Dissertations / Theses on the topic 'Breast – Cancer – Etiology'

Breast cancer is the most commonly diagnosed cancer amongst Canadian women. Though numerous treatments are available, in many instances tumours become refractory or recur. Therefore, understanding the biological events that lead to the progression and therapeutic resistance of breast cancer is essential for the development of novel treatment options for this disease. Numerous members of the protein arginine methyltransferase (PRMT) family, which are the enzymes responsible for catalyzing methylation on arginine residues are aberrantly regulated in breast cancer. Hence, understanding the precise contribution of PRMTs to the development and progression of breast cancer is important. This Thesis will present my findings on the alternatively spliced PRMT1 isoform, PRMT1v2, previously identified to be overexpressed in breast cancer cell lines and here shown to promote breast cancer cell survival and invasion. Second, a novel role is ascribed to PRMT6, another PRMT aberrantly expressed in breast cancer. PRMT6 promotes chemoresistance to the drug bortezomib by mediating stress granule formation through down-regulation of eIF4E. Increased stress granule formation in bortezomib-resistant cancer cells promotes cell survival. Third, DDX3, a prototypical PRMT substrate which is overexpressed in breast cancer cell lines and stimulates transformation of mammary epithelial cells is a novel substrate of PRMT1, CARM1, and PRMT6. Lastly, TDRD3, a reader/effector of arginine methylation also overexpressed in breast tumours regulates breast cancer cell proliferation, anchorage-independent growth and cell motility and invasion.

CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICO
Este trabalho teve como objetivo principal avaliar as representações sociais, elaboradas por mulheres que tiveram câncer de mama, sobre a doença, sua etiologia e tratamento. Desenvolvemos teoricamente o tema a partir de quatro perspectivas: biológica, psicossomática, psicossocial e multifatorial. Realizamos uma pesquisa de campo, de natureza qualitativa, estudando 10 casos de mulheres que tiveram câncer de mama com idades entre 35 e 50 anos, que se submeteram à mastectomia, podendo ter feito ou não a reconstrução mamária, e que participavam como membros de uma associação de apoio a mulheres com câncer de mama da cidade de Niterói, Rio de Janeiro. Como instrumento desta pesquisa, utilizamos um questionário identificador e entrevistas semidirigidas, aplicados a tais mulheres individualmente e, depois, a seus familiares, com base em roteiro pré-elaborado. Para avaliação dos dados obtidos, empregamos a análise de discurso intra-sujeito e intersujeito. Na primeira, buscamos identificar, em cada caso, a percepção das entrevistadas sobre a doença, sua etiologia e as repercussões do tratamento oncológico em sua identidade feminina. Na segunda, construímos 10 categorias de análise. Os resultados revelaram que o câncer é apreendido pelas mulheres como um risco e ameaça à vida, que a retirada da mama afeta, majoritariamente, a identidade corporal e feminina, e que o adoecimento provoca muitas mudanças em suas vidas.
The prime purpose of this paper is to assess the social representations created by women who have had breast cancer, and to discuss the disease, its etiology and treatment. We developed the theme theoretically, based on four perspectives: biological, psychosomatic, psychosocial and multi-factorial. We performed field research of a qualitative nature, studying ten cases of women who had breast cancer in the 35 to 50 age group and had undergone a mastectomy, could have done mammary reconstruction or not, and who participated as members of a support association to women with breast cancer in Niterói city, Rio de Janeiro State. As an instrument of this research, we used an identifying questionnaire and semi-focused interviews with those women individually and later with their relatives, based on a previously prepared script. In order to assess the obtained data, we used intra-subject and inter-subject discourse analysis. In the former, in each case we looked to identify the interviewee s perception of the disease, its etiology and the repercussions of cancer treatment on her female identity. In the latter, we created ten analytical categories. The results showed that women are apprehensive of cancer as life threatening and a risk, that breast removal in most cases affects the corporal and female identity, and that contracting the disease causes many changes in their lives.

The pituitary hormone prolactin (Prl) is essential for alveolar morphogenesis and plays a role in breast carcinogenesis, however the mechanism that underlies these actions remains to be defined. Alterations in serum Prl provide the primary endocrine signal regulating developmental events in the mammary gland in sexually mature mammals. Prl production and post-translational phosphorylation by the pituitary is regulated by the neuropeptide Galanin (Gal) in response to hypothalamic signals integrating neuronal and endocrine inputs. Prl exerts its effects on the mammary epithelium in two ways, indirectly by modulation of the systemic hormonal environment, for example the release of progesterone from the corpus luteum, and directly by binding to Prl receptors (Prlr) within the mammary epithelium. Prl binding to Prlr initiates signalling predominantly via activation of the Jak2/Stat5 pathway, leading to altered patterns of gene transcription. One of these target genes is the ets transcription factor Elf5, which is required by the epithelium for alveolar morphogenesis. This thesis aims to further our understanding of the mechanisms by which prolactin exerts its influence on the mammary gland during alveolar morphogenesis and carcinogenesis. Transcript profiling revealed a lactation signature of 35 genes in Prlr+/- mice, Gal-/- mice and mice treated with a Prl mutant (S179D) that mimics phosphorylated Prl. We discovered that the majority of changes in gene expression were produced by prolactin rather than by Gal. The action of Gal was predominantly via modulation of Prl phosphorylation and release, as its effects were very similar to that of S179D. Knockout of Elf5 phenocopied knockout of Prlr, resulting in failure of alveolar morphogenesis and reduced expression of milk and lipid synthesis genes. Forced Elf5 expression at puberty resulted in aberrant differentiation of the terminal end buds and milk protein synthesis during ductal morphogenesis. Re-expression of Elf5 in Prlr-/- mammary epithelial cells completely rescued alveolar morphogenesis. These observations indicate that Elf5 is a master regulator of alveolar morphogenesis downstream of the Prlr. Loss of mammary epithelial Prlr resulted in reduced proliferation of low-grade neoplastic lesions resulting in increased tumour latency in the C3(1)/SV40T model of mammary carcinogenesis. There was no change in the growth rate, proliferation nor the morphology of tumours in Prlr-/-/C3(1)/SV40T transplants, thus Prl acts early in carcinogenesis to drive the proliferation of pre-invasive lesions resulting in faster progression to cancer.

Introdução: O câncer de mama tem se mostrado a neoplasia mais incidente entre as mulheres de todo o mundo. Entretanto, percebe-se que a incidência apresenta grande variação geográfica, sugerindo que a ação dos fatores de risco varie acentuadamente entre as diferentes populações. Assim, estudos em determinadas populações sobre os seus fatores determinantes para câncer de mama podem contribuir para melhorar as estratégias de saúde pública, reduzindo sua morbi-mortalidade. Objetivo: Avaliar potenciais fatores de risco para câncer de mama em uma população de Porto Alegre e construir um modelo multivariado com estes fatores para predição de risco de câncer de mama. Delineamento: Estudo de coorte de base populacional. Método: Foram selecionadas 4.242 mulheres com idades entre 40 e 69 anos, sem história pregressa de câncer de mama, em atendimento em unidades básicas de saúde de Porto Alegre, as quais foram submetidas a rastreamento mamográfico. Elas foram avaliadas em relação aos seguintes fatores de risco: raça, tabagismo, etilismo, idade da menarca, idade do nascimento do primeiro filho, número de gestações, idade da última gestação, tempo de amamentação, história de ooforectomia e histerectomia, idade da menopausa, tempo de uso de reposição hormonal, uso de contraceptivo hormonal, histórico de biópsias mamárias, história familiar, peso e altura. A coleta de dados referente aos potenciais fatores de risco para câncer de mama foi realizada em dois momentos distintos, sendo a primeira coleta realizada durante o período de recrutamento das participantes compreendido entre os anos de 2004 e 2006 nas unidades básicas de saúde e a segunda coleta de dados foi realizada no momento em que as participantes compareciam ao centro de referência para a primeira visita de rastreamento mamográfico. As variáveis coletadas em ambos os momentos eram complementares, porém algumas variáveis estavam presentes em ambos os instrumentos de coleta de dados, as quais foram analisadas apenas as variáveis coletadas no segundo momento por serem mais atuais. As variáveis categóricas foram descritas por frequências e percentuais. As variáveis quantitativas com distribuição simétrica foram descritas pela média e o desvio padrão e as variáveis com distribuição assimétrica pela mediana e o intervalo interquartil (percentis 25 e 75). A associação entre câncer de mama e potenciais fatores de risco foi avaliada através de um modelo logístico multivariado. Em todas estas análises, um valor de p abaixo de 0,05 foi considerado estatisticamente significativo e foi analisado e considerado o IC95%. Resultados: Um total de 73 participantes de 4.242 apresentaram diagnóstico de câncer de mama. A análise multivariada considerando todas as pacientes, de 40-69 anos, mostrou que quanto maior a idade (OR=1,08, 95%IC: 1,04-1,12), maior a altura (OR=1,04, 95%IC: 1,00-1,09) e história de biópsia mamária anterior (OR=2,66, 95%IC: 1,38-5,13) estavam associadas a desenvolvimento de câncer de mama. Por outro lado, o número de gestações (OR=0,87, 95%IC: 0,78-0,98) e uso de terapia de reposição hormonal (OR=0,39, 95%IC: 0,20-0,75) foram associados como fator protetor para câncer de mama. Adicionalmente, realizamos análise separando as participantes em grupos de 40-49 anos e 50-69 anos, pois algum fator de risco poderia ter comportamento específico nestas faixas etárias. Nenhum fator de risco adicional foi identificado com esta estratificação etária, sendo que alguns fatores perderam significância estatística. No grupo de 40-49 anos, altura e biópsia mamária anterior mantiveram-se como fatores de risco. No grupo de 50-69, biópsia mamária anterior manteve-se como fator de risco e número de gestações e uso de terapia de reposição hormonal mantiveram-se como fator protetor. Diversas sub-análises não contribuíram para o entendimento como reposição hormonal o qual foi identificado como fator protetor. Conclusão: Em nosso estudo o modelo de predição de risco indica que devem ser avaliadas as seguintes variáveis nesta população específica de 40 a 69 anos: idade, altura, realização de biópsias mamárias anteriores, número de gestações e utilização de terapia de reposição hormonal. Estes achados estão de acordo com a literatura e agregados a outros estudos podem ajudar a compreender melhor o modelo causal de câncer de mama na região sul do Brasil.
Introduction: Breast cancer has been the most common cancer among women worldwide. However, it is clear that the incidence has great geographic variation, which suggests that the action of risk factors varies substantially between different populations. Thus, studies on the determining factors for breast cancer in certain populations may contribute to improve public health strategies and reduce morbimortality. Objective: Assess potential risk factors for breast cancer in a population in southern Brazil and build a multivariate model using these factors for breast cancer risk prediction. Methods: 4,242 women aged between 40 and 69 years without a history of breast cancer were selected at primary healthcare facilities in Porto Alegre and submitted to mammographic screening. They were evaluated for the following risk factors: race, smoking, alcohol consumption, age at menarche, age at the birth of first child, number of pregnancies, age at the last pregnancy, duration of breastfeeding, history of oophorectomy and hysterectomy, age at menopause, duration of hormone replacement therapy, use of hormonal contraceptives, history of breast biopsies, family history, weight and height. The collection of data related to potential risk factors for breast cancer was conducted at two different times. The first collection was held during the recruitment of participants from 2004 to 2006 at primary healthcare units and the second data collection was performed at the time the participants went to the reference center for the first mammographic screening visit. The variables collected at both times were complementary, but some variables were present in both data collection instruments, and only the variables collected in the second phase were analyzed because they were more current. Categorical variables were described as frequencies and percentages. Quantitative variables with symmetric distribution were described as the mean and standard deviation, and variables with asymmetrical distribution as median and interquartile range (25th and 75th percentiles). The association between breast cancer and potential risk factors was evaluated using a multivariate logistic model. In all these analyses, a p-value less than 0.05 was considered statistically significant with a 95% CI. Results: A total of 73 participants among 4,242 had a breast cancer diagnosis. The multivariate analysis considering all patients aged 40-69 years showed that older age (OR = 1.08, 95% CI: 1.04-1.12), higher height (OR = 1.04, 95% CI: 1.00-1.09) and history of previous breast biopsy (OR = 2.66, 95% CI: 1.38 - 5.13) were associated with the development of breast cancer. Conversely, the number of pregnancies (OR = 0.87, 95% CI: 0.78-0.98) and use of hormone replacement therapy (OR = 0.39, 95% CI: 0.20 - 0 75) were associated as a protective factor for breast cancer. Additionally, we performed an analysis separating the participants into groups of 40-49 years old and 50-69 years old, since a risk factor could have a specific behavior in these age groups. No additional risk factors were identified within this age bracket, and some factors lost statistical significance. In the 40-49 year old group, height and previous breast biopsy remained as risk factors. In the 50-69 year old group, a previous breast biopsy remained as a risk factor and the number of pregnancies and use of hormone replacement therapy remained as a protective factor. A number of sub-analyses did not help us understand why or how hormone replacement acted as a protective factor. Conclusion: In our study, the risk prediction model indicates that the following variables should be assessed in this specific population from 40 to 69 years old: age, height, having had previous breast biopsies, number of pregnancies, and use of hormone replacement therapy. These findings are consistent with the literature and combined with other studies may help to better understand the causal model of breast cancer in southern Brazil.

Epidemiological data with disease characteristic information can be modelled in several ways. One way is taking each disease characteristic as a response and constructing binary or polytomous logistic regression model. Second way is using a new response which consists of disease subtypes created by cross-classification of disease characteristic levels, and then constructing polytomous logistic regression model. The former may be disadvantageous since any possible covariation between disease characteristics is neglected, whereas the latter can capture that covariation behaviour. However, cross-classifying the characteristic levels increases the number of categories of response, so that dimensionality problem in parameter space may occur in classical polytomous logistic regression model. A two staged polytomous logistic regression model overcomes that dimensionality problem. In this thesis, study is progressen in two main directions: simulation study and data analysis parts. In simulation study, models that capture the covariation behaviour are compared in terms of the response model parameter estimators. That is, performances of the maximum likelihood estimation (MLE) approach to classical polytomous logistic regression, Bayesian estimation approach to classical polytomous logistic regression and pseudo-conditional likelihood (PCL) estimation approach to two stage polytomous logistic regression are compared in terms of bias and variation of estimators. Results of the simulation study revealed that for small sized sample and small number of disease subtypes, PCL outperforms in terms of bias and variance. For medium scaled size of total disease subtypes situation when sample size is small, PCL performs better than MLE, however when the sample size gets larger MLE has better performance in terms of standard errors of estimates. In addition, sampling variance of PCL estimators of two stage model converges to asymptotic variance faster than the ML estimators of classical polytomous logistic regression model. In data analysis, etiologic heterogeneity in breast cancer subtypes of Turkish female cancer patients is investigated, and the superiority of the two stage polytomous logistic regression model over the classical polytomous logistic model with disease subtypes is represented in terms of the interpretation of parameters and convenience in hypothesis testing.

Wang Ya-Ping.
Thesis (Ph.D.)--Chinese University of Hong Kong, 1998.
Includes bibliographical references (p. 152-161).
Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web.
Mode of access: World Wide Web.
Abstracts in English and Chinese.

As a master regulator of the epithelial state, p63 is a family member of the well-known tumor suppressor p53. It has previously been connected to a cancer-associated process, epithelial-to-mesenchymal transition (EMT), and here we find that it can be regulated by oncogenes involved in breast tumorigenesis. Specifically, activated forms of PIK3CA and H-RAS are able to strongly repress expression of ∆Np63α, which is the major p63 isoform in epithelial cells. In mammary epithelial lines, this oncogene downregulation occurs at the transcriptional level, and complete repression occurs over the course of several days. As p63 is repressed, the cells undergo EMT and acquire the ability to invade individually through a 3D collagen matrix. Strikingly, even when p63 is suppressed but no oncogene action is present, these cells undergo a mesenchymal shift, suggesting the importance of this gene in maintaining the epithelial state. Furthermore, it is particularly interesting that p63 protein and RNA levels are often low in breast tumors. By connecting H-RAS and PIK3CA signaling to p63, it is hypothesized that such oncogene suppression could account for tumor progression in cases where p63 levels are low. Here, it is proposed that p63 acts in a tumor-suppressive manner, although it can be overcome by oncogenes leading to changes in differentiation state and migratory capability, therefore drastically affecting breast carcinogenesis.

Yau, Ka Long.
Thesis (M.Phil.)--Chinese University of Hong Kong, 2013.
Includes bibliographical references (leaves 97-113).
Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web.
Abstracts also in Chinese.

M.Tech.
Natural occurring components in human breast milk, cow milk and soy milk have shown anticarcinogenic abilities. The human breast milk protein, -lactalbumin, was found to induce apoptosis in cancer cells, embryonic cells and rapidly growing cells, when converted from its native form to a partial denatured apoptotic-inducing form. Moreover, radiation may cause irreversible changes of protein conformation at the molecular level. Native -lactalbumin is one protein that has shown a decrease in aromatic amino acid concentration and the formation of high and low molecular weight fractions when exposed to high doses of ionizing radiation. The effect of human breast milk, cow milk, soy milk and galactose (positive control) on SNO, A549 cancer cells and normal lymphocytes were investigated. Human breast milk was irradiated with low doses of Co60 ionizing radiation (0.1Gy, 1.0Gy and 5.0Gy) in order to establish the effect of these doses on the apoptotic-inducing ability of human breast milk. The techniques used included, Trypan blue dye exclusion (cell viability), haematoxylin and eosin stain (cell morphology), modified comet assay (halo) (DNA damage) and flow cytometry (apoptosis and necrosis). Findings showed that human breast milk, irradiated human breast milk and galactose induced apoptosis in the SNO, A549 cells and lymphocytes. The cell viability, cell morphology and DNA fragmentation patterns of irradiated human breast milk were similar to that of non-irradiated human breast milk, although the flow cytometry results did not correlate. Cow and soy milk did not induce apoptosis in the SNO, A549 cells and lymphocytes. The modified comet assay (halo) detected DNA damage as apoptotic or necrotic cells. A clear distinction could not be made between the two cell populations using this assay. Flow Cytometry discriminated and quantified apoptotic cells and necrotic/late apoptotic cells using Annexin V and Propidium Iodide (PI), respectively.

Introduction: The wide-ranging prognostic implications of a breast cancer diagnosis highlight the need to better enable women to make informed decisions regarding screening and treatment options. As several cancer susceptibility syndromes have been linked to germline mutations resulting in defective DNA repair, including the predisposition to breast cancer due to BRCA1 and BRCA2 mutations, more subtle defects in DNA repair capacity may contribute to the components driving differential susceptibility within the general population. Hence, understanding the role of DNA repair capacity in breast cancer onset may aid in the development of a more comprehensive risk profile, thereby furthering the effort to target relevant populations for early screening. In the studies undertaken for this dissertation, we employed various methodologies capturing endpoints across different repair pathways detectable in blood to both further elucidate the etiologic basis of breast cancer development and leverage the information into the potential development of a screening biomarker. Methods: For the phenotypic assessment of nucleotide excision repair (NER) capacity, we developed an ELISA-based method to determine benzo(a)pyrene diolepoxide (BPDE)-DNA adduct capacity in lymphoblastoid cell lines. Gene expression levels were assessed with pre-designed Taqman kits in RNA-derived cDNAs from mononuclear cells using a real-time PCR-based platform. Methylation analysis was conducted with in-house designed assays on bisulfite-converted DNA from mononuclear cells using a pyrosequencing platform. Finally, single nucleotide polymorphisms (SNP) genotyping was assessed in DNA derived from white blood cells with pre-designed Taqman SNP genotyping assays using a real-time PCR-based platform. All studies were conducted in sister-sets enrolled in the New York site within the Breast Cancer Family Registry and all statistical analysis was conducted using the R Foundation for Statistical Computing (2011). Results: We did not detect an association between the ELISA-based phenotypic assessment of NER capacity in the lymphoblastoid cells lines of the sister-sets (n=246, 114 sister-sets) and breast cancer risk (OR = 1.0, 95%CI=0.95, 1.04). Furthermore, we did not observe a correlation with previously determined NER capacity in the same population using an immunohistochemical-based method (r= -0.01, p=0.86). In our gene expression study (n=569, 218 sister-sets), women in the lowest tertile of ATM expression had a heightened risk of breast cancer compared to women in the highest tertile of expression, adjusted for age at blood draw and smoking status (OR=2.12, 95%CI=1.09, 4.12). This association was largely restricted to women with an extended family history of breast cancer (pinteraction = 0.06). Additionally, women in the lowest tertile of MSH2 expression also had a heightened risk of breast cancer compared to women in the highest tertile of expression, adjusted for age at blood draw and smoking status (OR=2.75, 95%CI=1.31, 5.79). The association observed between reductions in ATM expression level and breast cancer risk was lost upon incorporating previously determined end-joining capacity of EcoRI-generated sticky end substrates (OR=1.28, 95%CI=0.15, 11.2) and HincII-generated blunt end substrates (OR=1.55, 95%CI=0.15, 15.5) into the model, suggesting that the impact on risk due to reductions in ATM expression maybe partially driven by the reduction in double strand break repair capacity. In our study investigating breast cancer risk due to the impact of epigenetic modulation on DNA repair gene activity (n=569, 218 sister-sets), no association with risk was observed due to differential promoter methylation levels of BRCA1 (OR=1.09, 95%CI=0.98, 1.20), MLH1 (OR=1.19, 95%CI=0.91, 1.55) or MSH2 (OR=0.89, 95%CI=0.48, 1.64). Furthermore, no correlation between BRCA1 and expression (r=-0.05, p=0.39) or MSH2 methylation and expression (r=-0.04, p=0.39) was observed. Finally, our mismatch repair genotyping study (n=714, 313 sister-sets) indicated an association between the variant MutY_rs3219489 (OR=2.23, 95%CI=1.10, 4.52) and breast cancer risk, as well as a borderline association with risk due to the variant MSH2_rs2303428 (OR=1.71, 95%CI=0.99, 2.95). Furthermore, a protective effect was observed due to the variant MLH3_rs175080, restricted to women without an extended family history of breast cancer (pinteraction = 0.03). Conclusion: These studies suggest that the deregulation of targets spanning various DNA repair pathways contribute to the risk of familial breast cancer.

"July, 2003"
"Amendments of the thesis" and "abbreviations (additional)" inside back cover.
Includes bibliographical references (leaves 195-231)
x, 231, [20] leaves : ill., plates ; 30 cm.
Title page, contents and abstract only. The complete thesis in print form is available from the University Library.
Thesis (Ph.D.)--University of Adelaide, Dept. of Paediatrics, 2003

Indiana University-Purdue University Indianapolis (IUPUI)
Purpose: Obesity is a growing public health problem and the second most preventable cause of death in the US. Obesity has been linked as a risk factor for several cancers. However, there are limited studies that have examined the roles of metabolic syndrome (MetS) and C-reactive protein (CRP), as well as change in body composition from early adulthood to late adulthood on the risk of cancer. The overall objective of this dissertation was to determine the association of obesity and obesity-related markers with breast and colorectal cancer occurrence and mortality. Methods: Three datasets were used. The first study used 4,500 asymptomatic adults who were surveyed during a colorectal cancer screening study. The second study was based on the National Health and Nutrition Examination Survey (NHANES) 2005-2010. The dataset had 172 breast cancer survivors and 2,000 women without breast cancer. The last manuscript resulted from the NHANES follow-up study (NHANES III). A total of 120 cancer deaths from breast and colorectal deaths were identified from 10,103 women aged 18 years or older. Results: Overall, obesity and obesity related markers were associated with breast and colorectal cancer occurrence and mortality. BMI change and WC change were positively associated with increased risk of advanced colorectal neoplasia (AN). WC measures (both static and dynamic) were generally a better predictor of AN compared to BMI. In the second study involving breast cancer survivors, neither MetS nor CRP were associated with having a breast cancer diagnosis. Also, none of the individual components of MetS (WC, Triglycerides, HDL, fasting blood glucose and blood pressure) were associated with a breast cancer diagnosis. In the last study, MetS was associated with increased risk of mortality from obesity-related cancers. In addition, all components of MetS, except dyslipidemia, were associated with increased risk of mortality for the obesity-related cancers. Conclusion: Obesity expressed in terms of BMI and WC, or their change, MetS and CRP are important factors in regard to the occurrence, survivorship and mortality of breast and colorectal cancer. The results of this research underscore the importance of maintaining a healthy weight.