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<p>Ionizing radiation is used to screen for, diagnose, and treat breast cancer. Noncancerous breast cells are exposed to a range of doses as a result of these procedures in addition to the low levels of natural background radiation that they are always exposed to. With the consistent increase in medical radiation procedures, and the climbing rates of breast cancer in most populations, understanding the effects of these exposures is of interest and importance. Radiation exposure results in DNA double strand breaks which can trigger various cellular responses including cell cycle arrest, and cell death. Apoptosis is a form of highly regulated cell death that is controlled by the Bcl-2 family of proteins. Bcl-2 and Bcl-XL are anti-apoptotic proteins that are commonly overexpressed in human cancers including breast cancer. This thesis was focused on investigating the effects of Bcl-2 and Bcl-XL expression on the radiation response of human mammary epithelial cells. Bcl-2 and Bcl-XL were exogenously expressed in MCF-10A cells, and Bcl-XL expression was knocked down. Cytogenetic techniques were used to characterize the MCF-10A cells used. Automated image based assays were used to validate the anti-apoptotic effects of the exogenous proteins against known apoptotic stimuli, and to probe the effects of radiation exposure. The influence of Bcl-2 and Bcl-XL expression on the immediate and short term effects of radiation exposure was investigated using cell growth assays, flow cytometry, and</p> / Doctor of Philosophy (PhD)

Ultra-wideband microwave imaging, with its advantages of absence of breast compression, nonionizing and noninvasive properties, is a complementary method to X-ray mammography for breast cancer detection that is safe and reasonably inexpensive. The motivation for employing microwave imaging techniques for detecting early-stage breast cancer stems from published research results showing the strong contrast in the dielectric properties at microwave frequencies between normal breast tissue and malignant lesion. This thesis contributes to development of novel techniques for the detection of early-stage breast cancer tumors well below a centimeter with specificity and high degree of accuracy, i.e., with minimum false negatives/positives. In our proposed approach, a modified Shannon entropy criterion (SEC) is formulated for determining when the time-reversed wave focuses back to the source target in the presence of an inhomogeneous lossy medium. It is demonstrated through two examples, the time-reversal mirror and cavity, that the SEC is found to be more robust than the inverse varimax norm. TR has been shown to be superior to other simple delay-based focusing techniques and here we have extended the TR algorithm by making it more robust in localizing small tumors. The importance of this finding becomes evident as the SEC allows for the detection of tumors that are sub-wavelength in size. Our novel sub-wavelength ultra-wide band (UWB) microwave radar imaging technique exploits the principle of phase-shifting mask (PSM) from optical lithography and is implemented using a time-reversal (TR) algorithm based on the transmission-line matrix (TLM) method. We incorporate the SEC in a TR algorithm to achieve a robust imaging algorithm exploiting the measurements acquired by our phase-shifting mask (PSM) experimental set-up. Unlike the FDTD TR algorithm by Kosmas et al., which excites one of the 23 antenna elements, we propose a different system where all antennas are stimulated simultaneously with their excitation based on the PSM principle. A 0.5-mm diameter tumor was detected and located using a 200-ps UWB pulse in a realistic inhomogeneous two dimensional breast model. The breast model was derived from magnetic resonance imaging data and simulated using the TLM method. The effect of the dielectric contrast and proximity of tumor to the antenna receivers are examined. A TLM-based TR algorithm employing two types of time reversal mirrors (TRMs) is proposed to improve the accuracy of localizing the sub-wavelength tumors. The final part of the thesis examines the feasibility and the design of a narrowbeam UWB antenna for microwave breast cancer detection focusing on the antenna feed structure and the printed TEM horn antenna. A feed structure of an UWB antenna for microwave radar imaging is designed. The UWB antennas are fundamental components of the UWB radar imaging hardware. The performance of the antenna is crucial for the resolution and the reliability of the whole imaging system. A TEM horn antenna is studied and suggestions are made regarding the hardware implementations of the experimental setup. We conclude by suggesting future work toward hardware and practical implementation of UWB microwave radar imaging with high resolution. / Thesis / Master of Applied Science (MASc)

Breast cancer (BC) is a complex disease with over 25,000 new diagnoses made in Canadian women every year. The disease can be caused by inactivation of the ataxia telangiectasia mutated (ATM) pathway, a major anti-tumor mechanism that protects against the abnormal cell division and growth that occurs in breast cancer, but how the pathway is inactivated has yet to be completely elucidated. BMI1 is an established oncogene that is overexpressed in BC and is associated with poor disease prognosis. BMI1 is a component of the polycomb repressive complex 1 (PRC1) that acts to repress transcription of the ARF/INK4A locus encoding two important tumor suppressor genes. We have recently shown a novel property of BMI1 in attenuation of ATM function independent of this locus. We thus hypothesize a role of BMI1 in promoting BC formation through inhibiting oncogene-induced ATM activation, allowing cancer-promoting genes to induce abnormal cellular growth. To examine this hypothesis, we transiently expressed oncogene c-Myc with or without BMI1 co-expression. As expected, ectopic c-Myc expression upregulated γH2AX, a demonstrated target of ATM; concurrent BMI1 expression reduced the γH2AX levels. Similar observations were also obtained using a BMI1 mutant deficient in promoting PRC1-mediated repression of the ARF/INK4A locus. These observations support the concept that BMI1 contributes to ATM inactivation during BC tumorigenesis through mechanisms independent of PRC1. To further examine this concept, we investigated the association of γH2AX and BMI1 in vivo. In MCF7 cell-produced xenograft tumors, the presence of γH2AX nuclear foci was clearly observed, indicative of ATM activation during BC tumorigenesis. In xenografts generated by MCF7 cells stably expressing BMI1, a trend of reduction in γH2AX nuclear foci was observed. To further model BMI1’s pathological relevance in c-Myc induced BC under a more physiological setting, we are developing transgenic mouse models (GEM) with breast-specific c-Myc expression with or without a breast-specific BMI1 knockout. The goal of these experiments is to recapitulate the above in vitro and in vivo observations. The expectation, should it be achieved, will significantly strengthen the connection between BMI1 and ATM during breast cancer tumorigenesis. / Thesis / Master of Science (MSc) / Breast cancer (BC) is a complex disease with over 25,000 new diagnoses made in Canadian women every year. Normally there are anti-tumor mechanisms in place to protect against the abnormal cell division and growth that is associated with breast cancer. We propose a novel function of protein BMI1 to explain how breast cancer cells override these protective pathways. BMI1 is known to contribute to BC through inhibiting production of key tumor suppressing proteins and has recently been shown to decrease activity of the ataxia telangiectasia mutated (ATM)- mediated tumor inhibiting pathway. We propose a novel role of BMI1 in promoting breast tumor formation through inhibiting the ATM-mediated anti-tumor barrier, allowing cancer-promoting genes (oncogenes) to induce abnormal cellular growth. BMI1 was shown to be able to reduce oncogene induced ATM activity, in an action independent of established mechanisms. Additionally in MCF7 BC tumors, the presence of BMI resulted in a trend of reduction in ATM activity. Continued work to develop a transgenic mouse model with a breast specific BMI1 knockout will help further our understanding of BMI1’s role in BC tumorigenesis.

OBJECTIVES: During health guideline development, panel members often have implicit, different definitions of health outcomes that can lead to variability in evidence synthesis and recommendations. McMaster GRADE Centre researchers developed a standardized description of health outcomes using the health marker state format. We aimed to determine which aspects of the development, content, and use of marker states were valuable to guideline developers. STUDY DESIGN & SETTING: We conducted a case study of marker state development with the European Commission Initiative on Breast Cancer (ECIBC) Guidelines Development Group (GDG). Eighteen GDG members provided written and interview feedback on the process. Using the health marker states, 2 health utility rating surveys were conducted near the beginning and end of development respectively. RESULTS: We developed 24 marker states for outcomes related to breast cancer screening and diagnosis. Feedback from GDG members revealed that marker states could be useful for developing recommendations and improving transparency of guideline methods. Comparison of the two health utility surveys showed a decrease in standard deviation in the second survey across 21 (88%) of the outcomes. CONCLUSIONS: Health marker states are a promising method, satisfying the pre-requisite of being feasible, acceptable, and with some initial result on reduction of variance of health utility scores. / Thesis / Master of Public Health (MPH) / OBJECTIVES: During health guideline development, panel members often have implicit, different definitions of health outcomes that can lead to variability in evidence synthesis and recommendations. McMaster GRADE Centre researchers developed a standardized description of health outcomes using the health marker state format. We aimed to determine which aspects of the development, content, and use of marker states were valuable to guideline developers. STUDY DESIGN & SETTING: We conducted a case study of marker state development with the European Commission Initiative on Breast Cancer (ECIBC) Guidelines Development Group (GDG). Eighteen GDG members provided written and interview feedback on the process. Using the health marker states, 2 health utility rating surveys were conducted near the beginning and end of development respectively. RESULTS: We developed 24 marker states for outcomes related to breast cancer screening and diagnosis. Feedback from GDG members revealed that marker states could be useful for developing recommendations and improving transparency of guideline methods. Comparison of the two health utility surveys showed a decrease in standard deviation in the second survey across 21 (88%) of the outcomes. CONCLUSIONS: Health marker states are a promising method, satisfying the pre-requisite of being feasible, acceptable, and with some initial result on reduction of variance of health utility scores.

Objective: To evaluate whether abnormal concentrations in cardiac and inflammatory biomarkers could predict reductions in left ventricular ejection fraction (LVEF) for cancer patients undergoing curative treatment. Materials and Methods: Longitudinal testing was performed for high-sensitivity cardiac troponin I (hs-cTnI), N-terminal pro-B-type natriuretic peptide (NT-proBNP), heart-type fatty acid binding protein (H-FABP) and C-reactive protein (CRP) in HER2+ breast cancer (BC) patients receiving adjuvant trastuzumab treatment (n=22) and in lymphoma patients treated with radiotherapy (n=4). Sex-specific and overall upper limit of normal (ULN) cutoffs were used to identify abnormal results with a reduction in LVEF (<50% and decrease of ≥10% from baseline) indicative of cardiotoxicity. A secondary analysis was performed on the BC patients with normal LVEFs (n=12 with baseline prior to chemotherapy through to 6-months on trastuzumab) with 15 blood collections spaced between 6- and 254-days post-baseline LVEF measurement. Results: A majority of the BC patients had evidence of myocardial injury (hs-cTnI >female ULN=90%) or myocardial dysfunction (NT-proBNP >overall ULN=91%) at any timepoint with fewer patients having abnormal CRP or H-FABP concentrations (H-FABP >ULN=14%; CRP >ULN=45%). Myocardial injury and dysfunction were most evident during the first two cycles of trastuzumab treatment, with myocardial injury also evident during this early timeframe in the female lymphoma patients (3 with hs-cTnI >ULN). In the 12 patients who completed trastuzumab with normal LVEFs (median=60% at 6-months), myocardial injury (hs-cTnI >ULN) and dysfunction (NT-proBNP >ULN) was evident in >50% of patients. Four of the 22 patients did develop cardiotoxicity, but there was no difference in biomarker concentrations between patients with or without cardiotoxicity. Conclusion: The use of the recommended ULN cutoffs identified myocardial injury and dysfunction in a majority of cancer patients in this setting. Biomarker assessments did not relate to cardiac functional imaging studies. Future studies are warranted to assess different cutoffs or biomarker combinations for predicting cardiotoxicity. / Thesis / Master of Science (MSc)