Medicine and Health Sciences Commons^™

Investigating Cellular Imaging Techniques For Cancer Cell Tracking, Natasha Knier

Electronic Thesis and Dissertation Repository

Introduction: Breast cancer remains a leading cause of mortality among women due to the propensity of breast tumours to spread and metastasize to distant sites, including the brain. Early detection of metastatic disease has been challenging, and typical methods of treatment often fail. A significant roadblock in advancing the detection and treatment of breast cancer brain metastases is the lack of representative experimental preclinical models and methods of studying its progression in vivo. Methods: First, we use iron-based cellular MRI to noninvasively track the progression of a brain metastatic breast cancer cell line in murine models with varying immune …

Clinical And Genetic Predictors Of Aromatase Inhibitor-Induced Arthralgia, Adrienne Elizabeth Borrie

Electronic Thesis and Dissertation Repository

Aromatase inhibitors (AIs) are the most commonly used first-line endocrine treatment for postmenopausal women with estrogen receptor-positive breast cancer. Significant adverse drug reactions are associated with AIs, the most common being arthralgia. We hypothesized that a comprehensive assessment of pharmacogenetic and clinical variables that affect AI tolerability could improve AI selection and treatment for breast cancer patients. We recruited 196 patients diagnosed with breast cancer initiating AI therapy at the London Regional Cancer Program. Patients completed questionnaires regarding arthralgia symptoms and provided blood samples at baseline, 2 months and 6 months after AI initiation. Plasma letrozole drug concentration was measured …

Mt1-Mmp Mediates The Migratory And Tumourigenic Potential Of Breast Cancer Cells Via Non-Proteolytic Mechanisms, Mario Cepeda

Electronic Thesis and Dissertation Repository

Membrane Type-1 Matrix Metalloproteinase (MT1-MMP) is a multifunctional protease that affects cell function via proteolytic and non-proteolytic mechanisms such as promoting degradation of the extracellular matrix (ECM) or augmentation of cell migration and viability, respectively. MT1-MMP has been implicated in metastatic progression ostensibly due to its ability to degrade ECM components and to allow migration of cells through the basement membrane. Despite in vitro studies demonstrating this principle, this knowledge has not translated into the use of MMP inhibitors (MMPi) that inhibit substrate catalysis as effective cancer therapeutics, or been corroborated by evidence of in vivo ECM degradation mediated by …

Characterizing The Role Of The Neuropeptide Y-Y5r System In Breast Cancer, Jenna Kara

Electronic Thesis and Dissertation Repository

Studies have demonstrated a correlation between stress and an increased risk of breast cancer. Neuropeptide Y (NPY) is up- regulated in chronic stress and induces proliferation and chemotaxis of 4T1 breast cancer cells via Y5 receptor (Y5R) activation. In the studies performed in this thesis, we characterize NPY-Y5R as a regulatory system that promotes breast cancer metastasis. We compared three cancer cell sublines derived from the same murine mammary fat pad tumour, that greatly differ in metastatic potential (67NR, 168FARN, and 4T1) in addition to a 4T1-Y5R knockdown established in our labs. In this thesis we demonstrate significance of up-regulation …

Magnetic Resonance Imaging Of Breast Cancer Brain Metastasis Progression And Responses To Radiotherapy, Donna H. Murrell

Electronic Thesis and Dissertation Repository

Introduction: The incidence of brain metastasis due to breast cancer is increasing and prognosis is poor. Treatment is challenging for this disease because systemic therapy has limited efficacy due to the presence of the blood-brain barrier. In addition, it is thought that disseminated dormant cancer cells persist in metastatic organs and may evade treatment, thereby facilitating a mechanism for later recurrence. Methods: In this thesis, we use contrast-enhanced MRI and high resolution anatomical MRI to characterize blood-brain barrier integrity associated with the development of brain metastases due to HER2+ breast cancer in the SUM-190-BR3, JIMT-1-BR3, and MDA-MB-231-BR-HER2 experimental models. We …

Characterization Of Microbial Communities In The Mammary Glands And The Influence Of This Microbiota On Health And Disease, Camilla Urbaniak

Electronic Thesis and Dissertation Repository

The collective microbes and their genomic activity within us, referred to as the human microbiome, is crucial in maintaining health, and disruptions in composition and activity have been associated with various diseases. Considering the importance of breast milk in neonatal development and the high rate of breast cancer in women, the objective of my thesis was to obtain a comprehensive analysis of the microbiota of the mammary glands and to examine the influence of these organisms on health and disease.

Human milk is an important source of bacteria for the developing infant. While a variety of studies over the last …

Interpretation Of Mutations, Expression, Copy Number In Somatic Breast Cancer: Implications For Metastasis And Chemotherapy, Stephanie Dorman

Electronic Thesis and Dissertation Repository

Breast cancer (BC) patient management has been transformed over the last two decades due to the development and application of genome-wide technologies. The vast amounts of data generated by these assays, however, create new challenges for accurate and comprehensive analysis and interpretation. This thesis describes novel methods for fluorescence in-situ hybridization (FISH), array comparative genomic hybridization (aCGH), and next generation DNA- and RNA-sequencing, to improve upon current approaches used for these technologies. An ab initio algorithm was implemented to identify genomic intervals of single copy and highly divergent repetitive sequences that were applied to FISH and aCGH probe design. FISH …

The Role Of Cytoplasmic Polyadenylation Element Binding Protein-2 (Cpeb-2) In Breast Cancer, Asma Hasan

Electronic Thesis and Dissertation Repository

Over-expression of inflammation associated enzyme cyclo-oxygenase (COX)-2 promotes breast cancer progression, metastasis and sustains cancer stem-like cells (SLCs) by activating prostaglandin E₂ receptor EP4. Two COX-2 induced oncogenic miRNAs, miR-655 and miR-526b, target and down-regulate the cytoplasmic polyadenylation element binding protein (CPEB)-2. Hypothesis: Down-regulation of CPEB2 promotes an aggressive breast cancer phenotype through SLC induction and epithelial to mesenchymal transition (EMT). We found that high COX-2/miRNA expressing cell lines MDAMB231 and MCF7-COX-2 had significantly lower expression of CPEB2 than MCF7 cells (low COX-2/miRNA). CPEB2 knockdown in CPEB2-high MCF7 cell line resulted in increased migratory and invasive capacity in …

The Role Of Bone-Derived Osteopontin In The Migration And Stem-Like Behavior Of Breast Cancer Cells, Graciella Pio

Electronic Thesis and Dissertation Repository

The majority of breast cancer deaths occur due to metastasis, with the most common site of breast cancer metastasis being bone. Previous work in our laboratory has established that stem-like breast cancer cells with high aldehyde dehydrogenase (ALDH) activity and expression of a CD44⁺CD24^- phenotype have enhanced metastatic capacity. This study tested the hypothesis that bone-derived osteopontin (OPN) promotes the migration and stem-like behavior of breast cancer cells. We demonstrate that bone- derived OPN promotes migration, tumorsphere-forming ability and colony-forming ability of whole population and ALDH^hiCD44⁺CD24^- breast cancer cells in bone marrow- …