Les cellules dendritiques sont les principales cellules présentatrices d’antigènes, qui initient et modulent les réponses immunitaires. Parmi elles, les cellules dendritiques plasmacytoïdes (pDC) représentent les cellules effectrices clés de la réponse antivirale par leur production de fortes quantités d’interférons de type I (IFN). Leur infiltration dans les tumeurs mammaires est un facteur de mauvais pronostique, indiquant que l’environnement tumoral détourne la fonction des pDC pour qu’elles favorisent la croissance tumorale. Dans ce contexte, nous avons démontré que les pDC infiltrant les tumeurs (TiPDC) mammaires conservent leur capacité d’acquérir un phénotype mature en réponse aux ligands des TLR 7 et 9 et d’activer la prolifération des lymphocytes T naïfs, alors qu’elles sont fortement altérées pour leur production d’IFN de type I. Cette altération fonctionnelle est induite par le TGF-β et le TNFα produits par l’environnement tumoral. La phosphorylation de SMAD dans les TipDC in situ confirme le rôle de la signalisation du TGF-β dans la dysfonction des pDC. Ces observations i) démontrent les mécanismes par lesquels les tumeurs mammaires inhibent la fonction des pDC et ii) fournissent de nouvelles pistes thérapeutiques visant à bloquer les facteurs tumoraux responsables de l’altération fonctionnelle des pDC. Outre leur capacité à infiltrer différents types de tumeurs dont les carcinomes, les pDC sont également recrutées dans les épithéliums inflammés lors d’infections virales ou de pathologies autoimmunes. Les mécanismes régulant cette migration restent à ce jour peu élucidés. Dans ce contexte, nous démontrons qu’une sous-population de pDC dans l’amygdale co-exprime CCR6 et CCR10, les récepteurs aux chimiokines CCL20 et CCL27/28 responsables du recrutement des cellules immunes dans les sites épithéliaux. In situ, les pDC sont retrouvées en contact étroit avec les ligands de CCR6 et CCR10 dans les épithéliums inflammés, suggérant que les couples CCR6-CCL20 et CCR10-CCL27/28 contrôlent la migration des pDC dans ces sites. Ces observations ont été confirmées in vivo puisque le recrutement des pDC dans des tumeurs de mélanome induit lors d’une inflammation est aboli dans les souris déficientes pour CCR6. De plus, les pDC circulantes humaines acquièrent l’expression de CCR6 et CCR10 in vitro en présence d’IL-3 tout en conservant parallèlement leur capacité de produire de l’IFN de type I en réponse au virus. Ainsi, nos résultats démontrent que les pDC circulantes pourraient êtres conditionnées via l’expression de CCR6 et CCR10 à migrer dans les épithéliums inflammés lors de pathologies infectieuses et non-infectieuses, où elles seraient capables d’exercer leurs fonctions innées. Ces travaux pourraient mener au développement de nouvelles stratégies thérapeutique basées sur la mobilisation et la manipulation des fonctions des pDC de l’induction de tolérance à l’induction d’immunité anti-tumorale de type anti-virale / Dendritic cells are professional antigen presenting cells initiating and modulating immune responses. Among them, plasmacytoid dendritic cells (pDC) represent key antiviral effectors through their production of high amounts of type I interferons (IFN). Their infiltration in breast tumors was correlated with a adverse clinical outcome, suggesting that the tumor environment somehow subvert pDC functions which in turn may promote the tumor growth. In this line, we demonstrated that breast tumor-associated pDC (TApDC) keep their ability to acquire a fully mature phenotype after TLR7 or 9 triggering and to activate naïve T cells proliferation, while they are strongly impaired for their capacity to produce type I IFN. This alteration of their main innate function is mediated by tumor-derived TGF-β and TNFα. SMAD phosphorylation in breast TApDC in situ further confirmed TGF-β signaling involvement in their dysfunction. These observations represent mechanistic of how breast tumors impair pDC function, and provide insights for developing new therapeutic strategies preventing the negative impact of tumor factors on infiltrating pDC. In addition to their description in many types of tumors including carcinoma, pDC also traffic into inflamed epithelial sites during viral infections or autoimmunity. But mechanisms underlying such pDC homing still remain unclear. Here we also report that a subset of tonsil pDC express CCR6 and CCR10 receptors for epithelial homing chemokines CCL20 and CCL27/28 respectively. In situ, pDC in inflamed epithelia are found in close contact with CCR6 and CCR10 ligands, indicating that CCR6/CCL20 and CCR10/CCL27/28 axis might mediate pDC homing in inflamed peripheral sites. These observations were further confirmed in vivo since inflammation-induced recruitment of pDC into melanoma tumor was abrogated in CCR6-deficient mice. Importantly, CCR6 and CCR10 expression was induced on human blood pDC in vitro in presence of IL-3 and such differentiated pDC keep their ability to produce type I IFN upon viral stimulation. Thus, our results also demonstrate that blood pDC might be conditioned through CCR6 and 10 upregulation to home inflamed epithelia during infectious or non-infectious disorders where they can exert their innate functions. This work may lead to the development of new therapeutic strategies to mobilize and manipulate the function of pDC - from inducing tolerance to inducing antiviral-like anti-tumor immunity

Background: Breast cancer is the most frequently diagnosed cancer and a leading cause of cancer death among females, both worldwide and in the UK. Although, UK incidence of breast cancer is rising, breast cancer mortality rates are falling, due largely to early detection and improved treatment. As a result there are more women living with a diagnosis of breast cancer than ever before. Due mainly to side-effects of adjuvant therapy, breast cancer patients may require diagnostic, therapeutic, supportive or palliative services many years post-diagnosis, which poses a major challenge to already stretched healthcare services. Accordingly, effective and inexpensive interventions that can alleviate treatment side-effects, improve health, quality of life and potentially reduce risk of early mortality are required for breast cancer patients. Awareness of the positive influence that physical activity can have on breast cancer development and outcome is an important determinant of physical activity levels. A higher level of physical activity before and after breast cancer diagnosis is related to a lower risk of all-cause and breast cancer-related mortality. Randomised controlled trials have reported beneficial effects of physical activity interventions on outcomes relating to health, quality of life and mortality risk among breast cancer survivors. Aims: The present project aimed to: 1) assess awareness of the role of physical activity on breast cancer risk and the sufficiency of physical activity undertaken in women attending the NHS breast screening programme (NHSBSP), 2) compare physical activity levels of women at different stages of breast cancer pathway, 3) investigate the effects of a low-cost six-month home-based physical activity intervention on physical activity, body mass, health-related quality of life (HRQoL), insulin resistance and blood lipid profiles of breast cancer survivors and 4) assess the effects of our home-based intervention on cardiorespiratory fitness in a subset of breast cancer survivors. Methods: A total of 309 volunteers (188 NHSBSP attendees, 41 breast cancer patients undergoing chemotherapy and 80 post-treatment breast cancer survivors) participated in the current project. Physical activity was assessed via the International Physical activity Questionnaires (IPAQ). In studies one and two, Body mass and body mass index (BMI) were assessed directly in chemotherapy patients and breast cancer survivors, and indirectly from self-reported values in NHSBSP attendees. While in study three, body fat percentage was measured via bioelectrical impedance analysis, HRQoL was assessed using the Functional Assessment of Cancer Therapy-Breast (FACT-B) questionnaire and fasting blood samples were taken to measure lipid, glucose and insulin concentrations at baseline and post-six month home-based physical activity intervention. In study four, a random subsample of 32 breast cancer survivors undertook an exercise tolerance test to establish peak oxygen uptake values. Results: A high proportion (70%) of NHSBSP attendees engaged in low-moderate levels of physical activity and performed low amounts of recreational physical activity. Attendees demonstrated high awareness (75%) of the role of physical activity in reducing breast cancer risk but those categorised as “low activity” were significantly unaware of insufficiency of activity (p<0.05). Chemotherapy patients and breast cancer survivors had significantly lower levels of total physical activity than NHSBSP attendees (p<0.001 and p<0.05, respectively). The randomised controlled trial revealed significant improvements in total physical activity, body mass (p<0.05), BMI (p<0.05) HRQoL (breast cancer subscale, p<0.01; trial outcome index, p<0.05) and total (p<0.01) and low-density lipoprotein (p<0.05) cholesterol concentrations in the intervention group compared to usual care, and significant improvements in cardiorespiratory fitness (p<0.05) in a subsample of breast cancer survivors allocated to intervention. Conclusions: Physical activity interventions that incorporate strategies aimed at increasing awareness of recommended physical activity guidelines may be required in populations at risk of breast cancer. A relatively large proportion of women at risk of breast cancer may not be sufficiently exposed to the potential benefits of physical activity on breast cancer outcomes. Post-treatment breast cancer patients may be more receptive to physical activity interventions as the negative effects of chemotherapy begin to resolve, and therefore, may benefit from physical activity interventions. Results suggest that a low-cost home-based physical activity intervention with counselling and telephone support can improve the health and HRQoL of breast cancer survivors, which may in turn potentially reduce risk of breast cancer and cardiovascular disease-related mortality. Given the encouraging results and its highly portable and feasible nature, our intervention represents a promising tool for use in health and community settings to benefit large numbers of breast cancer survivors. The current project supports the inclusion of physical activity promotion as an integral component for the management and care of breast cancer survivors.

Cytochrome P450 enzymes (P450s) are involved in cancer development and treatment due to their roles in the oxidative metabolism of various endogenous (e.g. oestrogen) and exogenous (e.g. tamoxifen) compounds. It is well-known that intermediate P450 metabolites derived from oestrogen metabolism are associated with breast carcinogenesis. The main aim of this project was to profile the cytochrome P450 and P450-regulatory nuclear receptor mRNAs in a series of breast cancer cell lines (BCCs) and compare this profile with normal breast cells. This study used the qualitative reverse transcriptasepolymerase chain reaction (RT-PCR) to detect mRNA expression of target genes. Results showed CYP1B1, CYP2D6, CYP2J2, CYP2R1, CYP2U1 and CYP4X1 mRNA to be present in all cell lines. CYP2A6, CYP2C8, CYP2C18, CYP2F1 and CYP4Z1 mRNA were expressed in oestrogen receptor (ER)-positiveCaucasian and ER-negative Afro- Caribbean BCCs. Although no differences in P450 mRNA were observed between the different ethnic groups, these preliminary findings suggest potential similarities in the ERpositive Caucasian and ER-negative Afro-Caribbean BCCs which warrant further investigation The CYP4Z1 PCR product was identified as two distinct bands. Specific primer sets were used to demonstrate potential intron retention in CYP4Z1. Using established in vitro models for the study of regulatory mechanisms of CYP4Z1, T47D and ZR-75-1 breast cancer cell lines were used to determine the appropriate nuclear receptors (i.e. progesterone receptor, glucocorticoid receptor or peroxisome proliferator-activated receptor alpha ). These findings suggest that there may be an alternative receptor mechanism involved in CYP4Z1 mRNA induction in these cells. In conjunction, pre-treatment of these two cell lines with the RNA synthesis inhibitor actinomycin D followed by the agonists showed a significant reduction (p < 0.05) of CYP4Z1 mRNA levels and inhibited CYP4Z1 induction by either progesterone, dexamethasone or pirinixic acid, indicating that these agonists have effects on CYP4Z1 mRNA transcription or stability. In contrast, cycloheximide differentially affected the level of CYP4Z1 mRNA induction by these agonists. Taken together, these results suggest that CYP4Z1 mRNA induction in T47D and ZR-75-1 is mediated through differential cell type specific regulatory mechanisms and there is evidence for differential regulation of the splice variants.

According to the 1 991 Annual Report of the Department of Health and Social Services of former Bophuthatswana, there were 364 reported malignant conditions found in women with cancer of the breast and cervix being the most prevalent. What causes great concern is t.he fact that patients present for the first time at health facilities during advanced stages of these diseases thus making the prognosis poor. Black patients in this study were found to present with cancer of the breast at an earlier age than their white counterparts. In addition to the above named problems, no facility exists for the treatment of cancer in the area of study and patients have to be referred to other areas. It was on the strength of the above observations that the researcher embarked upon this study to establish the effects of the diagnosis cancer and mastectomy on the victims. The aims of the study therefore were: to explore and describe the psycho-social effects of the diagnosis and treatment on Black women; develop guidelines for oncology nurses and doctors to assist with the adaptation of these patients to the diagnosis and treatment; and provide information that could lead to better training of oncology personnel as well as develop a proper support system to facilitate adjustment of the mastectomised patient to the disease and its treatment. Data were collected using the qualitative and quantitative approaches with individual in-depth interviews forming the main strategy. The findings revealed that the diagnosis cancer of the breast was equated with death among all respondents. The mastectomy added more stress for the patient, which was further compounded by chemo- and radiotherapy. The latter was described as causing more pain than the tumour itself. Problems experienced by the patients were reported to include: financial difficulties; general weakness; fear of recurrence and metastasis; concern for dependent children and fear of unemployment. All respondents in this study expressed the need for the formation of a voluntary care group, which could assist them with adaptation to the disease and its treatment. / Advanced Nursing Sciences / D. Lit. et Phil. (Advanced Nursing Sciences)

According to the 1 991 Annual Report of the Department of Health and Social Services of former Bophuthatswana, there were 364 reported malignant conditions found in women with cancer of the breast and cervix being the most prevalent. What causes great concern is t.he fact that patients present for the first time at health facilities during advanced stages of these diseases thus making the prognosis poor. Black patients in this study were found to present with cancer of the breast at an earlier age than their white counterparts. In addition to the above named problems, no facility exists for the treatment of cancer in the area of study and patients have to be referred to other areas. It was on the strength of the above observations that the researcher embarked upon this study to establish the effects of the diagnosis cancer and mastectomy on the victims. The aims of the study therefore were: to explore and describe the psycho-social effects of the diagnosis and treatment on Black women; develop guidelines for oncology nurses and doctors to assist with the adaptation of these patients to the diagnosis and treatment; and provide information that could lead to better training of oncology personnel as well as develop a proper support system to facilitate adjustment of the mastectomised patient to the disease and its treatment. Data were collected using the qualitative and quantitative approaches with individual in-depth interviews forming the main strategy. The findings revealed that the diagnosis cancer of the breast was equated with death among all respondents. The mastectomy added more stress for the patient, which was further compounded by chemo- and radiotherapy. The latter was described as causing more pain than the tumour itself. Problems experienced by the patients were reported to include: financial difficulties; general weakness; fear of recurrence and metastasis; concern for dependent children and fear of unemployment. All respondents in this study expressed the need for the formation of a voluntary care group, which could assist them with adaptation to the disease and its treatment. / Advanced Nursing Sciences / D. Lit. et Phil. (Advanced Nursing Sciences)