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Western University

2018

Breast cancer

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Brca1 And Brca2 5′ Noncoding Region Variants Identified In Breast Cancer Patients Alter Promoter Activity And Protein Binding, Leslie J. Burke, Jan Sevcik, Gaetana Gambino, Emma Tudini, Eliseos J. Mucaki, Ben C. Shirley, Phillip Whiley, Michael T. Parsons, Kim De Leeneer, Sara Gutiérrez-Enríquez, Marta Santamariña, Sandrine M. Caputo, Elizabeth Santana Dos Santos, Jana Soukupova, Marketa Janatova, Petra Zemankova, Klara Lhotova, Lenka Stolarova, Mariana Borecka, Alejandro Moles-Fernández, Siranoush Manoukian, Bernardo Bonanni, Stacey L. Edwards, Marinus J. Blok, Thomas Van Overeem Hansen, Maria Rossing, Orland Diez, Ana Vega, Kathleen B.M. Claes, David E. Goldgar, Etienne Rouleau Dec 2018

Brca1 And Brca2 5′ Noncoding Region Variants Identified In Breast Cancer Patients Alter Promoter Activity And Protein Binding, Leslie J. Burke, Jan Sevcik, Gaetana Gambino, Emma Tudini, Eliseos J. Mucaki, Ben C. Shirley, Phillip Whiley, Michael T. Parsons, Kim De Leeneer, Sara Gutiérrez-Enríquez, Marta Santamariña, Sandrine M. Caputo, Elizabeth Santana Dos Santos, Jana Soukupova, Marketa Janatova, Petra Zemankova, Klara Lhotova, Lenka Stolarova, Mariana Borecka, Alejandro Moles-Fernández, Siranoush Manoukian, Bernardo Bonanni, Stacey L. Edwards, Marinus J. Blok, Thomas Van Overeem Hansen, Maria Rossing, Orland Diez, Ana Vega, Kathleen B.M. Claes, David E. Goldgar, Etienne Rouleau

Biochemistry Publications

© 2018 The Authors. Human Mutation published by Wiley Periodicals, Inc. The widespread use of next generation sequencing for clinical testing is detecting an escalating number of variants in noncoding regions of the genome. The clinical significance of the majority of these variants is currently unknown, which presents a significant clinical challenge. We have screened over 6,000 early-onset and/or familial breast cancer (BC) cases collected by the ENIGMA consortium for sequence variants in the 5′ noncoding regions of BC susceptibility genes BRCA1 and BRCA2, and identified 141 rare variants with global minor allele frequency < 0.01, 76 of which have not been reported previously. Bioinformatic analysis identified a set of 21 variants most likely to impact transcriptional regulation, and luciferase reporter assays detected altered promoter activity for four of these variants. Electrophoretic mobility shift assays demonstrated that three of these altered the binding of proteins to the respective BRCA1 or BRCA2 promoter regions, including NFYA binding to BRCA1:c.-287C>T and PAX5 binding to BRCA2:c.-296C …

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In Vivo Tracking Of Tumour Associated Macrophages In Breast Cancer With Magnetic Resonance Imaging, Ashley V. Makela Nov 2018

In Vivo Tracking Of Tumour Associated Macrophages In Breast Cancer With Magnetic Resonance Imaging, Ashley V. Makela

Electronic Thesis and Dissertation Repository

Introduction: The environment in which a tumour exists and functions is called the tumour microenvironment (TME). In breast cancer, the presence of tumour associated macrophages (TAMs) in the TME is associated with tumour aggressiveness and poor outcomes. Despite evidence for a link between TAM content and outcome, there are few strategies to measure TAMs and no in vivo approach. Iron or fluorine-19 (19F)-based MRI can be used to detect macrophages post intravenous injection of either an iron or perfluorocarbon (PFC) agent. Iron-based MRI is sensitive but difficult to quantify. 19F MRI is specific and signal is proportional …

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Lung-Derived Selectins Interact With Cd44 And Enhance The Migration Of Breast Cancer Cells, Sami U. Khan Oct 2018

Lung-Derived Selectins Interact With Cd44 And Enhance The Migration Of Breast Cancer Cells, Sami U. Khan

Electronic Thesis and Dissertation Repository

The lung is among the deadliest sites of breast cancer metastasis. Previous work from our laboratory demonstrated that aggressive CD44-expressing breast cancer cells preferentially metastasize to the lung in vivo, and observed the presence of multiple CD44-interacting proteins in the lung including E-, L- and P-selectin. We hypothesized that lung-derived selectins promote breast cancer migration and/or growth via interactions with CD44. Using an ex vivo model of the soluble lung-microenvironment, we demonstrate that lung-derived selectins enhance in vitro migration but not proliferation of breast cancer cells. Co-immunoprecipitation experiments reveal that CD44 expressed by breast cancer cells in vitro interacts …

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Space-Time Analysis Of Breast Cancer In Middlesex County Between 2003 And 2013, Jenny T. Tjhin Sep 2018

Space-Time Analysis Of Breast Cancer In Middlesex County Between 2003 And 2013, Jenny T. Tjhin

Electronic Thesis and Dissertation Repository

Breast cancer is the leading cancer among women in Canada and the incidence rate continues to increase despite improved screening programs and advanced cancer treatments. Some studies have linked breast cancer with risk factors such as genetics, the age of first menstruation, parity, and environmental exposures. This study investigated the spatial distribution of breast cancer cases between 2003 and 2013 in Middlesex County using geospatial techniques. Point data were analyzed with SaTScan and aggregated data were observed at two geographical units, census sub-divisions and dissemination areas using Moran’s Index to detect clusters. Both analyses showed consistency in the cluster locations …

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Clinical And Genetic Predictors Of Aromatase Inhibitor-Induced Arthralgia, Adrienne Elizabeth Borrie Jul 2018

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 …

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Proteomic Characterization Of Ovarian And Breast Cancer Microenvironments For Improved Diagnostics And Therapeutic Targeting, Dylan Z. Dieters-Castator Jun 2018

Proteomic Characterization Of Ovarian And Breast Cancer Microenvironments For Improved Diagnostics And Therapeutic Targeting, Dylan Z. Dieters-Castator

Electronic Thesis and Dissertation Repository

Cancers exist within complex microenvironments formed by heterogeneous cell types. This diversity creates significant challenges for detection, diagnosis and treatment. Mass spectrometry-based proteomics is a powerful approach capable of characterizing complex biological systems which are characteristic of cancer biology. In this thesis, proteomics was utilized to answer several questions related to ovarian cancer diagnosis and detection, and the effects of NODAL, an embryonic morphogen, on the breast cancer secretome and stromal cell recruitment. First, I compared multiple sample preparation techniques and found high-pH/low-pH fractionation to yield the greatest proteome coverage over commonly used approaches. Second, I compared the proteomes from …

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Half Brain Irradiation In A Murine Model Of Breast Cancer Brain Metastasis: Magnetic Resonance Imaging And Histological Assessments Of Dose-Response, Niloufar Zarghami, Donna H. Murrell, Michael D. Jensen, Frederick A. Dick, Ann F. Chambers, Paula J. Foster, Eugene Wong Jun 2018

Half Brain Irradiation In A Murine Model Of Breast Cancer Brain Metastasis: Magnetic Resonance Imaging And Histological Assessments Of Dose-Response, Niloufar Zarghami, Donna H. Murrell, Michael D. Jensen, Frederick A. Dick, Ann F. Chambers, Paula J. Foster, Eugene Wong

Paediatrics Publications

Background: Brain metastasis is becoming increasingly prevalent in breast cancer due to improved extra-cranial disease control. With emerging availability of modern image-guided radiation platforms, mouse models of brain metastases and small animal magnetic resonance imaging (MRI), we examined brain metastases' responses from radiotherapy in the pre-clinical setting. In this study, we employed half brain irradiation to reduce inter-subject variability in metastases dose-response evaluations. Methods: Half brain irradiation was performed on a micro-CT/RT system in a human breast cancer (MDA-MB-231-BR) brain metastasis mouse model. Radiation induced DNA double stranded breaks in tumors and normal mouse brain tissue were quantified using γ-H2AX …

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Oncoplastic Surgery: Is It Time To Change? From Innovation To Adoption Using Mentorship Program, Eman Khayat Apr 2018

Oncoplastic Surgery: Is It Time To Change? From Innovation To Adoption Using Mentorship Program, Eman Khayat

Electronic Thesis and Dissertation Repository

Oncoplastic surgery is considered the standard of care for breast cancer therapy in numerous Western World countries, particularly in Europe. Despite the advancement of knowledge, Canada still lags in adoption of oncoplasty into the standard surgical practice. In our study, a mentorship program was used to introduce oncoplastic surgery to practicing breast surgeons at LHSC. The change in perception and adoption of oncoplastic surgery were evaluated using semi-structured interviews, before and after the intervention, by qualitative thematic analysis method. Mentorship program was validated as a superior method of learning new surgical techniques by practicing surgeons, demonstrating acceptance of different levels …

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Influence Of The Metastatic Microenvironment On Stem-Like Human Breast Cancer Cells, Ashkan Sadri Jan 2018

Influence Of The Metastatic Microenvironment On Stem-Like Human Breast Cancer Cells, Ashkan Sadri

Electronic Thesis and Dissertation Repository

Ninety percent of breast cancer-related mortalities result from metastasis. We have previously demonstrated that stem-like ALDHhiCD44+ breast cancer cells are critical for metastasis, and preferentially target the lung and bone marrow (BM). We hypothesize organ tropism occurs through promotion of the ALDHhiCD44+ phenotype. Using a 2D ex vivo model, lung and BM conditioned media (CM) were utilized to assess their influence on stem-like phenotype and behavior. Exposure of human breast cancer cells to lung-CM significantly decreased the proportion of cells with a stem-like ALDHhiCD44+ phenotype, decreased expression of cancer stem cell (CSC)-related genes, and increased gene expression related to migration …

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