifen or raloxifene) or surgical approaches (bilateral mastectomy or oophorectomy). Prevention is only recommended for women at high risk for developing breast cancer; therefore, proper risk calculation is essential in identifying women that may benefit from prevention measures. There is an easy-to-use and easily accessible risk calculation tool for determining a woman's risk of developing breast cancer and need for referral for counseling, gene testing, and possibly preventive therapy. This article reviews the components of risk assessment, the most frequently used risk calculation tool, and approaches to breast cancer risk reduction including medical and surgical therapies. The use of these therapies results in a risk reduction of 50-90%.

Treatment outcomes of young patients with invasive breast cancer treated radically at Groote Schuur Hospital from 2013 to 2017: A single centre study Background: Breast cancer is the leading cause of cancer- related deaths globally, and the commonest cancer in women under 40 years. There is currently a lack of data relating to treatment outcomes of young women with breast cancer particularly in low-and middle-income countries. Aim: This study aims to evaluate the treatment outcomes of young patients (under 40 years) treated radically for invasive breast cancer in a low-and middle-income setting. Settings: Groote Schuur Hospital, Cape Town, South Africa Methods: A retrospective review of 101 women under 40 years, with invasive breast cancer treated radically, between 2013 and 2017 was conducted. Patient characteristics, tumour characteristics, disease stage, treatment, and follow-up were recorded. Primary objectives included evaluating overall and disease free survival, and analysing recurrence patterns and clinicopathological features. Results: The five-year overall and disease free survival for the entire cohort was 77% and 51%, respectively. Five-year overall survival by molecular subtype showed that Luminal A had the best survival, while triple negative breast cancer had the worst overall survival. Conclusion: Young women with breast cancer have poor survival outcomes despite early presentation. There is limited data regarding breast cancer treatment outcomes in patients under forty years.

M.A. / The aim of this study was to ascertain the coping methods of women in long term follow-up of breast cancer treatment. Furthermore, personality traits that deal with the spectrum of positive affectivity were introduced to determine whether these impact on women's appraisal of their situation and their subsequent choice of coping mechanism. Thus, a process approach to exploring coping strategies and a goal-attainment conceptualization of hope were used to determine whether hope is associated with coping appraisal in the long term follow-up of breast cancer treatment. Furthermore, high hope women were expected to use more problem focused coping methods and low hope women were expected to use more emotion focused coping skills. Women in cancer remission who attend yearly or six-monthly check-ups at the Johannesburg hospital were approached to complete the questionnaire and brief interview. Although the study did not confirm that low hope and high hope women use different kinds of coping strategies, the predicted relationship between hope and challenge appraisals was supported by significant correlations. However, it was found that hope may be analogous to positive affect, thus indicating the need for further validation of the Hope Scale. Finally, it was concluded that breast cancer need not be seen as a devitalising disease and that there are a variety of coping strategies which can be utilized to enhance patient's positive emotional state. The women in this study use the emotion focused coping skill of positive reappraisal which concentrates on the possibilities for mastery and growth that inhere in their long term follow-up treatment. Moreover, women are extremely positive and hopeful in their daily outlook and while this personality trait seems to suggest that denial is at play, it is more likely that women in long term remission have a strong belief in their own personal qualities and future. Women in this study choose to distance themselves from the implicit trauma of the threat of recurrence in favour of an active belief in their personal resilience to overcome any stressful event or outcome.