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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.
31

The putative role of matrix metalloproteinase 13 and oncostatin M in the establishment of bone metastases

Mancini, Stephanie Sarah Jane 11 1900 (has links)
Breast cancer has a high propensity to metastasize to bone. While the genetic and epigenetic changes associated with metastatic breast cancer progression are being identified, the changes that drive metastatic progression are poorly understood. Proteases, and in particular matrix metalloproteinases (MMPs), have been shown to play a pivotal role in certain aspects of tumor metastasis by modifying the affected microenvironment. Bone matrix-depositing mouse MC3T3 osteoblasts were co-cultured with metastatic human MDA-MB-23 1 (MDA23 1) cells or the bone-homing MDA-MB 231-1 833/TR (1 833/TR) variant in an effort to identify novel, osteoclast-independent, changes to the tumor/bone microenvironment. Co-culture-induced changes in the complete “protease and inhibitor” expression profile in the osteoblasts and the tumor cells were then determined using targeted murine and human specific microarray chips (CLIP-CHIP TM ). This analysis revealed an increase in the RNA expression of collagenase-3 (MMP 13) in the co-cultured osteoblasts that was confirmed by qPCR. Further, Western blotting indicated increased MIvIP13 protein secretion into the bone matrixltumor microenvironment by the co-cultured MC3T3 cells. The elevation in osteoblast-produced MMP13 was observed when the co- cultured tumor cells were in direct contact or separated by filters. Additionally, the elevation was also induced by conditioned medium derived from separate MDA23 1 or 1 833/TR cultures, which indicates that a soluble factor produced by the tumor cells is capable of inducing MMP 13. One soluble factor that appears to be produced by 1 833iTR cultures is oncostatin M. Oncostatin M is an interleukin-6 family cytokine that is known to upregulate MMP13 synthesis and secretion during chondrogenesis. Genome-wide Affymetrix® analysis revealed, and qPCR analysis confirmed, that oncostatin M receptor-specific subunit RNA was also significantly upregulated in co-cultured osteoblasts. Therefore, breast tumor cells may be capable of initiating protein degradative changes in the bone microenvironment that are independent of the much studied osteolytic degradation initiated by osteoclast activation.
32

An assessment of the effectiveness of knowledge of breast cancer and breast self-examination in women in Sierra Leone.

Shephard, Joan Hannah Elizabeth Estella. January 2004 (has links)
This research is a follow up of a "Breast Week" which was organized in Freetown, Sierra Leone. The specific objective of this study was to assess the effectiveness of the knowledge and teachings given to the women who participated in this project. The unrecorded cases of breast lumps and breast cancer observed in women in Sierra Leone prompted the researcher to undertake this present study. A quantitative approach was adopted and a structured interview schedule and an observational checklist guided the data collection process. A sample size of 120 women (10%) who participated in the "breast week" was obtained through systematic sampling. The first part of the study involved assessment of the theoretical background of the research topic followed by the second phase during which the women demonstrated Breast Self-Examination to detect abnormalities of the breasts. Discussions and analysis of the findings are presented in three sections. Texts from open ended questions were categorized and explained in numerical terms as the study was quantitative in nature. The data was processed through use of SPSS and Microsoft Excel. Frequency counts were applied to the data, use of non-parametric tests on the number of women who practiced Breast Self-Examination before and after the breast week showed a statistically significant difference in the number of women now practicing BSE as a screening method for breast cancer after receiving the health education. It was found that the majority of the women linked breast cancer to the signs and symptoms associated with it and were able to describe the disease as one that kills women if not promptly detected and/or treated appropriately. Findings indicate that the majority of the women (78.3%) had previously had mmor breast problems. An assessment of the effectiveness of knowledge on breast cancer showed that these women could identify breast cancer as a disease that affects women and may cause deaths if not detected on time or treated promptly. These women were able to demonstrate to the researcher how they examine their breasts to exclude abnormalities. Three women had breast lumps detected through examination of the breasts during the breast week. Two of them had had the lumps removed and are currently on medication. One of the women who had a breast lump detected was financially constrained and could not afford the cost of surgery. The number of women who can now perform BSE increased (95.0%) after having the knowledge on breast cancer and BSE. The majority of the women (97.4%) received information on how to examine their breasts for breast cancer through the information provided during the breast week. It is thus concluded that the objectives of the breast week were met. / Thesis (M.N.)-University of Natal, Durban, 2004.
33

Biological classification of clinical breast cancer using tissue microarrays

Cheang, Maggie Chon U 11 1900 (has links)
Gene expression profiles have identified five major molecular breast cancer subtypes (Luminal A, Luminal B, Basal-like, HER2+/estrogen receptor− , and Normal Breast-like) that show significant differences in survival. The cost and complexity of gene expression technology has impeded its clinical implementation. By comparison, immunohistochemistry is an economical technique applicable to the standard formalin-fixed, paraffin-embedded material commonly used in hospital labs, and has the advantage of simultaneously interpretation with histomorphology. In this thesis, I hypothesize that a surrogate panel of immunohistochemical biomarkers can be developed to discriminate the breast cancer biological subtypes. The main study cohort consists of over 4000 primary invasive breast tumors, assembled into tissue microarrays. These patients were referred to the British Columbia Cancer Agency between 1986-1992 and have staging, pathology, treatment and follow-up information. In summary, our results demonstrate that (1) the rabbit monoclonal antibody, SP1, is an improved standard for immunohistochemiscal estrogen receptor assessment in breast cancer; (2) the transcription factor, GATA-3, is almost exclusively expressed among estrogen receptor positive tumors but does not seem to predict for tamoxifen response among estrogen receptor positive patients; (3) the proliferation marker, Ki-67, together with HER2 can segregate Luminal A from Luminal B subtypes, which carry distinct risks for breast cancer relapse and death; and (4) the inclusion of the basal markers EGFR and ck5/6 to “triple negative” breast cancers provides a more specific definition of basal-like breast cancer that better predicts patient survival. These results consistently demonstrate that an immunopanel of six biomarkers (estrogen receptor, progesterone receptor, HER2, Ki-67, epidermal growth factor receptor and cytokeratin 5/6) can be readily applied to standard pathology specimens to subtype breast cancer samples based on their underlying molecular biology. These findings have been considered sufficient to justify application of this panel onto NCIC (MA5, MA12) and CALGB (9341 and 9741) clinical trials specimens. This followup work which is underway and will determine if the six marker immunopanel can guide decisions about which patients need aggressive systemic drug treatment, and thereby ensure patients get the most effective, individualized adjuvant systemic therapy for their breast tumor.
34

The putative role of matrix metalloproteinase 13 and oncostatin M in the establishment of bone metastases

Mancini, Stephanie Sarah Jane 11 1900 (has links)
Breast cancer has a high propensity to metastasize to bone. While the genetic and epigenetic changes associated with metastatic breast cancer progression are being identified, the changes that drive metastatic progression are poorly understood. Proteases, and in particular matrix metalloproteinases (MMPs), have been shown to play a pivotal role in certain aspects of tumor metastasis by modifying the affected microenvironment. Bone matrix-depositing mouse MC3T3 osteoblasts were co-cultured with metastatic human MDA-MB-23 1 (MDA23 1) cells or the bone-homing MDA-MB 231-1 833/TR (1 833/TR) variant in an effort to identify novel, osteoclast-independent, changes to the tumor/bone microenvironment. Co-culture-induced changes in the complete “protease and inhibitor” expression profile in the osteoblasts and the tumor cells were then determined using targeted murine and human specific microarray chips (CLIP-CHIP TM ). This analysis revealed an increase in the RNA expression of collagenase-3 (MMP 13) in the co-cultured osteoblasts that was confirmed by qPCR. Further, Western blotting indicated increased MIvIP13 protein secretion into the bone matrixltumor microenvironment by the co-cultured MC3T3 cells. The elevation in osteoblast-produced MMP13 was observed when the co- cultured tumor cells were in direct contact or separated by filters. Additionally, the elevation was also induced by conditioned medium derived from separate MDA23 1 or 1 833/TR cultures, which indicates that a soluble factor produced by the tumor cells is capable of inducing MMP 13. One soluble factor that appears to be produced by 1 833iTR cultures is oncostatin M. Oncostatin M is an interleukin-6 family cytokine that is known to upregulate MMP13 synthesis and secretion during chondrogenesis. Genome-wide Affymetrix® analysis revealed, and qPCR analysis confirmed, that oncostatin M receptor-specific subunit RNA was also significantly upregulated in co-cultured osteoblasts. Therefore, breast tumor cells may be capable of initiating protein degradative changes in the bone microenvironment that are independent of the much studied osteolytic degradation initiated by osteoclast activation.
35

Exploring Notch signaling pathways for breast cancer treatment

Han, Jianxun Unknown Date
No description available.
36

Interactive Effects of Flaxseed Oil and Trastuzumab on the Growth of Breast Tumours Overexpressing HER2

Mason, Julie 12 January 2011 (has links)
Flaxseed oil (FO), rich in α-linolenic acid, has been shown to inhibit breast cancer growth. One suggested mechanism is through modulation of HER2 expression and signalling. This study determined the effect of FO on the growth of established HER2-overexpressing breast tumours (BT-474) and its interaction with two doses of a primary anti-HER2 therapy, trastuzumab (TRAS), in athymic mice. FO alone had no effect on tumour size, cell proliferation and apoptosis. TRAS (2.5 and 5 mg/kg) reduced tumour size and cell proliferation but had no effect on apoptosis. TRAS (2.5 mg/kg) combined with FO reduced tumour size and cell proliferation and increased apoptosis compared to TRAS (2.5 mg/kg) alone and was just as effective as 5 mg/kg TRAS. TRAS (5 mg/kg) resulted in almost complete tumour regression with or without FO. In conclusion, FO has no effect on BT-474 tumour growth but can enhance the effectiveness of low dose TRAS.
37

THE MAMMARY EPITHELIAL CELL-SPECIFIC ROLE OF PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR (PPAR)γ IN DMBA-MEDIATED BREAST TUMOURIGENESIS

Roche, JENNIFER 04 September 2008 (has links)
Breast cancer is the most commonly diagnosed cancer, and the second leading cause of cancer-related deaths, among women world-wide. Improved understanding of breast tumourigenesis may facilitate the development of more effective therapies. Peroxisome proliferator-activated receptor (PPAR)γ is a transcription factor that regulates the genes involved in insulin sensitivity and adipogenesis. In vitro and in vivo studies also suggest that PPARγ suppresses breast tumour progression; however, the mechanisms remain to be clarified. In the current study, I investigated the mammary epithelial cell-specific role of PPARγ in 7,12-dimethylbenz[a]anthracene (DMBA)-mediated breast tumourigenesis. Mammary epithelial cell-specific PPARγ knockout (PPARγ-MG KO) mice and their congenic, wild-type controls (PPARγ-WT) were treated with either DMBA alone or in combination with a PPARγ ligand (rosiglitazone)-supplemented diet, and followed for tumour formation. DMBA-mediated mammary tumour multiplicity decreased 4.5-fold among PPARγ-WT, but only 1.2-fold in PPARγ-MG KO mice upon co-treatment with rosiglitazone. Similarly, compared to respective DMBA alone groups, mammary tumour volumes were decreased, and onset was delayed, more among DMBA + Rosiglitazone treated PPARγ-WT versus PPARγ-MG KO mice. To assess whether DMBA could alter cell growth, in vitro studies using two human breast cancer cell lines were performed. Human MCF-7 and MDA-MB-231 cells were treated with DMBA, rosiglitazone or both, and assessed for changes in proliferation, apoptosis and target gene expression. DMBA exerted minimal effects on proliferation; whereas, treatments induced apoptosis in MCF-7, and necrosis in MDA-MB-231, cells. The expression of MCF-7 PPARγ1 protein increased with all treatments, while MDA-MB-231 PPARγ2 protein and BRCA1 mRNA expression increased following rosiglitazone or co-treatment. This work advances our understanding of the mammary epithelial cell-specific role of PPARγ signaling in DMBA-mediated breast tumourigenesis, and supports a role for PPARγ activation in the suppression of breast tumour progression. These findings may assist with the development of more effective anti-breast cancer agents. / Thesis (Master, Pathology & Molecular Medicine) -- Queen's University, 2008-09-04 11:45:16.472
38

AN EXAMINATION OF CANADIAN FAMILY PHYSICIANS’ KNOWLEDGE AND PRACTICE PATTERNS REGARDING BREAST CANCER PREVENTION

TIGHE, MARY-KATHRYN 26 September 2009 (has links)
Family physician (FP) knowledge regarding breast cancer risk assessment and prevention strategies such as chemoprevention are important in ensuring that women at high risk for breast cancer are identified and receive proper preventive care. There are many factors which can moderately increase a woman’s risk of developing breast cancer, such as short-term hormone replacement therapy use and being nulliparous over the age of 30 years. Some factors increase a woman’s risk to such an extent that she is deemed “high risk” for breast cancer development, including having a family history of breast cancer or having a personal history of atypical benign breast disease. We conducted a cross-sectional survey of a stratified random sample of 2500 family physicians selected from across Canada to examine breast cancer risk assessment knowledge and practices, chemoprevention knowledge and prescribing practices, attitudes towards breast cancer chemoprevention, and barriers towards its utilization in Canadian FPs. We found that while the majority of physicians identified a woman with a family history of breast cancer (97%) as being high risk, a large proportion of physicians (40%) underestimated the risk associated with having a personal history of atypical benign breast disease. Physicians also tended to overestimate the risk associated with hormone replacement therapy use (70%) and the risk associated with nulliparity over the age of 30 years (50%). We also found that less than 15% of our sample had knowledge about chemoprevention and less than 7% had ever prescribed breast cancer chemoprevention (i.e. tamoxoifen or raloxifene) for primary prevention. Possible predictors of both knowledge of risk assessment and chemoprevention and prescription of chemoprevention were examined. Using multiple logistic regression, we found that several variables significantly predicted physician knowledge of these risk factors and prescription practices including patient load, medical experience and sex. The results of this study indicate that family physicians may need to become more aware about breast cancer prevention methods and risk factors for breast cancer, and in particular those that place a woman at high risk for breast cancer development. / Thesis (Master, Community Health & Epidemiology) -- Queen's University, 2009-09-19 13:11:22.899
39

THE NRF-1/GABP/BRCA1 TRANSCRIPTIONAL NETWORK IN MAMMARY EPITHELIAL DIFFERENTIATION

Thompson, Crista 11 September 2012 (has links)
Evidence indicates that the mammary epithelium is arranged in a hierarchy in which mature luminal and myoepithelial cells are derived from stem cells through a series of lineage-restricted intermediates. One of the more compelling hypotheses in breast cancer research is that transformation of a particular cell within the hierarchy will initiate a tumour with a specific molecular profile and clinical outcome. If this is true, valuable insight into tumourigenesis can be gained by investigating normal and malignant pathways of differentiation. A well-known tumour suppressor in breast cancer, BRCA1, plays a role in mammary epithelial differentiation. It has been proposed that haploinsufficiency or loss of BRCA1, either by germline mutation or sporadic downregulation, blocks differentiation producing a pool of genetically unstable mammary stem/progenitor cells that are prime targets for transformation. Thus, investigation of BRCA1 regulation and its role in differentiation are important to our understanding of breast cancer etiology. In this study, we determined that BRCA1 is at the end of a transcriptional network comprised of NRF-1 and GABP, a transcription factor comprised of two distinct subunits GABPalpha and GABPbeta. Decreased BRCA1 transcription in SK-BR-3 cells was found to be caused by aberrant activation of the GABPbeta promoter by an NRF-1 binding protein complex. We determined that the SWI/SNF family members BRG1, ARID1A and BAF155 may participate in the complex that activates GABPbeta transcription in conjunction with NRF-1. Examination of NRF-1, GABP and BRCA1 in 3D culture models suggests that mammary epithelial differentiation is biphasic with the transition between the phases being driven by changes in BRCA1 expression and localization. In the first phase, BRCA1 promotes differentiation in the nucleus, and in the second phase, BRCA1 is downregulated as a result of diminished GABP expression and relocated to an apical position, presumably to facilitate cell polarization. Following BRCA1 downregulation, NRF-1 and GABP levels increase indicating they are inducing oxidative phosphorylation in the second phase of differentiation. The involvement of NRF-1 and GABP in cellular respiration as well as differentiation through targets such as BRCA1 suggests that these proteins may integrate the cellular functions and mitochondrial metabolism required for mammary epithelial differentiation. / Thesis (Ph.D, Pathology & Molecular Medicine) -- Queen's University, 2012-09-11 14:22:26.407
40

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

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