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No description available.

Progression to metastatic disease is the leading cause of deaths resulting from breast cancer. Understanding the mechanisms underlying a cell's ability to move away from its site of origin and populate a distant site is important for the future development of therapies. The interactions between a tumor cell and the microenvironment can modulate a cell's ability to invade through tissues and access distant organs. In this study we present evidence indicating the differential modulation of invasive and proliferative phenotypes by hyaluronan present in the cellular microenvironment.We establish the role of CD44, the primary receptor for hyaluronan, in breast cancer progression and metastasis through the use of transgenic mouse models of breast cancer. While no differences were seen in the onset of primary breast tumors, mice expressing CD44 had a reduced rate of pulmonary metastasis compared to mice that lacked CD44. This establishes an anti-invasive role for CD44 in breast tumor progression. We also identify a decreased population of alveolar macrophages in CD44 negative mice that could affect metastatic breast cancer cell colonization of the lungs.We then focused our study in vitro, where we assessed the invasive properties of breast cancer cells as they move through three dimensional (3D) matrices containing or lacking hyaluronan. We show that in 3D type I collagen gels, breast cancer cells invade more readily in the absence of hyaluronan compared to when hyaluronan (HA) is embedded within the gel. HA mediated inhibition of invasion is dependent on CD44 binding as demonstrated through the use of a CD44 functional blocking antibody.We also show that HA promotes differential phenotypes of breast cancer cell. HA promotes filopodia formation and invasion when soluble in the cell microenvironment. Alternatively, matrix-embedded HA inhibits invasion and promotes migration through the formation of lamellipodia. The differential HA invasive and proliferative phenotypes are mediated by differential activation of ERK or γPAK. Activation of γPAK is mediated by CD44 while ERK activation by HA occurs by CD44 independent mechanisms.We also demonstrate an inhibition of MMP9 mediated invasion by HA when embedded within a type IV collagen matrix, but not a type I collagen matrix. This differential activity indicates that it is not only the immobilization of HA in a matrix that determines its activity, but also the context in which it is present within the matrix.These data underscore the importance of studying matrix components in an environment that closely resembles in vivo conditions. HA is a prime example as it has the capability of both promoting and inhibiting invasion depending on how it is presented to a cell. Differential HA activity also underlies the importance of understanding extracelluar matrix degradation and the release of matrix components as these can adversely affect disease progression.

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

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

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

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Since 1942, when Bittner reported the incidence of non-induced tumors occuring in mice, strains of laboratory mice producing mammary carcinomas have been used as tools in research. Although not ideal for human studies, the histological and morophological similarities of the human and mouse mammary glands make it an excellent model to study the development of breast cancer. This study was performed to develop a rapid and consistent classification system for mouse mammary tissue, and compare various tumors to this system.Laboratory mice from the A and Balb/c strains were utilized in these studies. The three types of tumors developed in these mice were, non-induced, induced, and transplanted. Specimens of these tumors were collected and studied via light and electron microscopy for cellularchanges of tumor cells. These tumors were then classified according to the new system. These various tumors ranged from Class 0, which were normal cells, through gradual cellular changes to a Class IV, which were totally undifferentiated cells. host induced and non-induced tumors were Class III or IV, while the transplanted tumors were Class IV. This system facilitated the classification of mouse mammary tumors.

In this study, the mRNA and protein levels of hypoxia inducible factor 1 (HIF-1α), and a number of genes regulated by hypoxia (VEGF, GLUT-1, p53), were determined in four breast carcinoma cell lines, peripheral blood mononuclear cells (PBMCs) of patients with breast cancer and Type 1 diabetes (TIDM), and in human breast and brain tumour tissue. Breast carcinoma cells and PMBCs from both patients and normal controls were exposed to hypoxia (≤1% 0 2) and/or high glucose. Both up-regulated and down-regulated HIF-1α, GLUT-1 and p53 mRNA expression was observed in the breast carcinoma cell lines exposed to hypoxia and/or high glucose, and in controls for osmolarity, confirming that hypoxic regulation of HIF-1α, p53 and possibly GLUT-1 occurs post-transcriptionally. Conversely, up-regulation of HIF- 1α and GLUT-1 mRNA was observed in patients with TIDM exposed to high glucose. The GLUT-1 mRNA up-regulation observed in patients without complications differed significantly from normal controls, where up to a 2 fold increase in expression was observed over that of patients with complications. This may indicate that the expression and function of glucose transporters differs in these patients, potentially leading to fewer complications. Investigation of breast and glial cell tumour tissue demonstrated that both HIF-1α and GLUT- 1 mRNA expression levels increase with disease progression, indicating that up-regulation of HIF-1α is partly at the transcriptional level (Søndergaard et al, 2002). Follow-up survival studies in all patients with glial cell tumours showed that HIF-1α protein expression is a significant prognostic factor in cumulative overall survival. An additional investigation of p53 or p73 polymorphisms in the development of carcinoma of the breast did not find that they were significant risk factors in the development of the disease in the British Caucasoid population. Further studies are required using larger sample populations investigating HIF-1α protein to determine the precise role of HIF-1 in the response to hypoxia and angiogenesis in disease in man.

No description available.