Dissertations / Theses on the topic 'Mouse model and breast cancer'
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Herschkowitz, Jason I. Perou Charles M. "Breast cancer subtypes, mouse models, and microarrays." Chapel Hill, N.C. : University of North Carolina at Chapel Hill, 2007. http://dc.lib.unc.edu/u?/etd,1728.
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Thesis (Ph. D.)--University of North Carolina at Chapel Hill, 2008.Title from electronic title page (viewed Sep. 16, 2008). "... in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Curriculum of Genetics and Molecular Biology." Discipline: Genetics and Molecular Biology; Department/School: Medicine.
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Lesurf, Robert. "Molecular pathway analysis of mouse models for breast cancer." Thesis, McGill University, 2009. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=32499.
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Human breast cancer is an extremely heterogeneous disease, consisting of a number of different subtypes with varying levels of aggressiveness reflected by distinct, but largely undefined, molecular profiles. Here we have analyzed several novel mouse models for breast cancer in the context of the human subtypes, and have shown parallels between the mice and humans at numerous biologically relevant levels. In addition, we have developed a statistical framework to help elucidate the individual molecular components that are at play across a panel of human breast or murine mammary tumors. Our results indicate that, while no mouse model captures all aspects of the human disease, they each contain components that are shared by a subset of human breast tumors. Furthermore, our statistical framework provides numerous advantages over previous methodologies, in helping to reveal the individual molecular pathways that make up the biology of the tumors.Le cancer du sein est connue pour être une maladie très hétérogène, composé d'un nombre de différents sous-types avec différents niveaux de l'agressivité et distinctes, mais indéfini, profils moléculaires. Ici, nous avons analysé plusieurs nouveaux modèles de souris pour le cancer du sein, dans le cadre des sous-types, et nous avons trouver des parallèles à un certain nombre de niveaux pertinents biologiques. En outre, nous avons développé une méthodologie statistique pour aider à élucider les différents composants moléculaires qui sont à jouer dans un groupe de tumours de sein d'humains ou mammaires murins. Nos résultats indiquent que, même si aucun modèle de souris capte tous les aspects de la maladie chez l'homme, chacun contiennent des composants qui sont partagées par un sous-ensemble de tumeurs mammaires humaines. En outre, notre outil statistique offre de nombreux avantages par rapport aux précédentes méthodes, pour aider à révéler les voies moléculaires qui composent la biologie des tumeurs.
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Simpson, Peter Thomas. "Differential gene expression analysis in a transgenic mouse model of metastatic breast cancer." Thesis, University of Liverpool, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.343681.
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Alhazmi, Aiman. "Role of Nucleosome Remodeling Factor (NURF) in Tumorigenesis Using a Breast Cancer Mouse Model." VCU Scholars Compass, 2012. http://scholarscompass.vcu.edu/etd/379.
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Understanding the impact of epigenetic mechanisms on tumorigenesis is essential, as epigenetic alterations are associated with tumor initiation and progression. Because epigenetic changes are reversible, they are potential targets for cancer therapy. Nucleosome Remodeling Factor (NURF) is a chromatin-remodeling complex that regulates gene expression by changing nucleosome positioning along the DNA sequence. Previous studies have shown a role for NURF in embryonic development as well as regulating genes involved in tumor progression. In this work we investigated the impact of eliminating NURF function in tumorigenesis in vivo. BALB/c mice challenged with syngeneic 67NR breast cancer cell lines, injected into the mammary fat pad, lacking NURF, due to knockdown of its essential subunits Bptf, showed reduction in tumor growth comparing to control tumors. The observed reduction in tumor growth was abrogated in immunodeficient mice lacking a functional immune system. Bptf KD and control 67NR cells grew at similar rates in vitro. Similar findings were observed in our lab using 66cl4 breast cancer cell lines. Using immunofluorescence staining, no significant difference in CD8+, CD4+, NK and MDSC cells infiltrations into the tumor microenvironment was observed in 66cl4 tumors. Preliminary results from 67NR tumors suggested more CD4+ and CD8+ cells. Gene expression profile of tumor tissues from BALB/c mice injected with 67NR and 66cl4 cell lines showed enrichment of genes associated with immune response. Our findings suggested a role of the immune system in targeting tumor cells lacking Bptf in vivo.
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Robey, Ian, and Natasha Martin. "Bicarbonate and dichloroacetate: Evaluating pH altering therapies in a mouse model for metastatic breast cancer." BioMed Central, 2011. http://hdl.handle.net/10150/610344.
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BACKGROUND:The glycolytic nature of malignant tumors contributes to high levels of extracellular acidity in the tumor microenvironment. Tumor acidity is a driving force in invasion and metastases. Recently, it has been shown that buffering of extracellular acidity through systemic administration of oral bicarbonate can inhibit the spread of metastases in a mouse model for metastatic breast cancer. While these findings are compelling, recent assessments into the use of oral bicarbonate as a cancer intervention reveal limitations.METHODS:We posited that safety and efficacy of bicarbonate could be enhanced by dichloroacetate (DCA), a drug that selectively targets tumor cells and reduces extracellular acidity through inhibition of glycolysis. Using our mouse model for metastatic breast cancer (MDA-MB-231), we designed an interventional survival study where tumor bearing mice received bicarbonate, DCA, or DCA-bicarbonate (DB) therapies chronically.RESULTS:Dichloroacetate alone or in combination with bicarbonate did not increase systemic alkalosis in mice. Survival was longest in mice administered bicarbonate-based therapies. Primary tumor re-occurrence after surgeries is associated with survival rates. Although DB therapy did not significantly enhance oral bicarbonate, we did observe reduced pulmonary lesion diameters in this cohort. The DCA monotherapy was not effective in reducing tumor size or metastases or improving survival time. We provide in vitro evidence to suggest this outcome may be a function of hypoxia in the tumor microenvironment.CONCLUSIONS:DB combination therapy did not appear to enhance the effect of chronic oral bicarbonate. The anti-tumor effect of DCA may be dependent on the cancer model. Our studies suggest DCA efficacy is unpredictable as a cancer therapy and further studies are necessary to determine the role of this agent in the tumor microenvironment.
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Pochampalli, Mamata Rani. "Characterization of Effects of Muc1 Expression on Epidermal Growth Factor Receptor Signaling in Breast Cancer." Diss., The University of Arizona, 2006. http://hdl.handle.net/10150/194355.
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EGF receptors are key regulators of cell survival and growth in normal and transformed tissues. Ligand binding results in formation of homo/hetero dimers of these receptors, followed by activation of the kinase activity and subsequent tyrosine phosphorylation of many downstream molecules. The activation of these receptors is not only mediated by the binding of their cognate ligands, but by transactivaton by other molecules as well. Recent studies have identified an oncogenic glycoprotein MUC1 as a binding partner for EGFR and that MUC1 expression can potentiate EGFR-dependent signal transduction. After receptor activation, EGFR is typically downregulated via an endocytic pathway that results in receptor degradation or recycling. We report here that MUC1 expression inhibits the degradation of ligand-activated erbB1. In addition, MUC1 expression results in prolonged activation of Akt, but not ERK1,2 MAPKinase. The MUC1-mediated protection against degradation occurs with a decrease in EGF-stimulated ubiquitination of erbB1, and an increase in erbB1 recycling. We then utilized the WAP-TGFα transgenic mouse model of breast cancer and determined that a loss of Muc1 expression dramatically alters mammary tumor progression. While 100% of WAP-TGFα/Muc1^(+/+) mice form mammary gland tumors, only 37% of WAP-TGFα/Muc1^(-/-) form tumors. Furthermore, expression of cyclin D1 expression is significantly suppressed in tumors derived from WAPTGFα/Muc1^(-/-) animals, and loss of Muc1 expression resulted in a significant inhibition in the formation of hyperplastic lesions in the mammary gland. We also observed metastatic pulmonary adenocarcinoma (1/29) and perivascular lymphoma of unknown origin (28/29) in the WAP-TGFα transgenic mice but not in the WAP TGFα/Muc1^(-/-) animals. To determine the effects of Muc1 expression on metastasis in a model lacking perivascular lymphoma, we crossed MMTV-Wnt-1 and MMTV-MUC1 transgenic mice and evaluated interactions between Muc1 and EGFR. Although the MMTV-Wnt-1 mice are non-metastatic, a majority (6/10) of the bitransgenic MMTVWnt- 1/MMTV-MUC1 formed pulmonary metastases. Furthermore, overexpression of MUC1 increases the breast cancer cell invasion in vitro. The MUC1 induced increase in invasion is found to be EGF and EGFR-kinase dependent. Collectively, these data indicate that MUC1 expression contributes to many of the hallmarks of cancer and in addition, is an important modulator of EGFR-associated mammary tumor progression.
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Ke, Jia-Yu. "Bioactivity of Naringenin in Metabolic Dysregulation and Obesity-Associated Breast Cancer in a Mouse Model of Postmenopause." The Ohio State University, 2015. http://rave.ohiolink.edu/etdc/view?acc_num=osu1437479457.
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Heilmann, Katharina [Verfasser], and Karin [Akademischer Betreuer] Müller-Decker. "Epigenetic characterization of the C3(1) SV40T mouse model of human breast cancer / Katharina Heilmann ; Betreuer: Karin Müller-Decker." Heidelberg : Universitätsbibliothek Heidelberg, 2017. http://d-nb.info/1178008134/34.
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Balderstone, Lucy Anne. "Use of fluorescent imaging to monitor drug responses in mouse models of tumourigenesis." Thesis, University of Edinburgh, 2014. http://hdl.handle.net/1842/17859.
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As our understanding of the complexities of cancer biology has increased, the ability to exploit unique features of tumour cells with molecularly targeted therapies has become a reality. However, despite unprecedented volumes of new molecules in clinical trials, the number of highly effective drugs approved by the regulatory authorities remains disappointingly low. Moreover, oncology drug development is plagued by high levels of attrition in late phase clinical development. Failure due to poor efficacy and toxicity issues are not believed to be a result of the development of molecules with inadequate pharmaceutical properties, but rather due to a lack of understanding of their full mechanism of action. All of this points to imprecise analysis of the drugs during the preclinical phase, highlighting the need for better preclinical drug development tools. Animal models provide a key preclinical tool, and as a therapeutic area, oncology is characterised by models which are not predictive of the true human pathology. Overexpression of the human epidermal growth factor receptor two (HER2) oncogene, and inactivation of the phosphatase and tensin (PTEN) tumour suppressor, are two important events in human breast cancer. A novel conditional mouse model driven by overexpression of HER2 coupled with / without the loss of PTEN has been characterised to interrogate the importance of these two cellular perturbations. Multifocal tumours arose in mice from both lines, while luminal tumour characteristics were shown to be reduced and basal characteristics increased with a reduction in PTEN expression. Disruption of PTEN rapidly accelerated tumour onset (from 138 to 82 days) and tumour growth (with the time from tumour onset to maximum tumour size reduced from 38 to 21 days), significantly reducing overall survival (from 165 to 102 days). The ability of tumour cells to colonize the lungs was not significantly affected by the loss of PTEN. Tumours arising in both mice genotypes were utilized to generate cell lines. These failed to provide an in vitro representation of the tumours, and found little utility in drug efficacy studies with HER family targeted agents, a situation which could be improved by the use of different culture methods. Since suppression of apoptosis is a hallmark of human cancer, and a desired endpoint of many anticancer therapies is the induction of cell death, the generation of cell lines inherently capable of sensing caspase-mediated apoptotic cell death would be a valuable drug development tool. Given that fluorescence imaging is also emerging as a potentially powerful modality for preclinical drug development, a novel fluorescent in house apoptosis reporter construct was generated (pCasFSwitch). Initial validation of pCasFSwitch by transient transfection into murine mammary carcinoma cells proved difficult due to transfection associated toxicity, yet proof-of-principle was indicated. Transfer of pCasFSwitch into a retroviral backbone vector enabled the generation of stably transfected squamous carcinoma cells more suitable for further analysis. Incubation of lysates from these cells with recombinant enzymes revealed the construct could be cleaved by caspase-3, but not by other members of the cysteine protease family. Furthermore, assessment of apoptosis levels in the cells upon staurosporine treatment proved the utility of the construct to quantify cell death, and was validated against data generated with a commercial competitor, NucView. Further comparison of the specificity of the imaging agents using caspase inhibitors was limited by the functionality of currently available inhibitors, but did reveal that in common with NucView, construct quantified levels of apoptosis were affected by inhibition. This thesis details the development of two preclinical drug development tools. A novel mouse model enables biological interrogation of two key events in human breast carcinogenesis. Since PTEN loss is associated with resistance to HER2 targeted therapies, it is ideally suited for efficacy testing to overcome such resistance. The in house fluorescent apoptosis imaging agent allows a temporal read-out of drug effects in live single cells. While the use of intravital imaging of stable cell lines implanted under imaging windows would allow in vivo validation of in vitro data. Taken together, such facilitation of thorough evaluation of therapies at the preclinical stage, will reduce the adverse effects felt by the pharmaceutical industry of failure late in the drug development pipeline.
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Milliken, Erin L. "USE OF A TRANSGENIC MOUSE MODEL OF OVARIAN HYPERSTIUMLUATION TO IDENTIFY THERAPEUTIC TARGETS AND MECHANISMS IN HORMONE-INDUCED MAMMARY CANCER." Case Western Reserve University School of Graduate Studies / OhioLINK, 2005. http://rave.ohiolink.edu/etdc/view?acc_num=case1121273034.
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Mitterer, Chantal. "The role of inflammation induced by radiation or lipopolysaccharides in the metastatic process in a mouse model of breast cancer." Mémoire, Université de Sherbrooke, 2012. http://hdl.handle.net/11143/6343.
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Mortality from breast cancer is primarily due to metastatic disease, which often appears years after treatment of the primary tumor. Radiation as well as bacterial infection induces inflammation, which by releasing cytokines can be implicated in metastatic processes. Using in vitro and in vivo models, the ability of radiation to awaken dormant lung metastases was assessed as well as the capacity of a bacterial infection to enhance metastatic progression in already proliferating lung metastases. As models, we used the D2.0R (dormant) and D2A1 (proliferative) cell lines, which are derived from spontaneous murine mammary tumors. The ability of radiation to awaken dormant D2.0R mammary cancer cells was assessed in a 3-dimension (3D) cell culture system, which resulted in the formation of microspheres of cancer cells. The addition of prostaglandin E 2 (PGE2 ; 100ng/m1) or conditioned media from irradiated (5 Gy) CALU-3 human bronchial epithelial cells stimulated the proliferation of the dormant D2.0R cells resulting in microspheres with a larger diameter compared to the untreated cells. Regarding the proliferative D2A1 microspheres, their rate of proliferation was not further increased by adding PGE2 or the conditioned media of irradiated CALU-3 cells. In Balb/c mice bearing dormant lung D2.0R micrometastases, our data showed that a fractionated radiation dose (5x7.5 Gy) to the mammary gland resulted in a significant increase in the development of metastases, as measured 42 days post-irradiation by bioluminescent reaction. We also evaluated whether a bacterial infection could stimulate the growth of D2A1 cancer cells. Gram-negative bacteria release the lipopolysaccharide (LPS) that induces an inflammatory response. In lungs of mice treated with LPS, a higher level of interleukin-1? (IL-1?) was measured supporting the induction of an inflammation. This was accompanied by an increase of cell adhesion molecules (VCAM-1 and ICAM-1) 5 hours after treatment. The ability of LPS mediated-inflammation to stimulate the quantity and size of the proliferating D2A1 lung metastases was also demonstrated by optical imaging. In aged mice, a significant increase in total surface area covered by the lung metastases was measured as well as a tendency to have more numerous metastases. Conversely, no difference in tumor size or quantity was observed in young mice, which nevertheless had increased expression in pro-inflammatory mediators and adhesion molecules. In conclusion, our study demonstrated that inflammation increases the awakening of dormant D2.0R microspheres in a 3D in vitro model, while in mice treated with LPS, an age-dependent stimulation of the proliferation and number of D2A1 lung metastases was measured.
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Knostman, Katherine A. B. "Sodium/iodide symporter regulation by oncogenes in the mammary gland and thyroid gland using mouse models." The Ohio State University, 2007. http://rave.ohiolink.edu/etdc/view?acc_num=osu1181659993.
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Alkhatib, Suehyb. "Characterizing the role of Nucleosome Remodeling Factor (NURF) in tumorigenesis and metastatic progression using mouse models of breast cancer." VCU Scholars Compass, 2012. http://scholarscompass.vcu.edu/etd/376.
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Increasingly the role of epigenetic machinery as a bridge between underlying DNA sequence and cellular phenotype is being discovered. The establishment of a myriad of unique cellular types sharing identical gene sequences in a multicellular organism gives a broad sense for the inherent role of epigenetic influence on cell differentiation. Importantly, the epigenetic mechanisms involved in establishing cell identity unsurprisingly contribute to diseased states, including cancer. Recent research continues to elucidate contributory roles of epigenetic mechanisms, such as DNA methylation, histone modification, and microRNA regulation, in human cancers. Additionally, chromatin remodelers, such as the Nucleosome Remodeling Factor (NURF), have been identified as important regulators for normal cell biology. While much has been done to identify and characterize the role of NURF chromatin remodeling complex as a key regulator of development in a number of model organisms, little has been published on the implications of NURF in diseases such as cancer. Our preliminary data shows dysregulation of E-cadherins, N-cadherins, and MHC-I genes in Bptf (an essential subunit of NURF) knocked down murine breast cancer cell lines. These proteins have well documented roles in the development and metastatic progression of cancers. To study the effect of Bptf knockdown on the development and progression of cancer we injected Bptf knocked down mouse breast cancer cell lines, 4T1, 66cl4, and 67NR, into syngenic BALB/c mice. Our findings reveal decreased tumor growth in 66cl4 and 67NR as measured by tumor weight at 3-4 weeks post injection. Tumor growth did not appear to be significantly affected in 4T1 challenged mice. However, mice inoculated with Bptf knockdown 4T1 cell lines have decreased metastasis to lungs as compared to control while metastasis of 66cl4 tumors to the lungs appear unaffected. To assess the role of the immune system in decreasing tumor growth in BALB/c mice, we injected 66cl4 tumors into NOD-SCID-Gamma (NSG) immune deficient mice. The tumors from these mice show no difference in tumor growth between Bptf knockdown and control tumors, implicating a role for the immune system regulating the decreased tumor weight in BALB/c mice. To delineate which immune cell effector may impede breast cancer carcinogenesis, we performed an in vitro natural killer (NK) cell cytotoxicity assay against 66cl4 tumors and found greater susceptibility to NK killing in Bptf knockdown tumors.
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Ordonez, Liliana. "Investigation of response and resistance to PARP inhibition in mouse models of human BRCA2-mutant breast cancer." Thesis, Cardiff University, 2014. http://orca.cf.ac.uk/68611/.
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Breast cancer is the most common cancer in the UK, but despite recent encouraging increases in survival rates, is still the second most common cause of cancer death in women in the UK. To try to reduce systemic toxicity during treatment of cancer patients, a plethora of targeted therapies are in various stages of development. PARP inhibitors have been shown to be particularly effective in BRCA-deficient cells, making them a contender as a personalised therapy. One of the challenges for targeted therapies is that of resistance, which limits the extent of benefit to the patient. The work described in this study continues previous work within our laboratory, investigating the PARP inhibitor olaparib in a conditional mouse model of BRCA2-mutated human breast cancer. The data presented here establish a correlation between histological tumour type and response to olaparib therapy, with poor responders classified exclusively as mesenchymal-like metaplastic spindle cell carcinomas (MSCC). This suggests that further patient stratification is required when deciding on whether this therapy may be suitable, and may explain why not all patients with BRCAmutated breast cancer have benefitted from olaparib therapy in current clinical trials. Investigation of olaparib resistance in this study indicated that several currently proposed mechanisms of resistance were not pertinent to the Brca2/p53 model, hence novel mechanisms were sought. Histopathological analysis of resistant tumours showed that the majority were MSCCs, representing a significant change in the proportion compared to an untreated cohort. Other resistant tumour types had epithelial morphology, but showed an increase in expression in some mesenchymal-like genes compared to untreated cohorts, suggesting that mesenchymal features may be important in causing resistance to olaparib. A similar tumour model, incorporating the additional deletion of E-cadherin, was used to investigate whether lack of this protein in tumours affected response and resistance to olaparib therapy. Loss of Cdh1 led to an increase in invasive ductal carcinomas of no special type (IDC-NST) and the absence of MSCCs, suggesting that genetic loss of expression does not drive the formation of mesenchymal-like tumours. Correlating with this, loss of E-cadherin did not drive epithelial-to-mesenchymal transition in these tumours and had no effect on response to olaparib therapy or resistance to the inhibitor. Taken together, the data presented in this thesis suggest that MSCCs have an intrinsic resistance to olaparib therapy, and tumours which initially respond to olaparib therapy harness or acquire certain mesenchymal characteristics in order to develop resistance during treatment.
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Bolin, Celeste, Caleb Sutherland, Ken Tawara, Jim Moselhy, and Cheryl Jorcyk. "Novel mouse mammary cell lines for in vivo bioluminescence imaging (BLI) of bone metastasis." BioMed Central, 2012. http://hdl.handle.net/10150/610032.
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BACKGROUND:Tumor cell lines that can be tracked in vivo during tumorigenesis and metastasis provide vital tools for studying the specific cellular mechanisms that mediate these processes as well as investigating therapeutic targets to inhibit them. The goal of this study was to engineer imageable mouse mammary tumor cell lines with discrete propensities to metastasize to bone in vivo. Two novel luciferase expressing cell lines were developed and characterized for use in the study of breast cancer metastasis to bone in a syngeneic mouse model.RESULTS:The 4 T1.2 luc3 and 66c14 luc2 cell lines were shown to have high levels of bioluminescence intensity in vitro and in vivo after orthotopic injection into mouse mammary fat pads. The 4 T1.2 luc3 cell line was found to closely model the sites of metastases seen in human patients including lung, liver, and bone. Specifically, 4 T1.2 luc3 cells demonstrated a high incidence of metastasis to spine, with an ex-vivo BLI intensity three orders of magnitude above the commercially available 4 T1 luc2 cells. 66c14 luc2 cells also demonstrated metastasis to spine, which was lower than that of 4 T1.2 luc3 cells but higher than 4 T1 luc2 cells, in addition to previously unreported metastases in the liver. High osteolytic activity of the 4 T1.2 luc3 cells in vivo in the bone microenvironment was also detected.CONCLUSIONS:The engineered 4 T1.2 luc3 and 66c14 luc2 cell lines described in this study are valuable tools for studying the cellular events moderating the metastasis of breast tumor cells to bone.
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Walker, Kelcey Manae Becker. "Inhibitory actions of Ah receptor agonists and indole-containing compounds in breast cancer cell lines and mouse models." Texas A&M University, 2002. http://hdl.handle.net/1969.1/2433.
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The aryl hydrocarbon receptor (AhR) binds synthetic and chemoprotective phytochemicals, and research in this laboratory has developed selective AhR modulators (SAhRMs) for treatment of breast cancer. Activation of the AhR through agonists such as TCDD inhibits hormone activation of several E2-responsive genes in breast cancer cell lines. In this study, inhibition of E2-induced proliferation and gene expression by TCDD has been investigated in the uterus of wildtype, ERKO and AhRKO mice. Cyclin D1, DNA polymerase ?, and VEGF mRNA levels are induced by E2 through ER? in the uterus as determined by in situ hybridization studies. TCDD down-regulated E2-induced cyclin D1 and DNA polymerase ? expression, but not E2-induced VEGF expression, in wild-type mice, but not AhRKO mice, confirming the role of the AhR. Furthermore, protein synthesis was not necessary for induction of cyclin D1 or DNA polymerase ?gene expression by E2 or inhibition of these responses by TCDD. Therefore, AhR-ER? crosstalk directly regulates the expression of genes involved in cell proliferation in vivo.
AhR agonists induce down-regulation of ErbB family receptors in multiple tissues/organs suggesting possible inhibitory interactions with chemotherapeutic potential. Recently, it has been reported that the SAhRM 1,1??,2,2??-tetramethyldiindolylmethane inhibited DMBA-induced mammary tumor growth in rats and also inhibited MAPK and PI3-K pathways in human breast cancer cells. BT-474 and MDA-MB-453 cell lines are ErbB2-overexpressing breast cancer cells that express functional AhR and exhibit constitutive activation of MAPK and PI3-K pathways. Therefore, 1,1??,2,2??-tetramethyldiindolylmethane-induced inhibition of ErbB2 signaling was investigated in these cells lines and in the MMTV-c-neu mouse mammary tumor model, which overexpresses ErbB2 in the mammary gland. The growth of ErbB2 overexpressing cell lines and mammary tumors was inhibited by 1,1??,2,2??-tetramethyldiindolylmethane; however, modulation of MAPK or PI3-K pathways and cell cycle proteins nor induction of apoptosis by 1,1',2,2'-tetramethyldiindolylmethane was observed in the ErbB2overexpressing cell lines. Current studies are investigating mitochondrial effects of 1,1??,2,2??-tetramethyldiindolylmethane in the ErbB2-overexpressing cell lines, as well as continuing studies on gene expression profiles in the mammary glands of MMTV-c-neu mice to better understand and identify critical genes that are responsible for ErbB2-mediated transformation and growth of cancer cells/tumors.
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Collier, Jenna Lynn. "Investigation into the role of eosinophils in pulmonary metastasis and primary tumours in mouse models of breast cancer." Thesis, University of British Columbia, 2017. http://hdl.handle.net/2429/62442.
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Eosinophils are multifunctional granulocytes with potent immune modulatory and cytotoxic capabilities. Despite the presence of eosinophils in various solid tumours and eosinophilia being a prognosistic indicator in some cancers, the role of this innate immune cell has been largely overlooked in the context of cancer. Specifically, the role of eosinophils in pulmonary metastasis is poorly described despite their prevalence in the lung and association with various pulmonary diseases. I sought to delineate the role of eosinophils in murine models of metastatic breast cancer using novel mouse models of genetic eosinophil deficiency (ddGATA) and by immunodepletion in orthotopic mouse models of cancer using an anti-IL-5 antibody. I hypothesize that eosinophils enhance pulmonary metastasis in mouse models of breast cancer, but do not affect the vascularization of the primary tumour. Eosinophils are increased 5.8-fold in the lungs of mice bearing 4T1 metastatic mammary tumours (p<0.001) which may be due to an observed 4-fold increase in the expression of CCL24 (p<0.0001) that is produced by mMDSCs. Moreover, some resident eosinophils appeared to differentiate into a novel CD11bhiGr-1hi subset in the pre-metastatic lungs. Immunological depletion of eosinophils using anti-IL-5 antibody did not affect the growth or vascularization of 4T1 tumours, or metastatic development by 3 weeks post-implant of the primary tumour. Surprisingly, there was a trend towards an increase in tumour cell colonization of the lungs by IV injected LLC—but not E0771-LMB—tumour cells in ddGATA mice relative to WT controls; indicating that eosinophils may exert anti-tumour effects in this model. Furthermore, IL-5Tg mice exhibiting eosinophilia had a 5-fold decrease in the number of lung Tregs (p<0.001) and were significantly protected from tumour cell colonization of the lungs. Our data suggests that a pro-inflammatory subset of CD11b hiGr-1hi eosinophils may be present in the pre-metastatic lungs and additional eosinophils are recruited to the metastatic lung in response to CCL24 produced by mMDSCs. However, eosinophils do not significantly influence pulmonary metastasis or primary tumour growth or vascularization in mouse models of breast cancer. Furthermore, our data indicates that IL-5 may be exerting pleiotropic effects on other immune cell populations.Medicine, Faculty of
Pathology and Laboratory Medicine, Department of
Graduate
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Creedon, Helen. "Use of genetically engineered mouse models in preclinical drug development." Thesis, University of Edinburgh, 2015. http://hdl.handle.net/1842/15911.
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The paucity of well validated preclinical models is frequently cited as a contributing factor to the high attrition rates seen in clinical oncological trials. There remains a critical need to develop models which are accurately able to recapitulate the features of human disease. The aims of this study were to use genetically engineered mouse models (GEMMs) to explore the efficacy of novel treatment strategies in HER2 positive breast cancer and to further develop the model to facilitate the study of mechanisms underpinning drug resistance. Using the BLG--HER2KI-PTEN+/- model, we demonstrated that Src plays an important role in the early stages of tumour development. Chemopreventative treatment with dasatinib delayed tumour inititation (p= 0.046, Wilcoxon signed rank test) and prolonged overall survival (OS) (p=0.06, Wilcoxon signed rank test). Dasatinib treatment also induced squamous metaplasia in 66% of drug treated tumours. We used 2 cell lines derived from this model to further explore dasatinib’s mechanism of action and demonstrated reduced proliferation, migration and invasion following in vitro treatment. Due to the prolonged tumour latency and the low metastatic rate seen in this model, further studies were undertaken with the MMTV-NIC model. This model also allowed us to study the impact of PTEN loss on therapeutic response. We validated this model by treating a cohort of MMTV-NIC PTEN+/- mice with paclitaxel and demonstrated prolonged OS (p=0.035, Gehan Breslow Wilcoxon test). AZD8931 is an equipotent signalling inhibitor of HER2, HER3 and EGFR. We observed heterogeneity in tumour response but overall AZD8931 treatment prolonged OS in both MMTV-NIC PTEN FL/+ and MMTV-NIC PTEN+/- models. PTEN loss was associated with reduced sensitivity to AZD8931 and failure to suppress Src activity, suggesting these may be suitable predictive biomarkers of AZD8931 response. To facilitate further studies exploring resistance, we transplanted MMTV-NIC PTEN+/- fragments into syngeneic mice and generated 3 tumours with acquired resistance to AZD8931. These tumours displayed differing resistance strategies; 1 tumour continued to express HER2 whilst the remaining 2 underwent EMT and lost HER2 expression reflecting to a very limited degree some of the heterogeneity of resistance strategies seen in human disease. To further explore resistance to HER2 targeting tyrosine kinase inhibitors, we generated a panel of human cell lines with acquired resistance to AZD8931 and lapatinib. Western blotting demonstrated loss of HER2, HER3 and PTEN in all resistant lines. Acquisition of resistance was associated with a marked change in phenotype and western blotting confirmed all lines had undergone EMT. We used a combination of RPPA and mass spectrometry to further characterise the AZD8931 resistant lines and identified multiple potential novel proteins involved in the resistant phenotype, including several implicated in EMT. In conclusion, when coupled with appropriate in vitro techniques, the MMTV-NIC model is a valuable tool for selection of emerging drugs to carry forward into clinical trials of HER2 positive breast cancer.
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Chahrour, Ghada. "Estrogen-related receptor [alpha] (ERR[alpha]), estrogen receptor [alpha] (ERA[alpha]) and erbB-E (Neu) crosstalk in a mouse model of human breast cancer." Thesis, McGill University, 2003. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=80237.
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Estrogen (17-beta estradiol) and its receptor (ERalpha) have important physiological roles and are well implicated in human breast cancer, but less is known about the function of estrogen-related orphan nuclear receptor alpha (ERRalpha). The close kinship between ERalpha and ERRalpha and the existing, but yet to be fully characterized, interplay between ERalpha and erbB2 (Neu) protooncogene signaling pathways, suggest that ERRalpha may also play a significant role in breast cancer. Thus, the focus of the current study was to determine the extent of ERRalpha cross talk with ERalpha, its physiological role, as well as its possible implication in erbB2-driven mammary tumorigenesis. Using a well characterized erbB2 mouse model of human breast cancer where tumorigenesis occurs following a long latency period, we generated ERRalpha deficient mice (ERRalphaKO) expressing an activated erbB2 oncogene.
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Rossdeutscher, Lionel Philip David. "The role of tumoral 1,25 dihydroxyvitamin D3 in inhibition of tumor growth and progression in the PyVMT MMTV#634 transgenic breast cancer model /." Thesis, McGill University, 2007. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=112354.
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Vitamin D3 must be metabolically activated by the liver to 25-hydroxyvitamin D3 (25OHD3) and then by the kidney 1alphahydroxylase (1alphaOHase) to become 1,25dihydroxyvitamin D 3 (1,25(OH)2D3). 1,25(OH)2 D3 is a potent inhibitor of tumor growth in vitro and in vivo. Recent studies indicate that metabolic activation of 1,25(OH) 2D3 also occurs in cancer cells such as breast cancer. Consequently, the major objective of this project was to determine if tumoral 25OHD 3-1alphahydroxylase modulates any or all of the stages of breast tumor progression without inducing the hypercalcemic side effects of 1,25(OH) 2D3. For this purpose we used the PyVMT breast cancer mouse model in which the oncoprotein, polyomamiddle T antigen (PyMT) is under the control of mouse mammary tumor virus LTR (MMTV LTR). Mice exhibited tumors restricted to the mammary epithelium progressing to the various stages of breast cancer. Animals were treated with either vehicle, 25OHD3 (2000 pM/24h) or 1,25(OH)2D3 (12pM/24h). Mice treated with the vitamin D precursor, 25OHD3, exhibited a marked reduction in tumor onset and growth comparable to the 1,25(OH)2D3 treated group. Furthermore, biomarkers of tumor progression were markedly reduced in 25OHD3 and 1,25(OH)2D3 animals as compared to vehicle-treated animals. However, mean circulating calcium concentrations remained unchanged in 25OHD3 treated animals but increased significantly in 1,25(OH)2D3 treated animals as compared to controls. Tumoral levels of 1,25(OH)2D3 in mice treated with 25OHD3 were increased 79% in comparison to vehicle control mice. Additionally, 25OHD3 and 1,25(OH)2D 3 treated animals had a significant decrease in the mean number of lung metastases per animal as compared to vehicle treated control animals. This study therefore suggests an important autocrine role of 1alphaOHase expression in breast tumor cells. Furthermore, accumulation of intra-tumoral 1,25(OH) 2D3 in response to 25OHD3 administration strongly suggests that locally produced 1,25(OH)2D3 plays a significant role in restraining tumor growth without inducing the hypercalcemic side effects associated with 1,25(OH)2D3.
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Ahmad, Fahmida. "Modelling heterogeneity of triple-negative breast cancer in mice to uncover and target signaling essentiality." Thesis, Aix-Marseille, 2020. http://www.theses.fr/2020AIXM0225.
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Le cancer du sein triple négatif (TNBC) est un sous-type de cancer du sein très agressif et hétérogénène qui ne bénéficie actuellement d'aucun traitement efficace. Le but de mon projet de Thèse était d'explorer les mécanismes qui conduisent au TNBC pour concevoir de nouvelles approches thérapeutiques.Dans notre équipe, nous avons généré un modèle de souris unique (souris MMTV-R26Met) dans lesquelles le récepteur tyrosine kinase MET est faiblement augmenté. Elles développent spontanément et exclusivement des TNBC. Ce modèle récapitule la formation de métastases pulmonaires, la résistance aux agents chimiothérapeutiques classiques et à un ensemble de thérapies moléculaires ciblées combinées.Une analyse protéomique des tumeurs MMTV-R26Met combinée à une approche de type "machine learning" ont montré que le modèle MMTV-R26Met récapitule largement l'hétérogénéité du TNBC observée chez les patients TNBC.Nous avons identifié deux nouvelles combinaisons d'agents très délétères pour les lignées cellulaires dérivées de tumeurs MMTV-R26Met et un panel de cellules TNBC humaines. La première cible le facteur anti-apoptotique BCL-XL et CDK1/2 (régulateurs du cycle cellulaire). La deuxième, validée in vivo, agit sur BCL-XL et WEE1 (régulateur du cycle cellulaire et épigénétique). Mécanistiquement, nous montrons que le ciblage combiné de WEE1 et de BCL-XL induit des dommages à l'ADN, une entrée prématurée en mitose, une catastrophe mitotique et l'apoptose.Nos travaux peuvent être très pertinents pour leur transposition potentielle à la clinique, compte tenu également des études prometteuses de monothérapie avec les inhibiteurs de BCL-XL et WEE1 dans les essais cliniques de phase IITriple-negative breast cancer (TNBC) is a highly aggressive, heterogeneous breast cancer subtype, and has currently no effective treatment. The aim of my PhD project was to understand the mechanisms triggering TNBC and to develop new therapeutic approaches.In our lab, we have generated a unique mouse model (MMTV-R26Met mice) in which a subtle increase in the expression levels of the wild-type MET receptor tyrosine kinase leads to spontaneous, exclusive TNBC formation. This model recapitulates formation of lung metastasis, resistance to conventional chemotherapeutic agents and to a set of combined targeted molecular therapies.Proteomic profiling of MMTV-R26Met tumors and machine learning approach showed that the MMTV-R26Met model largely recapitulates TNBC heterogeneity observed in TNBC patients. We identified two new drug combinations highly deleterious for the MMTV-R26Met tumor-derived cell lines, and a panel of human TNBC cells. The first drug combination targets the anti-apoptotic factor BCL-XL and CDK1/2 (cell cycle regulators). The second drug combination, validated by in vivo studies, is based on a combinatorial targeting of BCL-XL and of WEE1 (cell cycle and epigenetic regulator). Mechanistically, we show that combined inhibition of WEE1 and BCL-XL leads to DNA damage, premature entry into mitosis, resulting in mitotic catastrophe and apoptosis.Our findings may be highly relevant for their potential translation to the clinic, also in view of promising studies of monotherapy with BCL-XL and WEE1 inhibitors in phase II clinical trials
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Nanduri, Siva Lahiri Kanth [Verfasser], Ralph [Akademischer Betreuer] Witzgal, Christoph [Akademischer Betreuer] Klein, and Stephan [Akademischer Betreuer] Schneuwly. "Isolation and in vitro expansion of disseminated cancer cells from bone marrow of a transgenic mouse model of breast cancer / Siva Lahiri Kanth Nanduri. Betreuer: Ralph Witzgal ; Christoph Klein ; Stephan Schneuwly." Regensburg : Universitätsbibliothek Regensburg, 2014. http://d-nb.info/1068055642/34.
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FOY, KEVIN CHU. "COMBINATION IMMUNOTHERAPY WITH HER-2/NEU AND VEGF PEPTIDE MIMICS IN BOTH TRANSGENIC AND TRANSPLANTABLE MOUSE MODELS OF HUMAN BREAST CANCER." The Ohio State University, 2011. http://rave.ohiolink.edu/etdc/view?acc_num=osu1299532419.
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Pérez, lanzón María. "Modeling Hormone Receptor Positive Breast Cancer in Immunocompetent Mice Blocking tumor-educated MSC paracrine activity halts osteosarcoma progression Organoids for Modeling Genetic Diseases. In: International Review of Cell and Molecular Biology A preclinical mouse model of osteosarcoma to define the extracellular vesicle-mediated communication between tumor and mesenchymal stem cells Failure of immunosurveillance accelerates aging The metabolomic signature of extreme longevity: Naked mole rats versus mice Lurbinectedin synergizes with immune checkpoint blockade to generate anticancer immunity Laminin-binding integrins are essential for the maintenance of functional mammary secretory epithelium in lactation Immunoprophylactic and immunotherapeutic control of hormone receptor-positive breast cancer." Thesis, université Paris-Saclay, 2021. http://www.theses.fr/2021UPASL019.
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Les progrès de la recherche sur le cancer du sein dépendent de la disponibilité d’outils appropriés, comme les lignées cellulaires qui peuvent être implantées chez des souris immunocompétentes. La souche de souris C57Bl/6 est la plus étudiée et c’est la seule pour laquelle certaines variantes génétiques sont disponibles. Étant donné qu'aucune lignée cellulaire de carcinome mammaire à récepteurs hormonaux positifs de souche C57Bl/6 n'est disponible, nous avons décidé d'établir des lignées cellulaires de ce type. Nous avons induit des cancers du sein chez des souris C57BL/6 femelles en utilisant un analogue synthétique de la progestérone combiné à un agent endommageant l'ADN. Des lignées cellulaires ont été établies à partir de ces tumeurs et sélectionnées pour leur positivité au niveau du double récepteur (estrogène + progestérone), ainsi que pour leur transplantabilité chez les femelles C57BL/6. Parmi plusieurs lignées, une lignée cellulaire, que nous avons appelée MD5, remplissait ces critères et a permis l'établissement de tumeurs mal différenciées et très prolifératives. Ces tumeurs ont réduit leur croissance (sans toutefois régresser) lors du traitement par des antagonistes des récepteurs d’œstrogènes, ainsi que par une chimiothérapie à base d'anthracylines. Cependant, ce dernier effet n'a pas été influencé par la déplétion des lymphocytes T et, en outre, ces tumeurs n'ont pas répondu au blocage de PD-1, ce qui suggère que les tumeurs MD5 sont immunologiquement froides. En conclusion, les cellules MD5, dérivées des animaux C57BL/6, constituent un modèle de cancer du sein à récepteurs hormonaux positifs de mauvais pronosticProgress in breast cancer research relies on the availability of suitable cell lines that can be implanted in immunocompetent laboratory mice. The best explored mouse strain, C57Bl/6, is also the only one for which multiple genetic variants are available. Driven by the fact that no hormone receptor-positive C57Bl/6-derived mammary carcinoma cell lines are available, we decided to establish such cell lines. Breast cancers were induced in female C57BL/6 mice using a synthetic progesterone analogue combined with a DNA damaging agent. Cell lines were established from these tumors and selected for dual (estrogen + progesterone) receptor positivity, as well as transplantability into C57BL/6 females. One cell line, which we called MD5,fulfilled these criteria and allowed for the establishment of poorly differentiated, highly proliferative, immune cold tumors. Such tumors reduced their growth (though did not regress) upon treatment with estrogen receptor antagonists, as well as with anthracyline-based chemotherapy. However, the latter effect was not influenced by T cell depletion and MD tumors failed to respond to PD-1 blockade, suggesting that they are immunologically cold. In conclusion, C57BL/6-derived MD5 cells constitute a model of poor prognosis hormone receptor-positive breast cancer
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Vallerand, David. "Etude du stroma de tumeurs mammaires humaines xénogreffées et de modèles transgéniques murins." Thesis, Paris 11, 2014. http://www.theses.fr/2014PA11T001.
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La progression tumorale est un processus multi-étapes dépendant notamment des interactions entre les cellules cancéreuses et le stroma environnant. Le développement du cancer du sein implique une communication étroite entre les cellules épithéliales mammaires, les cellules inflammatoires, les myofibroblastes et les cellules endothéliales. Ainsi, le microenvironnement tumoral apparaît comme une cible de choix dans le traitement anti-tumoral. L’utilisation de modèles précliniques est une étape clé dans le développement et la validation de nouvelles thérapies. Néanmoins, peu d’études sont disponibles sur le rôle du stroma péri-tumoral dans ces modèles.Dans le but d’étudier le stroma péri-tumoral des modèles précliniques de cancers du sein, nous avons combiné une analyse par cytométrie en flux à une analyse par immunohistochimie afin d’identifier, puis de quantifier, les différentes populations stromales hématopoïétiques (lymphocytes, monocytes/macrophages, polynucléaires) et non hématopoïétiques (myofibroblastes, cellules endothéliales). Vingt et un modèles de xénogreffe de tumeurs humaines de cancers du sein ainsi que 2 modèles transgéniques (MMTV-PyMT et MMTV-ErbB2), ainsi que leurs allogreffes respectives, furent utilisés lors de ce travail.Les analyses des tumeurs humaines et murines ont montré un infiltrat stromal très hétérogène d’une tumeur à l’autre, avec pour composante majoritaire les macrophages. Un infiltrat important en polynucléaires a également été détecté dans les modèles de PDX, caractéristique d’une inflammation locale importante dans ces modèles. L’analyse phénotypique de macrophages a montré une expression variable de marqueurs M1 et M2 dans les modèles de PDX. Les macrophages issus de tumeurs murines transgéniques, spontanées ou allogreffées, présentaient quant à eux un profil majoritairement M1. L’étude transcriptomique de macrophages triés, a permis à la fois de valider les résultats obtenus au niveau protéique mais a également mis en évidence des différences majeures dans l’expression de nombreux gènes, impliqués dans des voies de signalisation variées telles que la croissance tumorale, l’invasion et la métastase.Cette étude nous a permis de mettre en évidence le rôle de la tumeur sur son microenvironnement. En effet, celle-ci est à la fois capable d’attirer un panel de cellules stromales qui lui et propre et ensuite de l’activer de façon spécifiqueTumor development is a multi-step process influencing by interactions between tumor cells and surrounding stroma. Breast cancer development involves a high level of communication between mammary epithelial cells, inflammatory cells, myofibroblasts and endothelial cells. So, the tumoral microenvironment appears as a prime target for anti-tumoral treatment. The use of preclinical models is a critical step in development and validation processes of new therapies. Nevertheless, the role of stroma in these models is poorly understood.In order to evaluate stromal cell populations in breast cancer preclinical models, we combined flow cytometry analysis and immunohistochemistry to identify, and then quantify, various stromal populations as hematopoietic cells (lymphocytes, monocytes/macrophages, polymorphonuclear leukocytes) and non-hematopoietic cells (myofibroblasts, endothelial cells). Twenty-one breast cancer patient-derived xenografts as well as 2 transgenic mouse models (MMTV-PyMT and MMTV-ErbB2), and their respective allografts, were studied.Analysis of human and murine tumors showed a strong heterogeneity between tumors regarding infiltrating stroma-cells, with a high proportion of macrophages. A significant amount of polymorphonuclear leukocytes was also detected in PDXs, indicating a local inflammation in these models. The phenotypic analysis of macrophages showed a variable expression of M1 and M2 markers in PDXs. Macrophages infiltrating transgenic mouse tumors, spontaneous or allografted, were mainly M1. Transcriptomic analyses of sorted macrophages, allowed us to validate previous results but also highlighted major differences in the expression of numerous genes implicated in various pathways as tumor growth, invasion and metastasis.Finally, this study highlighted the impact of tumor cells on their surrounding stroma. Indeed, we demonstrate that cancer cells are able to attract a specific panel of stromal cells and activate them in a specific way
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Scully, Jaqueline Susan. "Insertion of oncogenes into mouse mammary epithelium." Thesis, University of Cambridge, 1989. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.315287.
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Chambers, Julie Anne. "Analysis of the BRCA1 region in human and mouse." Thesis, University College London (University of London), 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.298465.
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Abram, Clare L. "Expression of oncogenes in mouse mammary epithelium by transplantation." Thesis, University of Cambridge, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.307957.
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Worrall, Lisa Kirsty. "A 3D in vitro breast cancer model." Thesis, University of Nottingham, 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.436812.
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Kishi, Masae. "Strategies of Cancer Immunotherapy : Model of Triple Negative Breast Cancer." Thesis, Université Paris-Saclay (ComUE), 2019. http://www.theses.fr/2019SACLS070.
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Les cellules souches cancéreuses (CSC) sont à l’origine de la progression tumorale, des métastases et rechutes tardives. Elles ont été identifiées dans de nombreux cancers, comme le cancer du sein triple négatif (TNBC) et cancers de grade III-IV. Elles sont résistantes aux chimiothérapies et radiothérapie et résident dans une niche immuno-répressive. Cette étude vise à évaluer une stratégie d’immunothérapie qui cible sélectivement les CSC dans le modèle murin 4T1-GFP-Luc mimant le TNBC. Le phénotype/ génotype des mamosphères a été initialement caractérisé. Basée sur l’analyse génomique des CSC, nous avons développé une immunothérapie active associée à des agents immuno-modulateurs. Nous avons mesuré la taille des tumeurs et suivi l’apparition des métastases par bioluminescence. Une étude immunologique et analyse génomique de la tumeur a été réalisée. La combinaison thérapeutique provoque le recrutement dans la tumeur de lymphocytes T (CD4 +, CD8 +) et lymphocytes B par augmentation de CXCL13, une réduction des lymphocytes T reg et cellules myéloïdes suppressives. Cette induction de réponse immunitaire provoque la diminution de la taille de la tumeur et des métastases. Cette nouvelle immunothérapie active de type vaccinale pourra être utilisée en association avec les traitements actuels pour des mesures prophylactiques et curatives dans une grande variété de cancersCancer stem cells (CSCs) are responsible for tumor progression, metastases, and late relapses. They have been identified in many cancers, such as triple negative breast cancer (TNBC) and grade III to IV cancers. They are resistant to chemotherapy and radiotherapy and reside in an immuno-repressive niche.This study aims to evaluate a immunotherapy strategy that selectively targets CSCs in the mouse model 4T1-GFP-Luc mimicking TNBC. The phenotype / genotype of mammosphere was initially characterized. Based on genomic analysis of CSC, we have developed an active immunotherapy associated with immunomodulatory agents. We measured the size of tumors and monitored the appearance of metastases by bioluminescence. We performed an immunological study and genomic tumor analysis. The therapeutic combination causes the recruitment of CD4 + and CD8 + T lymphocytes and B lymphocytes with increased CXCL13, the reduction of T reg cells and suppressive myeloid cells in the tumor. This induction of intra-tumor immune response leads to a decrease in tumor size and metastases.This new active immunotherapy can be used in combination with current treatments for prophylactic and curative measures in a wide variety of cancers
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Meaney, Mary Patricia. "The growth of murine breast cancer cells in dystrophic mice." Diss., Virginia Tech, 2011. http://hdl.handle.net/10919/40177.
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The American Cancer Society predicted that 230,480 women would be diagnosed with, and 39,520 women would die from breast cancer (BC) in the United States in 2011. While the incidence of female BC has been decreasing, BC remains the second leading cause of cancer death among women in the United States. Cancer cachexia, the cancer-related loss of muscle, affects up to 25% of BC patients and is associated with poor prognosis and decreased quality of life. Alterations to the dystrophin glycoprotein complex (DGC), a transmembrane, multi-subunit protein complex with structural and signaling roles, have been reported in mammary tumors of BC patients and skeletal muscles of cachectic cancer patients. However, this complex is most frequently studied for its role in Duchenne muscular dystrophy (DMD), a severe, progressive muscle wasting disease. Despite the similar alterations reported in these diseases, it is unclear whether alterations in the DGC in one tissue can impact the progression of disease in another. Purpose: The purpose of the studies described in this dissertation was to identify differences in body composition, energy expenditure and plasma cytokine content between the C57BL/10ScSn-Dmdmdx/J (mdx) mouse model of DMD and C57BL/10ScSnJ (BL/10) control mice and to determine whether systemic alteration of the DGC (as observed in the mdx mouse) alters the growth of E0771 murine mammary tumors. Results: There were differences in body composition and plasma cytokine profiles between mdx and BL/10 mice. We also found that, relative to controls, the tumorâ induced increase in cytokines that promote invasion and metastasis was not as severe in mdx mice. Conclusions: This study revealed several differences between mdx and BL/10 mice and provides support for the suggestion that the mdx mouse may not be an accurate model of DMD. In addition, the improved cytokine profile of tumor-bearing mdx mice suggests that the acute phase of DMD may be protective against BC invasion and metastasis. Further research should confirm this effect and determine whether alterations in the DGC of the mdx mouse are directly or indirectly responsible.Ph. D.
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Jones, Christina Michele. "Applications and challenges in mass spectrometry-based untargeted metabolomics." Diss., Georgia Institute of Technology, 2015. http://hdl.handle.net/1853/54830.
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Metabolomics is the methodical scientific study of biochemical processes associated with the metabolome—which comprises the entire collection of metabolites in any biological entity. Metabolome changes occur as a result of modifications in the genome and proteome, and are, therefore, directly related to cellular phenotype. Thus, metabolomic analysis is capable of providing a snapshot of cellular physiology. Untargeted metabolomics is an impartial, all-inclusive approach for detecting as many metabolites as possible without a priori knowledge of their identity. Hence, it is a valuable exploratory tool capable of providing extensive chemical information for discovery and hypothesis-generation regarding biochemical processes. A history of metabolomics and advances in the field corresponding to improved analytical technologies are described in Chapter 1 of this dissertation. Additionally, Chapter 1 introduces the analytical workflows involved in untargeted metabolomics research to provide a foundation for Chapters 2 – 5.
Part I of this dissertation which encompasses Chapters 2 – 3 describes the utilization of mass spectrometry (MS)-based untargeted metabolomic analysis to acquire new insight into cancer detection. There is a knowledge deficit regarding the biochemical processes of the origin and proliferative molecular mechanisms of many types of cancer which has also led to a shortage of sensitive and specific biomarkers. Chapter 2 describes the development of an in vitro diagnostic multivariate index assay (IVDMIA) for prostate cancer (PCa) prediction based on ultra performance liquid chromatography-mass spectrometry (UPLC-MS) metabolic profiling of blood serum samples from 64 PCa patients and 50 healthy individuals. A panel of 40 metabolic spectral features was found to be differential with 92.1% sensitivity, 94.3% specificity, and 93.0% accuracy. The performance of the IVDMIA was higher than the prevalent prostate-specific antigen blood test, thus, highlighting that a combination of multiple discriminant features yields higher predictive power for PCa detection than the univariate analysis of a single marker. Chapter 3 describes two approaches that were taken to investigate metabolic patterns for early detection of ovarian cancer (OC). First, Dicer-Pten double knockout (DKO) mice that phenocopy many of the features of metastatic high-grade serous carcinoma (HGSC) observed in women were studied. Using UPLC-MS, serum samples from 14 early-stage tumor DKO mice and 11 controls were analyzed. Iterative multivariate classification selected 18 metabolites that, when considered as a panel, yielded 100% accuracy, sensitivity, and specificity for early-stage HGSC detection. In the second approach, serum metabolic phenotypes of an early-stage OC pilot patient cohort were characterized. Serum samples were collected from 24 early-stage OC patients and 40 healthy women, and subsequently analyzed using UPLC-MS. Multivariate statistical analysis employing support vector machine learning methods and recursive feature elimination selected a panel of metabolites that differentiated between age-matched samples with 100% cross-validated accuracy, sensitivity, and specificity. This small pilot study demonstrated that metabolic phenotypes may be useful for detecting early-stage OC and, thus, supports conducting larger, more comprehensive studies.
Many challenges exist in the field of untargeted metabolomics.
Part II of this dissertation which encompasses Chapters 4 – 5 focuses on two specific challenges. While metabolomic data may be used to generate hypothesis concerning biological processes, determining causal relationships within metabolic networks with only metabolomic data is impractical. Proteins play major roles in these networks; therefore, pairing metabolomic information with that acquired from proteomics gives a more comprehensive snapshot of perturbations to metabolic pathways. Chapter 4 describes the integration of MS- and NMR-based metabolomics with proteomics analyses to investigate the role of chemically mediated ecological interactions between Karenia brevis and two diatom competitors, Asterionellopsis glacialis and Thalassiosira pseudonana. This integrated systems biology approach showed that K. brevis allelopathy distinctively perturbed the metabolisms of these two competitors. A. glacialis had a more robust metabolic response to K. brevis allelopathy which may be a result of its repeated exposure to K. brevis blooms in the Gulf of Mexico. However, K. brevis allelopathy disrupted energy metabolism and obstructed cellular protection mechanisms including altering cell membrane components, inhibiting osmoregulation, and increasing oxidative stress in T. pseudonana. This work represents the first instance of metabolites and proteins measured simultaneously to understand the effects of allelopathy or in fact any form of competition.
Chromatography is traditionally coupled to MS for untargeted metabolomics studies. While coupling chromatography to MS greatly enhances metabolome analysis due to the orthogonality of the techniques, the lengthy analysis times pose challenges for large metabolomics studies. Consequently, there is still a need for developing higher throughput MS approaches. A rapid metabolic fingerprinting method that utilizes a new transmission mode direct analysis in real time (TM-DART) ambient sampling technique is presented in Chapter 5. The optimization of TM-DART parameters directly affecting metabolite desorption and ionization, such as sample position and ionizing gas desorption temperature, was critical in achieving high sensitivity and detecting a broad mass range of metabolites. In terms of reproducibility, TM-DART compared favorably with traditional probe mode DART analysis, with coefficients of variation as low as 16%. TM-DART MS proved to be a powerful analytical technique for rapid metabolome analysis of human blood sera and was adapted for exhaled breath condensate (EBC) analysis. To determine the feasibility of utilizing TM-DART for metabolomics investigations, TM-DART was interfaced with traveling wave ion mobility spectrometry (TWIMS) time-of-flight (TOF) MS for the analysis of EBC samples from cystic fibrosis patients and healthy controls. TM-DART-TWIMS-TOF MS was able to successfully detect cystic fibrosis in this small sample cohort, thereby, demonstrating it can be employed for probing metabolome changes.
Finally, in Chapter 6, a perspective on the presented work is provided along with goals on which future studies may focus.
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Bobick, Todd M. "Transtheoretical model and exercise in breast cancer survivors." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1999. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape8/PQDD_0020/MQ47009.pdf.
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Fazeli, Amin. "Construction of a mouse model of colon cancer." Thesis, Massachusetts Institute of Technology, 1997. http://hdl.handle.net/1721.1/43348.
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Cong, Chunling. "Statistical Analysis and Modeling of Breast Cancer and Lung Cancer." Scholar Commons, 2010. http://scholarcommons.usf.edu/etd/3563.
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The objective of the present study is to investigate various problems associate with breast cancer and lung cancer patients. In this study, we compare the effectiveness of breast cancer treatments using decision tree analysis and come to the conclusion that although certain treatment shows overall effectiveness over the others, physicians or doctors should discretionally give different treatment to breast cancer patients based on their characteristics. Reoccurrence time of breast caner patients who receive different treatments are compared in an overall sense, histology type is also taken into consideration. To further understand the relation between relapse time and other variables, statistical models are applied to identify the attribute variables and predict the relapse time. Of equal importance, the transition between different breast cancer stages are analyzed through Markov Chain which not only gives the transition probability between stages for specific treatment but also provide guidance on breast cancer treatment based on stating information.
Sensitivity analysis is conducted on breast cancer doubling time which involves two commonly used assumptions: spherical tumor and exponential growth of tumor and the analysis reveals that variation from those assumptions could cause very different statistical behavior of breast cancer doubling time.
In lung cancer study, we investigate the mortality time of lung cancer patients from several different perspectives: gender, cigarettes per day and duration of smoking. Statistical model is also used to predict the mortality time of lung cancer patients.
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Patino, Patricia. "Breast cancer: Relationship between acculturation and barriers to breast cancer screening in Southwest Florida Latinas." Scholar Commons, 2006. http://scholarcommons.usf.edu/etd/2656.
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Despite multiple campaigns by the American Cancer Society, reports indicate that Latinas living in the United States who contract breast cancer are more likely than Anglos to die. These findings correlate with low participation in breast cancer screenings among Latinas. The objective of this study was to identify key obstacles that influence Latinas' low participation in breast cancer screenings, based on their health beliefs, knowledge of screenings, acculturation, and socio-economic factors.The study was a face-to-face informal interview, combined with a survey questionnaire conducted at churches, social clubs and/or at the participants' homes in a southwest Florida urban community. The sample consisted of a total of 50 women: all of the participants were Latinas 40 years of age and over; they had to be fluent in Spanish or English or both. A Spanish-English bilingual individual conducted a personal interview in the preferred language of each participant.
The first part of the interview was to identify barriers that affect screenings. The second part used a survey to weigh the identified factors in order to determine their importance to the participants' health decisions. This study used a health belief model scale to evaluate women's beliefs about breast cancer, and the benefits of screenings.The research results revealed that Latinas who participated in this study were acculturated to the United States culture; the largest group of participants reported being from Colombia, followed by Cuba and Puerto Rico; only two of the participants were Mexican. Seventy-eight percent of the participants self- reported having yearly mammograms, and 74% performed monthly breast self examination BSE; 60% were bilingual; 68% had some kind of health insurance. These results differ from earlier studies from the western United States where the majority of Latinas were of Mexican or Central American origin.
This suggested that Latinas from Southwest Florida are different from Latinas in other areas of the United States. A weak but significant correlation was found between acculturation and perceived barriers to breast cancer screenings, (r = 0.45, p = .01); Latinas who are more acculturated perceived more barriers than those who are less acculturated. There was not significant difference between participants who had health insurance and those who did not (t = 0.96, p = .35). The results of this study are significant for nurses and especially for advanced practice nurses, who can assess patients' knowledge about cancer in general, and breast cancer in particular when caring for Latinas; of particular concern should be the evaluation of patients' levels of acculturation, health beliefs, and understanding of the English language. Still the fundamental barrier to Latinas not bilingual in Spanish and English may be the lack of resources and information in Spanish.
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Želvienė, Aušra. "Women beliefs towards breast cancer, breast self-examination and mammography in connection with participation in breast cancer screening." Doctoral thesis, Lithuanian Academic Libraries Network (LABT), 2008. http://vddb.library.lt/obj/LT-eLABa-0001:E.02~2008~D_20080129_121108-78281.
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The aim of the study is to assess the connection between women’s participation in breast cancer screening and beliefs towards breast cancer, breast self-examination and mammography.
The objectives of the study:
1. To assess validity and reliability of Champion Health Belief Model Scale for beliefs towards breast cancer, breast self-examination and mammography screening for Lithuanian women.
2. To estimate perceived susceptibility, perceived severity, perceived benefits, perceived barriers, confidence and health motivation.
3. To compare beliefs towards breast cancer, breast self-examination and mammography screening of participant and non-participant women in the screening program.
4. To assess perceived barriers towards mammography screening.
5. To investigate the role of information about breast cancer and mammography screening for women‘s beliefs towards breast cancer, breast self-examination and mammography screening.
CONCLUSIONS
1. Champion Health Belief Model Scale is a valid and reliable to assess beliefs towards breast cancer, breast self- examination and mammography. The barriers- mammography item “Regular mammography screening would make me worry about breast cancer” was inappropriate to the scale and expunged from the questionnaire.
2. Surveyed women did not feel much threat to get breast cancer. They overvalued benefits of breast self-examination and positively rated mammography screening. However, confidence to perform breast self-examination was properly low... [to full text]Šio darbo tikslas buvo įvertinti atvykusių ir neatvykusių tikrintis mamografiškai moterų nuostatų į krūties vėžį, krūtų savityrą ir atrankinę mamografinę patikrą skirtumus. Tikslui pasiekti iškelti tokie uždaviniai: 1. Įvertinti Champion VL sveikatos įsitikinimų modelio klausimyno tinkamumą tirti Lietuvos moterų nuostatoms į krūties vėžį, krūtų savityrą ir atrankinę mamografinę patikrą. 2. Nustatyti moterų suvoktą krūties vėžio grėsmę, apsaugančios nuo krūties vėžio pasekmių elgsenos naudą ir kliūtis šiai veiklai, sveikos gyvensenos motyvaciją. 3. Palyginti atvykusių ir neatvykusių tirtis mamografiškai dėl krūties vėžio moterų nuostatas į krūties vėžį, krūtų savityrą ir atrankinę mamografinę patikrą. 4. Įvertinti dalyvavusių atrankinėje mamografinėje patikroje dėl krūties vėžio moterų kliūtis tirtis mamografiškai. 5. Ištirti papildomos informacijos apie krūties vėžį, mamografinę patikrą įtaką moterų nuostatoms į krūties vėžį, savityrą bei atrankinę mamografinę patikrą ir moterų dalyvavimui atrankinės patikros programoje. Išvados: 1. Patikrintas ir įteisintas VL Champion sveikatos įsitikinimų modelio skalės klausimynas yra tinkamas Lietuvos moterų nuostatoms į krūties vėžį, krūtų savityrą ir atrankinę mamografinę patikrą tirti. Sveikos gyvensenos motyvacijos skalė turi būti padalinta į požiūrio į sveiką gyvenseną ir veiklos sveikatos labui subskales. Kliūčių tirtis mamografiškai teiginys “reguliarus mamografinis ištyrimas verstų mane nerimauti dėl krūties vėžio” išbrauktas... [toliau žr. visą tekstą]
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Wang, Ying. "Mouse Models of Menopause and Ovarian Cancer Risks." Scholarly Repository, 2011. http://scholarlyrepository.miami.edu/oa_dissertations/681.
Full textAbstract:
Epithelial ovarian cancer (EOC) is the leading cause of death from gynecological malignancy in Western countries. A better understanding of the etiology and risk factors associated with this disease is crucial for the development of early detection protocols as well as more effective therapies. Epidemiological data has shown that the risks of EOC are highest among peri- or post- menopause women, while increased parity or the use of oral contraceptives is preventive. These data suggest that alterations in reproductive factors are associated with ovarian cancer risks; however, the molecular mechanisms underlying such a link remain to be understood. For decades, EOC was believed to arise from the epithelium that surrounds the ovarian surface, yet this concept fails to explain the morphological resemblance of ovarian epithelial neoplasms with the epithelial cells of the Müllerian-derived female reproductive tract. Alternative ideas have argued that EOC may originate from extra- or para-ovarian tissues such as the fallopian tube and ovarii rete. Studies of the origin of EOC will provide a better understanding of the disease and advance the protocols for early diagnosis. The aims for this thesis are to establish in vivo ovarian tumor models based on the germ cell deficient Wv/Wv mice that mimicking menopausal physiology. The Wv mice harbor a point mutation in c-Kit, which reduces its tyrosine kinase activity to about 1%, resulting in a premature loss of ovarian germ cells and follicles that recapitulates the initiation of menopause in human. We have developed ovarian tumor models by deleting the tumor suppressor genes p53 or p27kip1 in Wv/Wv mice. We found that both Wv/Wv:p27+/- and Wv/Wv :p27 -/- mice developed ovarian epithelial tumors, which consist of papillary structures lined by hyperchromatic neoplastic cells. Positive Cytokeratin 8 (CK8) staining indicated the epithelial origin of these tumors. In vitro primary cultures of mouse ovarian surface epithelial (MOSE) cells from wildtype, p27+/- and p27 -/- mice further confirmed the growth advantage caused by p27 deficiency. However, neither p27 +/- nor p27 -/- MOSE cells were transformed in vitro, probably due to the compensatory increase of cyclin dependent kinase inhibitor (CKI) proteins including p21, p16, p19. When p53 was deleted unilaterally in the ovarian surface epithelial cells of Wv/Wv:p53 loxP/loxP mice by single administration of Adenovirus containing Cre activity (Ad-Cre), ovarian tumors developed after long latency. The ovarian tumors were significantly enlarged when compared with the uninfected ovary from the same mouse. However, most of the lesions in Wv:p53 conditional knockout tumors was negative for epithelial and follicular markers. In vitro deletion of p53 in MOSE cells significantly increased the proliferation and passage numbers of these cells. A compensatory increase of the CKI protein p16, as well as the cellular senescence level was also observed in p53 deleted MOSE cells, suggesting that p53 deletion alone was not sufficient to bypass p16- mediated tumor defense mechanisms in MOSE cells. Taken together, single deletion of p27 and p53 significantly amplified the phenotype of benign tubular adenomas in Wv/Wv mouse. However, neither p27 nor p53 deletion was sufficient to induce the development of malignant ovarian carcinomas in Wv/Wv mice, probably due to the up-regulation of CKI family proteins such as p21, p16 or p19.
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Kim, Jong Bin. "Development of a fully "humanized" xenograft model of breast cancer." Thesis, University College London (University of London), 2005. http://discovery.ucl.ac.uk/1444826/.
Full textAbstract:
Until now there has been a distinct lack of a truly representative breast cancer model. The development of a complex heterologous multi-compartment xenograft model incorporating the relevant stromal elements will provide a realistic alternative to currently available chimeric xenograft models. The recent ability to immortalize primary human mammary endothelial cells and fibroblasts by the insertion of the hTERT and a temperature sensitive mutant variant of SV40 LT has made this possible. We have commenced the development of an organotypic, 3-compartment xenograft model of human breast cancer. The immortalized mammary stromal cells provide a viable and much needed tumour microenvironment of human origin for tumour proliferation. Results have confirmed the crucial importance of stromal cell support as well as tumour-stromal interactions in tumourigenesis. MCF-7 cells when xenografted in numbers insufficient to produce tumours alone, consistently produced tumours when combined with stromal cells. Also, heterologous xenografts produced not only faster growing but larger tumours than tumour cell lines alone. Immunohistochemical analysis using human cell specific markers demonstrated that initial tumour growth was supported by the stromal cells before the recruitment of host vasculature. The xenografts were composed predominantly of proliferating tumour cells, host ECM and vasculature. Surprisingly the LT antigen expressing immortalized stromal cells did not survive, proliferate or form organized structures in this environment for any reasonable time period. To conclude, these findings parallel observations made in 3-D organotypic cultures which indicates that progression of the epithelial cell tumour is not cell autonomous. Rather, that tumourigenesis is promoted, and probably sometimes induced, by the anomalies in the surrounding stroma and microenvironment. With further refinement and adjustments this model can be utilized as a credible pre-clinical model for the development and testing of new therapeutic strategies, such as those that target breast cancer stroma itself. This is very timely as stroma is now emerging as the dominant factor in modulating epithelial morphogenesis and mitogenesis.
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Clifford, Adrianne Brown. "Tumor Associated Macrophages in a MaFIA Mouse Model." Diss., CLICK HERE for online access, 2006. http://contentdm.lib.byu.edu/ETD/image/etd1427.pdf.
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Lawson, Jessica Clair. "Analysis of the anti-cancer activity of novel indigenous algal compounds in breast cancer: towards the development of a model for screening anti-cancer stem cell activity." Thesis, Rhodes University, 2010. http://hdl.handle.net/10962/d1003984.
Full textAbstract:
Breast cancer, the most common malignancy diagnosed in women, is one of the leading causes of death in women worldwide. In South Africa only 32% of women diagnosed with advanced breast cancer survive more than five years. The search for new chemotherapeutic agents capable of effectively treating breast cancer is therefore essential. Recent evidence supporting the cancer stem cell theory of cancer development for breast cancer challenges the current theories of cancer development and hence treatment. Cancer stem cells are a small subpopulation of tumour cells that possess properties of both cancer cells and stem cells and are believed to be the tumour-initiating population of many cancers. Cancer stem cells are inherently resistant to many chemotherapeutic agents and in this way have been associated with repopulation of tumours after chemotherapy. This phenomenon is proposed as a possible mechanism for cancer relapse after treatment. Cancer stem cells have also been implicated in metastasis, the major cause of mortality in cancer patients. Therefore, any treatment that is capable of targeting and removing breast cancer stem cells may have the theoretical potential to effectively treat breast cancer. However, there are currently no such treatments available for clinical use. We were provided access to a library of novel indigenous small molecules isolated from red and brown algae found off the Eastern Cape of South Africa. The aim of this project was to analyse the anti-cancer and anti-cancer stem cell properties of the compounds in this library and to identify „hit‟ compounds which could form the basis for future development into new anti-cancer drugs. Ten novel compounds of algal origin were tested for cytotoxicity, by determining their ability to inhibit the growth of MCF12A breast epithelial cells and MCF7 breast cancer cells using the colorimetric MTT [(3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] cell proliferation assay. All but one of the compounds tested exhibited cytotoxicity towards the MCF7 cancer cell line, with IC50 values (the concentration of the compound that leads to a 50% inhibition in cell growth) of between 3 μM and 90 μM. The chemotherapeutic drug paclitaxel was used as a positive control. Four of the compounds (RUMB-001, RUMB-002, RUMB-007 and RUMB-010/saragaquinoic acid) were significantly more toxic to the MCF7 cancer cell line, than the „normal‟ MCF12A breast cells and were selected as priority compounds for further analyses. In addition, two other compounds were selected as priority compounds, one highly cytotoxic towards both MCF12A and MCF7 cell lines (RUMB-015) and one which was non toxic to either cell line (RUMB-017/018). Preliminary studies into the mechanism of cytotoxicity using Western blot analysis for poly (ADP-ribose) polymerase (PARP) cleavage and Hoechst 33342 immunostaining in MCF-7 cells were largely unsuccessful. The Hoechst 33342 immunostaining assay did provide tentative evidence that selected priority compounds were capable of inducing apoptosis, although these assays will need to be repeated using a less subjective assay to confirm the results. The priority compounds were subsequently investigated for their cytotoxic effect on the cancer stem cell-enriched side population in MCF7 cells. The ability of the priority compounds to selectively target the cancer stem cell containing side population was assessed using two complementary flow cytometry-based techniques – namely the Hoechst 33342-exclusion assay, and fluorescent immunostaining for the expression of the putative cancer stem cell marker, ABCG2+. The ABCG2+ staining assay was a novel technique developed during the course of this study. It remains to be fully validated, but it may provide a new and reliable way to identify and analyse cancer stem cell containing side population cells. The MCF7 cells were treated with the compounds and the proportion of putative cancer stem cells compared with the size of the population in untreated cells was assessed. Three compounds (RUMB-010, RUMB-015 and RUMB-017/018) capable of reducing the proportion of side population cells within the MCF7 cell line were identified. Taking these data together, we identified two potential „hit‟ compounds which should be prioritised for future research. These are compounds RUMB-010/sargaquinoic acid and RUMB-017/018. RUMB-010 is of interest as it was shown to target the putative cancer stem cell population, in addition to the bulk MCF7 tumour line, but was relatively less toxic to the „normal‟ MCF12A cell line. RUMB-017/018 is of interest due to the ability to selectively target the cancer stem cell enriched side population, while having little effect on the normal (MCF12A) or bulk tumour (MCF7) cell lines tested. These compounds will be important as „hit‟ compounds for drug development and as tool compounds to study cancer and cancer stem cell biology.
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Antoniou, A. C. "Developing a comprehensive risk model for familial breast and ovarian cancer." Thesis, University of Cambridge, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.596129.
Full textAbstract:
The specific aim of this thesis was to combine data on mutation prevalence and risk from both high risk families and population based series, in order to develop a model for familial breast and ovarian cancer which incorporates both the effects of BRCA1, BRCA2 and other genes. The principal methodology used was segregation analysis and the genetic models were constructed using the computer program MENDEL. The first dataset consisted of 112 families containing two or more relatives with epithelial ovarian cancer. BRCA1 and BRCA2 germline mutations were detected in 50% of these families. When the effects of BRCA1, BRCA2 and a third ovarian cancer susceptibility gene were modelled simultaneously none of the models fitted gave significant evidence for a third gene. BRCA1 and BRCA2 were estimated to account for at least 38 % of the excess familial risk of ovarian cancer. Using data on the families of twelve BRCA1 mutation carriers in a study of 374 ovarian cancer cases unselected for family history, the estimated ovarian cancer risk by age 70 was 66% and the corresponding breast cancer risk was 45%. The breast cancer dataset consisted of 1484 women diagnosed with breast cancer under the age 55 from whom blood samples were analysed for mutations in BRCA1 and BRCA2. Using information on breast and ovarian cancer history in first degree relatives, and on the mutation status of the index cases we estimated the effects of BRCA1, BRCA2, a third gene BRCA3 and a polygenic effect. For this purpose the Hypergeometric Polygenic model was implemented in MENDEL.
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Titova, A. Yu. "Fuzzy Model Thermal Image Analysis for Detection Breast Cancer in Women." Thesis, Sumy State University, 2016. http://essuir.sumdu.edu.ua/handle/123456789/47075.
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Fuzzy model thermal image analysis diagnostic information system was described. Input and output linguistic variables of fuzzy model of information system diagnostic of breast cancer in women were characterized. Selection of membership functions was realized. Fuzzy knowledge base was created on the basis of expert statements.
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An, Wenxin, and 安文欣. "Validation studies of the Gail Model for breast cancer : a systematic review." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2014. http://hdl.handle.net/10722/206924.
Full textAbstract:
Background: The Gail Model is a statistical and risk assessment tool for women with given age and risk factors to estimate their probability that will develop invasive breast cancer. An accurate assessment of individual risk for developing breast cancer would be useful for health care providers to facilitate their risk communication with women at average risk and to make decision on taking chemoprevention for high-risk women in clinical practice. Currently, there are several validation studies of the Gail Model in western populations, however, model validity on Chinese people has not yet to be studied.
Objective: To conduct a systematic review on the studies that validated the performance accuracy of the Gail model for predicting risk of developing breast cancer at population level and individual level.
Methods and results: The literature search on the PubMed database and additional articles retrieved by hand searching reference lists. After applying the inclusion and exclusion criteria, a total of 11 studies met the criteria and finally include in the systematic review. Quality of review studies was assessed follow the STROBE checklist. The PRSMA guidelines were used to produce this review.
Conclusions: The Gail model was validated in general American white women with annual screening. However, there is insufficient evidence to approve that the Gail model can be applied to Chinese women in China widely.published_or_final_version
Public Health
Master
Master of Public Health
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Moyo, Buhle. "The screening and characterisation of compounds for modulators of heat shock protein (Hsp90) in a breast cancer cell model." Thesis, Rhodes University, 2013. http://hdl.handle.net/10962/d1004129.
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Breast cancer is a leading cause of cancer death in Africa. Hsp90 has been identified as a target for anti-cancer treatments as its inhibition results in the disruption and ubiquitin–proteasome degradation of activated oncoproteins. Currently, there are no US Food and Drug Administration approved Hsp90 inhibitor drugs and existing Hsp90 inhibitors such as geldanamycin and novobiocin are hepatotoxic and display a low affinity for Hsp90, respectively. Therefore, there is a need for the development of Hsp90 inhibitors with improved inhibitory properties. In this study twelve natural compounds bearing a quinone nucleus were screened and characterised for the modulation of Hsp90. The compounds analysed formed three series; the sargaquinoic acid (SQA), naphthoquinone, and pyrroloiminoquinone alkaloid series. Certain compounds exhibited half maximal inhibitory concentrations of between 3.32 μM and 12.4 μM, while others showed no antiproliferative activity at concentrations of up to 500 μM in the MDA-MB-231 breast adenocarcinoma cell line. Immunofluorescence and Western analyses indicated that the modulation of Hsp90 and partner proteins by SQA was more similar to that of novobiocin. Isothermal titration calorimetry analyses suggested that SQA interacted with Hsp90β with a low affinity, and saturation-transfer difference nuclear magnetic resonance confirmed that this interaction with Hsp90β occurred through the methyl moiety bound to 1, 4 benzoquinone of SQA. Pulldown assays indicated SQA disrupted the association between Hsp90 and Hop dose-dependently, more similarly to novobiocin. Immunofluorescence and Western analyses performed on naphthoquinone and pyrroloiminoquinone alkaloid compounds indicated modulation of Hsp90 and Hsp90 partner proteins by the compounds. Naphthoquinone compounds were prioritised for analysis for binding to Hsp90β over the pyrroloiminoquinone alkaloid compounds. Lapachol interacted with Hsp90β with a low affinity however; this interaction was thought to be too weak to disrupt the association of Hsp90 and Hop. The remaining naphthoquinone compounds showed no interaction with Hsp90β, thus allowing the determination of a preliminary structure-activity relationship for these compounds. To the best of our knowledge, this is the first study to describe a systematic subcellular analysis of the effects of geldanamycin and novobiocin in comparison to sargaquinoic acid and compounds of the naphthoquinone and pyrroloquinoline scaffold on Hsp90 and its partner proteins.Microsoft� Word 2010
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Bagshaw, Rachel Jane. "Expression and inhibition of subclass I receptor tyrosine kinases in a rat mammary model." Thesis, University of Liverpool, 1994. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.260352.
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Yu, Kin-wa Bless. "An exploratory design of a body-mind-spirit model for helping breast cancer patients." Click to view the E-thesis via HKUTO, 2002. http://sunzi.lib.hku.hk/hkuto/record/B31979397.
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Ouinten, Y. "Models to evaluate schemes for an early detection of breast cancer." Thesis, University of Southampton, 1988. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.380582.
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Devamitta, Perera Muditha V. "Statistical Analysis and Modeling of Ovarian and Breast Cancer." Scholar Commons, 2017. https://scholarcommons.usf.edu/etd/7395.
Full textAbstract:
The objective of the present study is to investigate key aspects of ovarian and breast cancers, which are two main causes of mortality among women. Identification of the true behavior of survivorship and influential risk factors is essential in designing treatment protocols, increasing disease awareness and preventing possible causes of disease. There is a commonly held belief that African Americans have a higher risk of cancer mortality. We studied racial disparities of women diagnosed with ovarian cancer on overall and disease-free survival and found out that there is no significant difference in the survival experience among the three races: Whites, African Americans and Other races. Tumor sizes at diagnosis among the races were significantly different, as African American women tend to have larger ovarian tumor sizes at the diagnosis. Prognostic models play a major role in health data research. They can be used to estimate adjusted survival probabilities and absolute and relative risks, and to determine significantly contributing risk factors. A prognostic model will be a valuable tool only if it is developed carefully, evaluating the underlying model assumptions and inadequacies and determining if the most relevant model to address the study objectives is selected. In the present study we developed such statistical models for survival data of ovarian and breast cancers. We found that the histology of ovarian cancer had risk ratios that vary over time. We built two types of parametric models to estimate absolute risks and survival probabilities and to adjust the time dependency of the relative risk of Histology. One parametric model is based on classical probability distributions and the other is a more flexible parametric model that estimates the baseline cumulative hazard function using spline functions. In contrast to women diagnosed with ovarian cancer, women with breast cancer showed significantly different survivorship among races where Whites had a poorer overall survival rate compared to African Americans and Other races. In the breast cancer study, we identified that age and progesterone receptor status have time dependent hazard ratios and age and tumor size display non-linear effects on the hazard. We adjusted those non-proportional hazards and non-linear effects by using an extended Cox regression model in order to generate more meaningful interpretations of the data.
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Draganov, Dobrin Draganov. "MFG-E8 Blockade Enhances Tumor Immunity in a Murine Breast Cancer Model." Thesis, Harvard University, 2012. http://dissertations.umi.com/gsas.harvard:10512.
Full textAbstract:
Milk fat globule - epidermal growth factor - factor 8 protein (MFG-E8) is an important mediator of the tolerogenic functions of GM-CSF, and a dominant-negative RGE mutant augments the therapeutic potential of irradiated, GM-CSF-secreting tumor vaccines (GVAX) in the MFG-E8-negative B16 melanoma model. The frequent expression of MFG-E8 in various solid and hematological malignancies, however, prompted us to investigate the effect of the RGE mutant in a MFG-E8-positive transplantable breast tumor model. Here, we report that MFG-E8 blockade augmented anti-tumor humoral responses and modulated immune infiltrates at vaccination sites, which was associated with defective phagocytosis and clearance of apoptotic tumor cells. The RGE mutant enhanced the therapeutic potential of two irradiated, GM-CSF-secreting vaccines and improved protection correlated with augmented tumor-specific IgG1 and IgG2a antibody responses as well as increased ratios of T effectors to Tregs in TILs. These findings are consistent with the notion that MFG-E8 blockade potentiates anti-tumor responses through the preferential expansion of effector over regulatory T cells. Our data also validate the use of the RGE mutant to achieve therapeutically effective MFG-E8 blockade even in the context of tumors and vaccines that express high levels of endogenous MFG-E8.