Thesis (Ph. D.)--Case Western Reserve University, 2010. / [School of Medicine] Department of Pharmacology. Includes bibliographical references.

Thesis (Ph. D.)--West Virginia University, 2004. / Title from document title page. Document formatted into pages; contains ix, 148 p. : ill. (some col.). Includes abstract. Includes bibliographical references (p. 132-148).

Thesis (Ph. D.)--West Virginia University, 2001. / Title from document title page. Document formatted into pages; contains xi, 147 p. : ill. (some col.). Vita. Includes abstract. Includes bibliographical references (p. 128-143).

Thesis (Ph. D.)--University of Washington, 2003. / Vita. Includes bibliographical references (leaves 174-188).

Thesis (Ph. D.)--University of Washington, 2002. / Vita. Includes bibliographical references (leaves 53-59).

Breast cancer is a very heterogeneous disease. This heterogeneity can be observed at many levels, including gene expression, chromosomal aberrations, and disease pathology. A clear understanding of these differences is important since they impact upon treatment efficacy and clinical outcome. Recent studies have demonstrated that the tumour microenvironment also plays a critical role in cancer initiation and progression. Genomic technologies have been used to gain a better understanding of the impact of gene expression heterogeneity on breast cancer, and have identified gene expression signatures associated with clinical outcome, histopathological breast cancer subtypes, and a variety of cancer-related pathways and processes. However, little work has been done in this context to examine the role of the tumour microenvironment in determining breast cancer outcome, or in defining breast cancer heterogeneity. Additionally, little is known about gene expression in histologically normal tissue adjacent to breast tumour, if this is influenced by the tumour, and how this compares with non-tumour-bearing breast tissue. By applying laser--capture microdissection and gene expression profiling to clinical breast cancer specimens the research presented in this thesis addresses these questions. / We have generated gene expression profiles of morphologically normal epithelial and stromal tissue, isolated using laser capture microdissection, from patients with breast cancer or undergoing breast reduction mammoplasty. We determined that morphologically normal epithelium and stroma exhibited distinct expression profiles, but molecular signatures that distinguished breast reduction tissue from tumour-adjacent normal tissue were absent. Stroma isolated from morphologically normal ducts adjacent to tumour tissue contained two distinct expression profiles that correlated with stromal cellularity, and shared similarities with soft tissue tumors with favourable outcome. Adjacent normal epithelium and stroma from breast cancer patients showed no significant association between expression profiles and standard clinical characteristics, but did cluster ER/PR/HER2-negative breast cancers with basal-like subtype expression profiles with poor prognosis. Our data reveal that morphologically normal tissue adjacent to breast carcinomas has not undergone significant gene expression changes when compared to breast reduction tissue, and provide an important gene expression data set for comparative studies of tumour expression profiles. / We compared gene expression profiles of tumour stroma from primary breast tumors and derived signatures strongly associated with clinical outcome. We present a new stroma-derived prognostic predictor (SDPP) that stratifies disease outcome independently of standard clinical prognostic factors and published expression-based predictors. The SDPP predicts outcome in several published whole tumour--derived expression data sets, identifies poor-outcome individuals from multiple clinical subtypes, including lymph node--negative tumors, and shows increased accuracy with respect to previously published predictors, especially for HER2-positive tumors. Prognostic power increases substantially when the predictor is combined with existing outcome predictors. Genes represented in the SDPP reveal the strong prognostic capacity of differential immune responses as well as angiogenic and hypoxic responses, highlighting the importance of stromal biology in tumour progression. / We show that gene expression in the breast tumour microenvironment is highly heterogeneous, identifying at least six different classes of tumour stroma with distinct expression patterns and distinct biological processes. Two of these classes recapitulate the processes identified in the stroma-derived prognostic predictor, while the others are new classes of stroma associated with distinct clinical outcomes. One of these is associated with matrix remodelling and is strongly associated with the basal molecular subtype of breast cancer. The remainder are independent of the previously published molecular subtypes of breast cancer. Additionally, based on independent data from over 800 tumors, the combinations of stroma classes and breast cancer subtypes identify new subgroups of breast tumors that show better discrimination between good and poor outcome individuals than the molecular breast cancer subtypes or the stroma classes alone, suggesting a novel classification scheme for breast cancer. This research demonstrates an important role for the tumour microenvironment in defining breast cancer heterogeneity, with a consequent impact upon clinical outcome. Novel therapies could be targeted at the processes that define the stroma classes suggesting new avenues for individualized treatment.

The process of metastasis is initiated through the acquisition of inherent and autonomous motile and invasive properties by tumor cells. These phenomena are initiated through a balance between forward cancer cell membrane protrusion and tail retraction, and occur via cell cytoskeleton remodeling, actin reorganization, and coordinated focal adhesion assembly and disassembly events. Among the vast network of cytoskeletal proteins, the actin-bundling protein fascin plays a major function in cell cytoskeleton remodeling. It is a 55-kDa protein involved in the formation of filopodia and cell migration, and found to be upregulated in many cancers. We report herein key functions for fascin in the regulation of prostate and breast cancer progression. Fascin expression is upregulated in localized and hormone refractory prostate cancer, responsible for a more aggressive clinical course. In addition, functional dissection of fascin reveals a novel function in the regulation of focal adhesion turnover dynamics, by modulating the phosphorylation state of central focal adhesion proteins through a potential collaboration with the protein tyrosine phosphatase, PEST. Together, our data support the importance of fascin in cancer cell invasion and as a significant prognostic marker and a potential therapeutic target for aggressive cancers.

Aim: The overall aim of this thesis was to study health-related quality of life (HRQoL) and return to work in the first 3 years following a breast cancer diagnosis, and to identify clinical and contextual factors associated with these outcomes. Method: The four studies were part of a population-based cohort study including women identified in the Breast Cancer Quality Register in central Sweden. Of 1,573 women asked to participate, 69% (n=1,093) responded to a baseline questionnaire, 62% (n=977) responded at the 1st follow-up and 54% (n=856) participated at the 2nd follow-up (mean time 4, 16 and 38 months post-diagnosis, respectively). Studies II and IV only included women aged <63 years at diagnosis. In Study IV, each woman was individually matched to five breast-cancer-free controls. Questionnaire data on HRQoL, socio-demographics and work-related variables were combined with clinical register, normative and social insurance data. Main findings: Study I: Women with breast cancer, particularly women aged <50 years, experienced poorer HRQoL at baseline than normative data. Chemotherapy, lack of social support, sick leave and a poor financial situation were associated with poorer HRQoL. Study II: Compared with pre-diagnosis working time, 72% of participating women reported no change, 2% had increased their working time, 15% reported a decrease in working time and 11% did not work at the 1st follow-up. Chemotherapy, cancer-related work limitations and less value attached to work increased the odds of job discontinuation/decreased working time. Study III: During the 3 years post-diagnosis, HRQoL generally improved. Less consistent improvements were found among women on sick leave/disability pension pre-diagnosis and women reporting job discontinuation/decreased working time post-diagnosis. Study IV: The proportion of women with breast cancer on sick leave steadily decreased during the 3 years post-diagnosis, but they were more likely to be on sick leave than the controls. Chemotherapy, fatigue and pre-diagnosis sick days predicted sickness absence during the 2nd and 3rd year post-diagnosis. Conclusions: Most women with breast cancer gradually recover, but there are subgroups of women who may be particularly vulnerable. In a clinical setting, increased attention should be directed towards women undergoing chemotherapy, young women, women on sick leave/disability pension pre-diagnosis and women who do not return to work to the same extent as pre-diagnosis.

Bakgrund: I Sverige drabbas 8000 kvinnor av bröstcancer varje år. Dessa kvinnor utsätts för både kroppsliga och emotionella biverkningar och förändringar. Syfte: Syftet med denna litteraturöversikt är att belysa hur kvinnor som drabbas av bröstcancer upplever att deras sexualitet påverkas av sjukdom och behandling. Metod: Metoden var en litteraturstudie. Resultat: Ett huvudtema framkom en förändrad identitet; och fem subteman: kroppsliga förändringar, känna sig okvinnlig, relationens betydelse, kommunikationens betydelse för att komma vidare och sjukvårdens betydelse. Slutsats: Resultatet visade att kvinnorna upplevde att de förlorat sin sexuella identitet och sin kvinnlighet. Förlusten gjorde att de inte kunde identifiera sig med den kvinna som de tidigare varit. De upplevde flera fysiska förändringar som ledde till minskad sexuell aktivitet. Men trots den minskade sexuella aktiviteten upplevde många av kvinnorna en ökad närhet till sin partner och stödet från en partner ansågs viktigt. Många kvinnor saknade dock stöd och information från sjukvården angående sexuella problem. De upplevde att vårdpersonalen tyckte det var genant eller oviktigt att tala om kvinnornas sexualitet. Då sjuksköterskans primära mål är att främja hälsa och välbefinnande bör sjuksköterskan beakta kvinnornas sexualitet eftersom sexualiteten är en viktig dimension för upplevelsen av hälsa. / Background: In Sweden 8000 women are afflicted by breast cancer every year. These women are subject to both physical and mental side effects and alternations. Aim: The objective of this literature review is to highlight how women in the case of breast cancer experience that their sexuality is affected by the disease and treatment. Method: The method is a review of the related literature. Results: One major theme emerges: a changed identity, and five minor themes: physiological changes, feeling unfeminine, the significance of relationship, the significance of communication in order to move on, and the significance of medical care. Conclusion: It turns out that these women experienced a loss of their sexual identity and their femininity. The deprival resulted in an inability to identify themselves with the women they once were. They also experienced physiological changes, e.g. dryness of the vaginal mucous membrane, pain from the removed breast, and less sexual arousal which impeded and reduced the sexual activity of the women. But despite reduced sexual activity, many of these women experienced acquiring a greater proximity to their partner, and that the support from a partner was regarded as important. Many of the women, though, lacked support and information from the medical institutions concerning sexual problems. They experienced that the medical staff thought that conversing upon the women’s sexuality was something embarrassing or of no importance. Since the primary objective of the nurse is to promote health and well-being, the nurse should take heed to and attend to the sexuality of the women, considering that sexuality is an important dimension in regard to experiencing health.

The Ras signaling cascade is a vital component in the processes that mediate cell survival, growth, differentiation and transformation through activation of MAP kinase (mitogen-activated protein kinase). The recent discovery of a new scaffold of the Ras signaling pathway, Kinase Suppressor of Ras (KSR), is found to be a positive effector of Ras signaling which further contributes to proliferation and transformation in the ERK/MAPK pathway. This thesis describes the roles of Ras and Kinase Suppressor of Ras 1 (KSR-1) in regulating the expression of tumor promoting genes such as urokinase plasminogen activator (uPA) in the development and progression of breast cancer in vitro and in vivo. Ras and KSR increase the proliferative capacity and migration of MDAMB-231 human breast cancer cells in vitro. In contrast, Ras and KSR decrease the invasiveness of MDA-MB-231 human breast cancer cells in vitro. Furthermore, uPA gene expression levels do not correlate with uPA protein expression levels suggesting a possible mutation induced by KSR and/or Ras. In vivo studies reveal that Ras and KSR increase tumor volume in mice, as well as more advanced osteolytic bone metastases. Collectively, these results indicate that Ras and KSR play significant roles in breast cancer development and metastasis.