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  • About
  • The Global ETD Search service is a free service for researchers to find electronic theses and dissertations. This service is provided by the Networked Digital Library of Theses and Dissertations.
    Our metadata is collected from universities around the world. If you manage a university/consortium/country archive and want to be added, details can be found on the NDLTD website.
1

Insertion of oncogenes into mouse mammary epithelium

Scully, Jaqueline Susan January 1989 (has links)
No description available.
2

Elucidating the role of the Fes tyrosine kinase in breast cancer

Zhang, Connie 18 December 2013 (has links)
Fes was first discovered as a protein-tyrosine kinase-encoded by the v-fes retroviral oncogene. Retrovirally encoded Fes oncoproteins induced tumors in chickens and cats and cause tumors in transgenic mice; however, a role for Fes in human cancer has not been established. This thesis identifies tumor promoting roles of Fes through effects on stromal cells using genetic mouse models. First, in an orthotopic mouse mammary gland engraftment model, I found that loss of Fes in the host correlated with reductions in engrafted tumor growth rates, metastasis and circulating tumor cells, which may be partly due to reduced vascularity and fewer tumor-associated macrophages. We also showed Fes-deficient macrophages were less capable of promoting tumor cell invasion in co-culture experiments. Next, I observed delayed tumor onset in the absence of Fes in a transgenic mouse model of breast cancer driven by an activated HER2/Neu allele. This longer tumor latency correlated with hyperinflammatory status of Fes-deficient normal mammary glands. Taken together, these observations argue that Fes inhibition might provide therapeutic benefits in breast cancer, by attenuating tumor-associated angiogenesis and the metastasis-promoting functions of tumor-associated macrophages, or by delaying breast tumor onset in women with HER2 overexpression. Finally, we showed that mice engrafted with IL-4 producing tumor cells developed tumors with significantly reduced growth rates and a complete attenuation of lung metastasis, which correlated with increased numbers of macrophages and enhanced phagocytic capability of macrophages in the tumor microenvironment. These observations suggest that IL-4 could be a good candidate for immunotherapy. / Thesis (Ph.D, Pathology & Molecular Medicine) -- Queen's University, 2013-12-18 11:44:40.294
3

Dynamics of oestrogen receptor regulation in breast cancer

Mohammed, Hisham January 2014 (has links)
No description available.
4

Exploration of the interplay between androgen receptor and FoxA1 in breast and prostate cancer

Robinson, Jessica Louise Louvain January 2014 (has links)
No description available.
5

Apoptosis, redox stress and cancer.

Moodley, Thunicia. 23 October 2013 (has links)
Apoptosis is a regulated "programme" by which cells are induced to die in a manner which does not result in pathological inflammatory reactions, and involves dismantling of the cell into membrane-bound fragments that are removed by phagocytosis. This process is induced in order to remodel tissues and maintain homeostasis in cell numbers. Apoptosis may be induced via many pathways, many of which are redox-regulated, and is dysregulated in cancer cells, mainly due to mutational inactivation of certain pathways. Cancer cells also have a non-linear response to redox imbalance, a potentially exploitable characteristic for the therapeutic selective induction of apoptosis in cancer cells in mixed cell populations. Model cell culture systems are required for the selective toxicity testing of anti-cancer drugs, many of which work by inducing redox stress. In the current study, hydrogen peroxide was selected as the redox stress-inducing agent, and the test cells were an immortal, non-invasive breast epithelial cell line (MCFlOA) and its rastransfected, pre-malignant derivative (MCF10AneoT). A reliable, sensitive, cost effective and least time-consuming system for detection of apoptosis in such a system was sort and two novel methods, cytochrome c release and caspase-3 activity assays, were finally selected and compared with results seen by conventional DNA laddering and morphological examination at the light and electron microscopic level. No single procedure was found to be reliable individually. For the model system used, a combination of electron microscopy and DNA laddering was sufficient for simply detecting apoptotic cell death and necrosis. The caspase activity assay distinguished between apoptosis and necrosis, and cytochrome c release proved the most sensitive indicator of cell response. However, since cytochrome c release may be reversible and may not necessarily proceed to the downstream events of apoptosis in the time frame used in the current assays, it is not certain that cytochrome c release ultimately leads to apoptosis. However, three forms of cytochrome c were observed on western blots, the nature and significance of which remains to be determined. A comparison of the results of different methods allowed a model for the sequence of specific apoptotic events to be proposed. / Thesis (M.Sc.)-University of Natal, Pietermaritzburg, 2000.
6

Breast cancer campaigns and research funding : the perfect storm

Potterf, Deana E. 24 July 2010 (has links)
Why does breast cancer receive so much more federal funding and fundraising efforts than other types of cancers, particularly lung cancer – the leading cause of cancer related deaths? This question is critical to public relations practitioners, in order to replicate or build on the success of breast cancer campaigns. This study was conducted in two parts. First, an Internet survey was distributed as a pilot study to examine public perceptions of cancer related issues. Next, depth interviews were conducted with 25 experts in the cancer field from across the nation. A comparison of pilot study results with actual statistics shows that breast cancer advocates are making a significant difference in people’s perceptions. Breast cancer advocacy campaigns are so pervasive, people don’t understand the significant numbers of other cancers that are diagnosed each year, as opposed to breast cancer. Interviews revealed that breast cancer awareness and funding have benefited from a perfect storm. According to interview participants, breast cancer advocacy may be attributed to: the feminist movement, the HIV/AIDS campaign, celebrity endorsers, and a passionate advocate named Nancy Brinker, who had just lost her sister, Susan G. Komen, to breast cancer. Screening and surgical technology also advanced at the right time, allowing breast cancer research funding and awareness to benefit from the perfect storm. It’s clear that Komen and other breast cancer advocates have made a huge impact on public perceptions of the disease and its research funding. Will other advocates be able to replicate it with the same degree of success, or will it take another perfect storm? / Department of Journalism
7

Screening for breast cancer : an assessment of various stochastic models

Joseph, Lawrence, 1959- January 1984 (has links)
No description available.
8

Screening for breast cancer : an assessment of various stochastic models

Joseph, Lawrence, 1959- January 1984 (has links)
No description available.
9

The role of epigenetics in the rat mammary gland

Kutanzi, Kristy, University of Lethbridge. Faculty of Arts and Science January 2010 (has links)
Epigenetics plays an important role in carcinogenesis with heritable changes in DNA methylation and histone modifications intricately linked to the initiation, promotion, and progression of cancer. Evidence shows that a number of chemical and physical agents can induce epigenetic changes during carcinogenesis. Two such agents, estrogen and ionizing radiation, are generally recognized as being carcinogenic. Yet the epigenetic repercussions of these carcinogens remain relatively unknown. More importantly, the combined effect of these carcinogens has never been addressed in vivo from an epigenetic standpoint. Therefore, we focused on the effect of estrogen and ionizing radiation applied separately or in conjunction. We have found that the exposure to estrogen, either alone or in combination with radiation, induced pronounced morphological alterations, which was paralleled by modifications to the epigenomic landscape in the mammary gland. The results obtained from these rodent models can potentially be extrapolated to humans. / xiv, 190 leaves : ill. (chiefly col.) ; 29 cm
10

Characterization of a novel DNA binding domain in the N-terminus of BRCA2 and evaluation of BRCA2 variants identified in breast cancer patients in the same region / Caractérisation d’un nouveau domaine de fixation à l’ADN dans le N-terminus de BRCA2 et évaluation des variantes BRCA2 non-classifiées identifiées dans les patients de cancer du sein dans la même région

Nicolai, Catharina von 13 June 2016 (has links)
Les mutations héréditaires dans le gène BRCA2 sont associées à une forte susceptibilité au développement du cancer du sein et de l’ovaire. La protéine suppresseur de tumeur BRCA2 est essentielle pour préserver l’intégrité des chromosomes après endommagement de l’ADN. BRCA2 est impliquée dans la recombinaison homologue (RH), une voie fiable de réparation des cassures de l’ADN. BRCA2 exerce aussi un rôle pendant la mitose afin d’assurer un point de contrôle et une division cellulaire correcte. Bien que le rôle de BRCA2 dans la RH soit bien établi, la littérature décrive une restauration partielle de la fonction de RH dans des cellules ne possédant pas le site de liaison à l’ADN en C-terminal (CT-DBD), ce que nous a encouragé à voir s’il existait un domaine secondaire de liaison à l'ADN. L'analyse in silico a révélé un domaine zf-PARP putatif dans la région N-terminale. Normalement, ce type de domaine s’associe à l’ADN, ce que nous a porté à l’examiner. En utilisant des fragments purifiés de la partie N-terminale comprenant le site putatif dans des analyses de changements de mobilité électrophorétique, nous avons montré une activité de liaison à l’ADN. En comparaison avec le CT-DBD canonique, le site de liaison à l’ADN en N-terminal (NT-DBD) manifeste une affinité plus forte pour divers substrats et contrairement du CT-DBD il est capable de s’associer à l’ADN à double brin. En utilisant des tests d’échange de brin, nous avons également montré que le NT-DBD peut stimuler la fonction de recombinaison de RAD51. De plus, des variantes faux-sens dans le NT-DBD trouvé chez les patients atteints de cancer du sein ont montré une activité réduite d’association à l’ADN et une stimulation diminuée de l’activité de RAD51 ce qui implique que ces amino-acides sont importants pour les deux fonctions. Ce travail révèle un nouveau sitede liaison à l’ADN, ce qui contrairement au CT-DBD est capable de s’associer à l’ADN double-bras(db) et stimuler l’activité de recombinaison de RAD51. Nous proposons que le NT-DBD positionne RAD51 à la jonction entre ADNdb et ADNsb, ce qui facilite le chargement de RAD51 sur l’ADN recouvert de RPA. Cette activité pourrait promouvoir la RH pendant la réparation des cassures de l’ADN (von Nicolai, C et al., 2016, under revision).Afin de définir la prévalence des mutations de NT-DBD pour la prédisposition au cancer, nous avons sélectionné des variants faux-sens non-classifiés (variants of unknown clinical significance), identifiés dans des familles à risque élevé de développer un cancer du sein. Nous avons effectué des tests afin d’étudier l’impact de ces variants sur la fonction de BRCA2 dans la RH et la mitose. Certains de ces variants ont conduit à une hypersensibilité aux agents endommageant l’ADN et aux inhibiteurs de PARP, caractéristique d’une RH défectueuse alors qu’un de ces variants était compétent pour la réparation. Tous les variants ont induit une duplication normale des centrosomes, mais la cytokinèse était défectueuse. Ce phénotype suggère un défaut dans la formation du midbody et de l’abscission. Cette étude aidera à classifier les VUS dans le NT-DBD et facilitera la consultation génétique pour des individus. BRCA2 est un médiateur de la RH dépendante de RAD51. Son homologue méiotique, DMC1, partage structure et fonction similaire et s’associe à BRCA2. Néanmoins, la pertinence fonctionnelle de cette interaction reste élusive. Nous avons montré que BRCA2 interagit avec DMC1 au travers des répétitions BRC et promeut la formation de molécules d'adhérence. Cet effet stimulant est dû au renforcement de la liaison de DMC1 à l’ADN. BRCA2 complet et fonctionnel était surtout capable de stimuler l’activité d’échange de brin de DMC1, ce qui confirme les résultats obtenus avec les répétitions BRC. Nos résultats identifient BRCA2 comme une protéine de médiation de la recombinaison méiotique et renforcent le rôle des répetitions BRC dans cette fonction (Martinez, von Nicolai, et al., PNAS, 2016). / Germline mutations in the BRCA2 gene lead to high susceptibility to the development of breast and ovarian cancer. The tumor suppressor protein BRCA2 is essential for preserving chromosome integrity after DNA damage emerging from endogenous or exogenous sources. BRCA2 functions in Homologous Recombination (HR), the most reliable pathway to repair DNA double strand breaks. BRCA2 exerts its tumor suppressor role also at several stages during mitosis where it ensures checkpoint control and proper cell division.Although the function of BRCA2 in HR is well established, evidence from the literature describing a partial restoration of HR function in cells lacking the C-terminal DNA binding domain (CT-DBD) brought us to test the hypothesis of a secondary DNA binding domain in BRCA2.In silico analysis of the protein revealed a putative zinc finger-PARP domain in exon 10 of the N-terminal region. This type of domain usually binds DNA which prompted us to examine this activity in vitro. Using purified N-terminal fragments comprising the putative DNA binding domain in electrophoresis mobility shift assay we demonstrated the DNA binding activity of the N-terminus of BRCA2. When compared to the canonical CT-DBD, the N-terminal DNA binding domain (NT-DBD) exhibits stronger affinity for various DNA substrates and unlike the CT-DBD, it can also associate with dsDNA. Using a DNA strand exchange assay we also showed that the NT-DBD stimulates the recombination function of RAD51. In addition, BRCA2 missense variants in the NT-DBD found in breast cancer patients showed reduced dsDNA binding and decreased stimulation of RAD51 recombination activity on dsDNA/ssDNA containing substrates, implying that these residues are important for both functions. This work revealed a novel DNA binding domain in the N-terminus of BRCA2 that, in contrast to the CT-DBD, can associate with dsDNA and promote RAD51 recombination activity. We propose that the NT-DBD positions RAD51 at the ssDNA/dsDNA junction facilitating RAD51 loading onto the RPA-coated ssDNA. This activity may promote HR in DSB repair and in daughter strand gap repair (von Nicolai, C et al., 2016 submitted).To define the relevance of NT DBD on cancer predisposition, we selected several missense variants of unknown clinical significance (VUS) found in families at high risk to develop breast cancer located in this region. We used in vitro and in vivo functional assays to study the impact of the mutations on BRCA2 function in HR and mitosis. Some of the variants exhibited hypersensitivity to DNA damaging agents and PARP inhibitors, a hallmark of defective HR while one variant was proficient in repair. All variants showed normal centrosome duplication, but exhibited delayed or failed cytokinesis. This phenotype suggests a defect of the variants in midbody formation and abscission as a consequence of impaired BRCA2 function. It remains to be established if the defects in HR and cytokinesis are related. In the future, this study will help to classify VUS in the NT-DBD and facilitate genetic counselling of individuals carrying these mutations.BRCA2 is a mediator protein in RAD51-dependent HR. Its meiotic counterpart, DMC1, shares similar structure and function and binds BRCA2. However, the functional relevance of this interaction remained elusive. In this work, we showed that through the BRC repeats, BRCA2 interacts with DMC1 and promotes joint molecule formation. This stimulatory effect is due to the enhancement of DMC1 assembly on ssDNA. Importantly, full-length BRCA2 also stimulated the DNA strand exchange activity of DMC1, confirming the results with the isolated BRC repeats. Our results identify BRCA2 as a mediator of meiotic recombination and underline the role of the BRC repeats on this function (Martinez, von Nicolai, et al., 2016, PNAS).

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