published_or_final_version / Anatomy / Doctoral / Doctor of Philosophy

published_or_final_version / Clinical Psychology / Doctoral / Doctor of Psychology

published_or_final_version / Clinical Psychology / Master / Master of Social Sciences

Background: One of ten women in Sweden will at some point in her life get breast cancer. In today's society, more women than ever before suffer from breast cancer, but the chance of survival increases. As a nurse, it is important to have knowledge about the woman's experiences of breast cancer in order to provide as optimal and individualized care possible. Aim: The aim of the study was to elucidate how the woman experience the first time with breast cancer. Method: A literature-based method is used to bring out the woman´s experiences of getting breast cancer. The results of the studies were analyzed using a qualitative content analysis consists of five steps. The analysis resulted in four themes and twelve subthemes. Results: The results showed that the woman are in great need of support, feeling anxiety and fear, experiencing an altered self-image, and that treatment hinders. Conclusion: The conclusion showed that regardless of the situation, it was important for the woman that someone always was there for them as support. An important aspect was the need for information to reduce fear and anxiety. Breast cancer affecting the whole of the woman's lives and she strove to reclaim as much as possible of her previous life. This could be difficult because of fatigue and other major changes the woman experienced after the treatments, both physically and mentally.

Résumé L’objectif de ce travail a été d’évaluer la toxicité du butyrate de sodium (NaBu), un inhibiteur des histones désacétylases (HDACs), et ses mécanismes d’action sur les cellules de cancer du sein humain, les cellules MCF-7 déficientes pour la caspase-3, et lignées dérivées : les cellules MCF- 7/caspase-3, et les cellules VCREMS résistantes à la vincristine, et dans une moindre mesure à la doxorubicine. La contribution de l’apoptose dans la létalité induite par le NaBu a été recherchée dans les cellules MCF-7wt en estimant l’exposition de la phosphatidylsérine ainsi que le clivage de la PARP. La présence de caspase-3, n’a ni amplifié ni accéléré l’apoptose qui a impliqué le rhéostat Bax/Bcl-2 en faveur d’une induction de Bax. La cytostasie du NaBu dans les cellules MCF-7 s’est manifestée par un blocage des cellules en phase G2/M. L’évaluation du niveau d’expression des régulateurs du cycle cellulaire dans les cellules MCF-7wt et MCF-7/caspase-3 a montré une surexpression de p21, de façon indépendante de p53. L’action cytostatique du NaBu a été associée à une accumulation légère et modeste des formes non-phosphorylées de pRB, un facteur dont la phosphorylation par les complexes cycline D/cdk4,6 et cycline E/cdk2 est nécessaire à la transition G1/S. Dans ces conditions, les niveaux de cdk2 et de Cdc25A, une oncoprotéine activatrice de cdk2, sont restés stables. Le NaBu est une molécule à effet pléïotropique, l’utilisation de la trichostatine A, inhibiteur par excellence des HDACs, a permis d’établir la relation de causalité entre l’inhibition des HDACs et la toxicité du NaBu. La plupart des inhibiteurs des HDACs induisent l’apoptose en perturbant le métabolisme oxydatif de la mitochondrie ce qui pourrait modifier le statut redox cellulaire. Nous avons cherché une implication du métabolisme du glutathion (GSH), le thiol anti-oxydant non-protéique majoritaire de la cellule, dans la toxicité induite par le NaBu. Les résultats montrent que le NaBu induit une déplétion du GSH dans les cellules MCF-7wt et dérivées de façon dose-dépendante, corrélée avec la mortalité cellulaire. Devant l’éventualité d’une consommation accrue de GSH par les enzymes associées à son métabolisme, nous avons évalué le niveau des activités des enzymes glutathion peroxydase, glutathion réductase et glutathion S-transférases. Dans les cellules MCF-7, le NaBu a induit de façon significative ces enzymes anti-oxydantes, à l’exception des GSTs, de même que la catalase, une enzyme indépendante de ce système. Les expériences visant à libérer le pool de GSH lié aux protéines ont montré que la déplétion du GSH intracellulaire est parallèle à celle du GSH lié aux protéines. Par conséquent, la consommation du GSH est réellement la cause de la chute du niveau de GSH générant un stress oxydant. La doxorubicine, un inhibiteur des topoisomérases, a une utilisation clinique limitée en raison de ses effets secondaires irréversibles (cardiotoxicité entre autres). Dans le but d’améliorer son efficacité, nous avons expérimenté des combinaisons NaBu/doxorubicine sur les cellules VCREMS et MCF-7, étant donné la capacité du NaBu à induire l’expression des topoisomérases et favoriser la conformation déployée de la chromatine. L’utilisation de la technique isobologramme nous a permis de déterminer les index de combinaison pour une application simultanée ou séquentielle des drogues. Les résultats indiquent que le NaBu sensibilise les cellules VCREMS et MCF-7 à l’action de la doxorubicine. Dans les cellules VCREMS, cet effet s’est produit en dépit de la stimulation des enzymes de détoxication, GSTs et GPX. L’ensemble de ces résultats indique que l’utilisation du NaBu en combinaison avec certains anticancéreux constitue une stratégie très intéressante en cancérothérapie.

It is well known in medicine that changes in tissue elasticity may be related to pathological phenomena such as cancer and other disease. Physicians routinely use palpation as means of inspecting the thyroid, prostate, and breast, where a palpably hard mass can often indicate the presence of a malignant lesion. Magnetic Resonance Elastography (MRE) has emerged as a relatively new elasticity imaging technique which can be used to spatially map and measure displacement patterns resulting from harmonic shear-wave propagation in soft tissue. Displacement fields are then used in reconstructing the tissue’s elastic property distributions. The feasibility of using MRE as a noninvasive means of characterizing the mechanical properties of silicone phantom mimicking human breast, was investigated though experiments involving MRE acquisitions of four phantoms. To achieve sufficient excitation of the phantom tissue, an acoustic actuator was developed. The results of these studies have shown the MRE acquisition to be successful in capturing sufficient data for elastic parameter reconstruction. Another different type of actuator has been developed and tested in the laboratory. The results show the potential for future use of this actuator in MRE experiments.

Metastasis is the leading cause of death in patients with cancer, and the extracellular matrix is critical to cancer dissemination. The adhesion receptor, CD44, mediates cellular communication with the extracellular matrix by binding to the glycosaminoglycan, hyaluronan (HA). CD44 and HA play critical roles in cancer progression and development. HA is deposited in extracellular and pericellular matrices where it directs intracellular signaling through interactions with cell-surface CD44. CD44-HA interactions, in turn, direct signaling that is relevant to cancer progression. Importantly, these molecules can both promote and inhibit the oncogenic cascade, although the mechanism by which they promote dual and contrasting functions is unknown.Here we show that HA can both activate and suppress EGFR, a critical regulator of oncogenic signaling, in a context-dependent fashion. Using a 3D collagen system in which HA is either polymerized in collagen matrix or provided soluble in the media (sHA) we report that collagen-embedded HA (eHA) inhibits EGFR activation, filopodia formation, and cell spreading on a collagen matrix. Additionally, we show that CD44 is subject to cell-type changes during cancer progression. We have found that CD44 is expressed in the myoepithelium of the developing mammary gland and regulates the normal function of this cell type. The myoepithelial function of CD44 is also relevant to its role in cancer progression as CD44 is expressed in the basal cells of early-stage breast and prostate cancer but undergoes a basal to luminal epithelial switch with increasing tumorigenicity and is strongly expressed by tumor epithelium. These findings demonstrate a novel role for eHA as a protective molecule when encountered in the collagen matrix during cancer progression and highlight the importance of understanding cell-type specific contributions during cancer progression. Taken together, the findings reported in this dissertation point to a mechanism by which CD44 and HA can function in tumor suppression and promotion, depending on cell-type specific expression and modulation of the extracellular matrix.

This paper is a test of several hypothesized predictors of frequency of breast self-examination among low-income Mexican American women. Current research points to several factors as important predictors of preventive care. Among these are self-efficacy – one’s perceived capacity to perform a given action – and social support from significant others. For Mexican Americans, environmental barriers to health care are important factors. While findings are inconclusive regarding the role of language proficiency as a predictor of preventive care, the model includes this as a hypothesized predictor of frequency of breast self-examination. The findings show a strong relationship between self-efficacy and frequency of breast self-examination. Barriers to health care have a weaker direct effect upon breast self-examination. The effects of English-language proficiency are indirect and mediated by self-efficacy.

Breast cancer, which in advanced stages often leads to bone metastasis, is the most frequent malignant tumor and the second deadliest form of cancer among women in the U.S. Skeletal metastasis is associated with imbalanced bone remodeling and eventual bone fracture that contributes to incapacitating pain and loss of mobility. Bone cancer pain remains a significant health problem due to the limited repertoire of analgesics available to treat this pain without negatively influencing the quality of life and "bone health" of the patient. Bone cancer results in a marked influx of pro- and anti- inflammatory hematological cells into the medullary cavity resulting in activation of nociceptors that express cytokine and chemokine receptors. Thus, blockade of these factors may result in a significant attenuation in bone cancer pain. The sustained release of cytokines by both primary tumor cells and invading leukocytes into the tumor microenvironment shapes the immune response to tumor invasion and ultimately mediates the shift in immune balance to the predominantly immunosuppressive state seen with late stage disease. Activation of cannabinoid receptor 2 (CB2), found on immune cells but not neuronal cells, has been shown to inhibit the release of cytokines from leukocytes; this inhibition plays an important role in CB2 agonist's ability to inhibit pain without producing the CNS side effects commonly associated with CB1. Cannabinoids have also been demonstrated in a number of cancer models to modulate the tumor microenvironment via effects specific to the tumor cells as well as regulation of invading leukocytes. Here, we show that the CB2 specific agonist JWH-015 mediates inflammatory factors in vitro and in vivo in the femoral intramedullary cavity in a murine model of bone cancer while simultaneously attenuating breast cancer induced bone pain and promoting overall health of the bone microenvironment. Further, we demonstrate JWH-015's ability to positively modify the systemic balance of regulatory to effector lymphocytes as well as modulate the suppressive function of regulatory T lymphocytes. We also show that JWH-015 attenuates breast cancer cell proliferation in vitro in a concentration dependent manner. Finally, utilizing a murine in vivo bioluminescence model, we demonstrate that JWH-015 treatment not only attenuates primary tumor growth, but also rate of metastasis. Taken together, these data establish CB2 as an innovative therapeutic target across multiple stages of breast cancer.

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