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Steroid hormones are reported to increase oxytocin (OXT) expression in skeletal muscle. It is possible that OXT may play essential roles in satellite cell (SC) proliferation and differentiation, which further contribute to skeletal muscle development and growth. In this dissertation, we tested this hypothesis with in-vivo and in-vitro studies in intrauterine growth restriction (IUGR) sheep, caloric restricted (CR) calves, tamoxifen (TAM) treated heifers, and bovine satellite cells (BSCs), respectively. In the in-vivo studies, we collected (1) longissimus dorsi muscle (LM) from IUGR sheep; (2) infraspinatus muscle (INF), LM, and semitendinosus muscle (ST) from CR calves; (3) LM muscle from TAM heifers. In all samples, mRNA abundance of targeted genes, such as OXT, were measured. Muscle fiber size and BSC number were also determined in skeletal muscle from TAM treated heifers. For the in-vitro studies, different treatments including 17β-estradiol (E2), trenbolone (TBA), TAM, OXT, and atosiban were applied to wild-type BSC and OXT knockout BSC (CRISPR-OXT) separately to investigate OXT's functions on BSC activity. For in-vivo studies, OXT expression significantly decreased (P<0.05) in IUGR LM muscle. Caloric restriction decreased OXT expression (P<0.05) in INF, LD, and ST muscle. Expression of OXT in LM from TAM animals decreased 50% (P<0.05). Moreover, TAM caused a small statistical reduction (P<0.05) in cross-sectional area (CSA). In in-vitro studies, OXT alone increased (P<0.05) fusion index but not proliferation in the wild-type BSC, whereas both proliferation and differentiation were stimulated (P<0.05) by OXT treatment in the CRISPR-OXT cell. By contrast, E2 and TBA increased (P<0.05) both proliferation rate and fusion index in wild-type BSC. However, E2 and TBA only stimulated proliferation rate (P<0.05) but not fusion index for CRISPR-OXT cells. Atosiban treatment resulted in lower proliferation and differentiation (P<0.05) in both wild-type BSC and CRISPR-OXT cell compared with OXT and E2 treatment groups. Together, our in-vivo studies indicate that OXT may play important roles in skeletal muscle development and growth. Our in-vitro studies demonstrate that OXT plays important roles in BSC proliferation and differentiation, and it is involved in steroid hormone stimulated BSC activity. / PHD / Oxytocin (OXT) is a mammalian neurohypophysial hormone. It has been demonstrated that OXT is highly expressed in skeletal muscle and satellite cell (SC) by steroid hormone administration. However, the role of OXT in SC proliferation and differentiation is not elucidated. In this dissertation, the in-vivo and in-vitro studies are combined and used to investigate if OXT is involved in bovine SC (BSC) activity. In the in-vivo studies, we collected muscle samples from intrauterine growth restriction (IUGR) sheep, caloric restricted (CR) calves, and tamoxifen (TAM) treated heifers. In all samples, mRNA abundance of OXT was measured. For the in-vitro studies, wild-type BSC and OXT knockout BSC (CRISPR-OXT) were treated with different factors including 17β-estradiol (E2), trenbolone (TBA), TAM, OXT, and atosiban separately to investigate OXT's functions on BSC activity. For in-vivo studies, OXT expression significantly decreased (P<0.05) in IUGR, CR, and TAM muscle. In in-vitro studies, OXT alone increased (P<0.05) fusion index but not proliferation in the wild-type BSC, whereas both proliferation and differentiation were stimulated (P<0.05) by OXT treatment in the CRISPR-OXT cell. By contrast, E2 and TBA, which can stimulate OXT expression in cultured BSC, increased (P<0.05) both proliferation rate and fusion index in wild-type BSC. However, E2 and TBA only stimulated proliferation rate (P<0.05) but not fusion index for CRISPR-OXT cells. Atosiban treatment resulted in lower proliferation and differentiation (P<0.05) in both wild-type BSC and CRISPR-OXT cell compared with OXT and E2 treatment groups. Together, our studies indicate that OXT plays important roles in BSC proliferation and differentiation, and it is involved in steroid hormone stimulated BSC activity. Studies to investigate specific biological mechanisms of steroid hormone stimulated OXT expression in SC are needed in the future.

Les hôpitaux génèrent des effluents riches en résidus pharmaceutiques (RP), fonctions de leurs activités de soins et de diagnostic. Certains de ces RP sont aujourd’hui retrouvés de manière ubiquitaire dans les écosystèmes aquatiques, en raison de leurs propriétés persistantes et/ou de leur émission continue. La variété de ces RP est telle qu’il est nécessaire de les hiérarchiser, en fonction des risques qu’ils représentent pour l’Environnement, à des fins d’étude et de gestion. Un de ces risques est le transfert des RP bioaccumulables (i.e. Kow élevé et faible biodégradabilité) dans les chaînes alimentaires, via les processus de bioconcentration, de bioaccumulation et de bioamplification. L’objectif principal de cette thèse est de caractériser expérimentalement la bioconcentration et la bioaccumulation de molécules identifiées comme prioritaires dans des travaux précédents. Le composé modèle que nous avons choisi est le tamoxifen, molécule utilisée contre le cancer du sein et déjà retrouvé dans l’Environnement. Les organismes étudiés, issus des trois niveaux trophiques de la chaine alimentaire modèle, sont Pseudokirchneriella subcapitata, Daphnia magna et Danio rerio. Pour mesurer la teneur de cette molécule dans les organismes, nous avons développé une méthode d’analyse reposant sur l’utilisation d’une molécule marquée par un isotope stable, le 15N tamoxifen.Nous avons mesuré des facteurs de bioconcentration (BCF) allant de 12800 chez D. magna à 85600 dans le foie de D. rerio en passant par 21500 chez P. subcapitata. Chez ces derniers, nous avons également évalué la part du régime alimentaire dans la bioaccumulation du tamoxifen. Nous avons observé que plus la concentration dans le milieu d’exposition est faible, plus le régime alimentaire contribue à la bioaccumulation. Ces travaux de thèse présentent de nombreuses perspectives que l’on peut regrouper autour de deux axes : connaissance de l’écotoxicité des RP et de l’écotoxicologie isotopique. / Hospitals generates effluents rich in pharmaceuticals compounds (PC), notably because of careand diagnostics activities. Some of these PCs are ubiquitous in aquatic ecosystems owing to itspersistent properties and/or because of continuous releasing in environment. The diversity of thesePCs is so strong that it is necessary to prioritize them, considering risks that PCs represents forthe Environment, in order to manage and study these compounds. One of these risks is the transferof bioaccumulatives PCs (i.e. PCs with high Kow and low biodegradability) along trophic webs,via bioconcentration, bioaccumulation and biomagnification processes. The main objective of thisthesis is to characterize bioconcentration and bioaccumulation of molecules identified as priorityin previous studies. The model compound choose in our work is the tamoxifen, a molecule usedin the treatment of breast cancer and already found in Environment. Organisms studied, typicalfrom three trophic levels of the model trophic chain, are Pseudokirchneriella subcapitata, Daphniamagna and Danio rerio. In order to measure content of tamoxifen in organisms, we developed aninnovative analytic method based on the use of stable isotopes labelled tamoxifen : 15N tamoxifen.We succeeded to measure bioconcentration factors (BCF) from 12800 in D. magna to 85600 in liverof D. rerio including BCF of 21500 in P. subcapitata. In this latter, we also assessed the contributionof dietary route to the total contamination of D. magna by tamoxifen. We observed that the morethe medium concentration was weak, the more the dietary route contribute to the contamination.These works shows numerous perspectives that we can gather inside two axes : ecotoxicity knowledgeof PCs an isotopic ecotoxicology.

nÃo hà / O cÃncer à um dos principais problemas de saÃde pÃblica em muitas partes do mundo e o cÃncer de mama à o mais comum em mulheres no mundo ocidental. Tamoxifeno tem sido o principal tratamento endÃcrino adjuvante por muitos anos. à o fÃrmaco mais prescrito no tratamento do cÃncer de mama, principalmente na modalidade adjuvante em pacientes prà ou pÃs menopausadas, receptor de estrÃgeno e/ou progesterona positivos, tambÃm utilizado no tratamento da doenÃa localmente avanÃada e metastÃtica e em menor proporÃÃo nas pacientes com contra-indicaÃÃo formal de cirurgia ou que se recusam a se submeter a esta modalidade de tratamento. Na neo-adjuvÃncia à utilizado apenas em ensaios clÃnicos. O tamoxifeno diminui, na adjuvÃncia por 5 anos, a probabilidade de recidiva em 47% e de morte por cÃncer de mama em 26%. Seus dois principais efeitos colaterais, apesar de raros, sÃo: aumento da prevalÃncia de cÃncer de endomÃtrio e de fenÃmenos tromboembÃlicos. Este estudo teve como objetivo avaliar os principais benefÃcios e recidivas tumorais em pacientes portadoras de cÃncer de mama tratadas com tamoxifeno, na forma adjuvante, acompanhadas no Instituto do CÃncer do CearÃ, no perÃodo de abril de 1999 a abril de 2004. A anÃlise dos pacientes avaliados foi feita de acordo com o estadiamento clÃnico e patolÃgico, receptores hormonais, e comparadas com dados histÃricos, bem como o efeito protetor no aparecimento de um segundo cÃncer na mama contralateral, recidiva local ou à distÃncia, de acordo com o estadiamento clÃnico e patolÃgico e, por fim, avaliou-se a qualidade da informaÃÃo e dos dados contidos nos prontuÃrios das pacientes do estudo. ProntuÃrios de duzentos e setenta e nove pacientes foram analisados quanto aos dados sÃcio-demogrÃficos, idade, status menopausal, estadiamento clÃnico e patolÃgico, dosagem de receptores de estrÃgeno e progesterona, casos de cÃncer de endomÃtrio, modalidade de tratamento, causas de Ãbito, tipo histolÃgico e status dos linfonodos axilares. Verificou-se que a maioria dos resultados encontrados està de acordo com os dados da literatura, ou seja, que o grupo de pacientes com estadiamento clÃnico inicial, a exemplo do EstÃdio ClÃnico I, tratadas com tamoxifeno, apresentaram maior beneficio clÃnico, quando comparado com o grupo com doenÃa localmente avanÃada, bem como menos metÃstases e recidivas, benefÃcio para pacientes positivos para receptores estrogÃnicos. A anÃlise dos dados teve prejuÃzo resultante da qualidade dos registros realizados nos prontuÃrios, ressaltando a importÃncia de se estimular os mÃdicos a documentar, de forma clara e legÃvel, o maior nÃmero de informaÃÃes possÃveis, nÃo apenas as positivas, mas todas aquelas que possam ter relaÃÃo com a utilizaÃÃo de qualquer medicamento prescrito e, ainda, a importÃncia da confirmaÃÃo do receptor hormonal. / Cancer is one of most worry public health problem in many parts of the world and breast cancer is the most common in the women in the Western World. Tamoxifen has been the mainstay of adjuvant endocrine treatment for many years and it is the drug more prescribed in the treatment of breast cancer, mainly in the adjuvant modality, in pre or post menopaused patients, positive estrogen and/or progesterone receptors, used too in the treatment of locally advanced and metastatic disease and in smaller proportion in patients with formal contraindication of surgery or that refuse to submit this treatment modality. In the neoadjuvancy it is just used in clinical research. The tamoxifen also reduces, in the adjuvant modality, used during five years, the probability of recurrence in 47% and deaths caused by breast cancer in 26% and the two main side effects, in spite of rare, are the increase of the prevalence of endometrial cancer and of thromboembolic phenomenon. This study had as main objective to evaluate the patients, breast cancer bearers, in the Institute of Cancer of CearÃ, treated with tamoxifen, in the adjuvant form, in the period of 1994 to 2004 regarding the main benefits and side effects. It had been performed the analysis in agreement with the hormonal receptors, clinical and pathological staging and compared with the historical data, as well as the tamoxifen protector effect against new contralateral breast cancer occurrence, main local relapse and distant metastasis in accordance with clinical and pathological staging, and at last, the quality of prontuary information and medical registers. Two hundred seventy nine patientsâ prontuaries were analyzed in respect to the demographic dataâs, age, menopausal status, clinical and pathological staging, estrogen and/or progesterone receptors status, cases of endometrial cancer, modality of treatment, death causes, histological type and axillary lymph nodes status. It had been evaluated that most of the data is in agreement with the literature, in other words, the early breast cancer group as Clinical Stage I, treated with tamoxifen, had clinical benefice, when compared with the group with locally advanced disease, as well as, less metastasis and locally relapse, benefices to patients with positive estrogen receptors . The damage of the analysis was resulting from the quality accomplished found in the prontuaries, so, doctors should be more and more stimulated to document, in a clear and readable way, the largest number of possible information, not just the positive ones, but all those that more frequently can have relationships with the use of any prescribed medicine or procedure, and the importance to confirm the status of hormonal receptor.

Bröstcancer är en multifaktoriell sjukdom och är den vanligaste cancerformen hos kvinnor, cirka var tionde kvinna får någon gång diagnosen. År 2017 var det drygt 10 000 kvinnor som diagnostiserades med bröstcancer och 1400 som avled till följd av sjukdomen i Sverige. Den vanligaste typen är en icke-invasiv form kallad duktal cancer in situ. De flesta bröstcancrarna uttrycker receptorer för östrogenreceptorn (ER) och klassas som ER-positiva tumörer, många tumörer uttrycker också receptorer för progesteron (PgR). ER är en prediktiv biomarkör där positivitet idag används för att identifiera de patienter som svarar på antiöstrogenbehandling med exempelvis läkemedlet tamoxifen (TAM). TAM används för behandling av bröstcancer hos pre- och postmenopausala ER-positiva kvinnor. Syftet med denna litteraturstudie var att undersöka huruvida effekten av TAM kan förutsägas med hjälp av prediktiva biomarkörer vid adjuvant behandling av ER-positiv bröstcancer hos pre- och postmenopausala kvinnor. Arbetet innefattade artikelsökningar och baseras på 9 retrospektiva vetenskapliga studier hämtade från en avhandling och databasen PubMed. Analyserade markörer var proteinuttrycket av HOXB13, AIB1, mTOR, Akt, ER, PgR, EGFR, HER2, CXCL10, CXCR3 samt genuttryck av HOXB13, IL17BR, CYP2C19, CCND1 och RSF1. Studierna analyserade patientmaterial från studier som jämfört TAM vs kontroll eller olika behandlingsregimer av TAM. Ett lågt proteinuttryck av HOXB13 var prediktivt för fördelaktig TAM-effekt samt att ett högt uttryck förutsäger mindre fördelaktig effekt hos ER-positiva patienter. Vidare visades att fosforylerat (p) mTOR enskilt och i kombination med p-ER och/eller p-Akt var prediktivt för ett reducerat TAM-svar. Resultaten som presenteras visar att ett högt uttryck av AIB1 var prediktivt för ett fördelaktigt TAM-svar hos ER-positiva. CXCL10 och CXCR3 var båda prediktiva för ett förbättrat TAM-svar jämfört med kontroll. Vidare visar resultaten att genuttrycken för HOXB13 och förhållandet mellan HOXB13:IL17BR förutsäger effekten av en längre behandling på 5 år jämfört med 2 år. En variant allel av CYP2C19*2 genotypen identifierar patienter med allvarlig prognos men som fördelaktigt kan behandlas med TAM. Resultaten påvisar även att endast ER-status inte är prediktivt för en fördelaktig TAM-behandling och att PgR-analys kan användas som tillägg vid ER-negativitet för att identifiera en liten subgrupp av bröstcancerpatienter som med fördel kan behandlas med TAM. HER2-positivitet påvisar ingen nytta av TAM hos ER-positiva patienter. Resultaten avseende CCND1 påvisar att genamplifiering ej var lämpad som prediktiv markör men att RSF1-genamplifiering kan vara en potentiell markör för avsaknad av TAM-fördel. Sammanfattningsvis kan TAM-effekt förutsägas med hjälp av prediktiva markörer så som HOXB13, AIB1, CXCL10/CXCR3 m.fl., det krävs dock verifiering av resultaten i större kontrollerade studier i form av retrospektiva metaanalyser eller prospektiva studier för att dra en generell slutsats. / For women breast cancer is the most common cancer diagnosis in Sweden, approximately 10 000 patients were diagnosed in 2017. Breast cancer is the leading cause of death among women around the world and in Sweden it is the second most common cause of death. Breast cancer arise from the terminal duct lobular units of the breast, most tumour types are classified as non-invasive called cancer in situ, specifically as ductal cancer in situ. When diagnosing breast cancer there are different ways to characterize tumours. One example is the use of prognostic and predictive biomarkes, which provides information about prognosis and treatment effect. The most common analysis is that of estrogen receptor (ER) and progesterone receptor (PgR) expression. Estrogen and progesterone regulate proliferation of mammary glands and the development of breast tissue. Approximately 85 % of tumours express these two steroid receptors. The presence of ER in cancer cells is the most important marker for prediction of adjuvant tamoxifen treatment effect. Tamoxifen is a selective estrogen receptor modulator, which upon binding to the ER in breast tissue regulate the proliferative effects and acts as an anti-estrogen. Tamoxifen is used in the treatment of breast cancer in pre and postmenopausal women with ER-positive tumours. Some patients, however, will still not respond to treatment and experience a breast cancer relapse within 15 years. Because of this it’s important to aquire knowledge of and validate these prognostic and predictive biomarkes as well as futher study breast cancer biology to better individualise treatment according to patient needs.  The aim of this study was to evaluate potential predictive biomarkers in the treatment of ER-positive breast cancer with adjuvant tamoxifen. Specifically, if the effect of tamoxifen can be predicted using specific biomarkers. Potential future biomarkes evaluated were the expression of HOXB13, IL17BR, CYP2C19, CCND1 and RSF1 genes and the protein expression of mTOR, Akt, ER, PgR, EGFR, HER2, HOXB13, AIB1, CXCL10 and CXCR3. This litterature study is based on the analysis of 10 different retrospecitve studies of predictive markers based on patient materials from original randomized controlled trials evaluating the efficacy of tamoxifen. Seven of the studies were collected using the database PubMed, however two studies were collected from a thesis. The search was limited to articles which studied tumour material of pre- or postmenopausal female breast cancer patients randomized to adjuvant tamoxifen treatment or control. Based on the results presented, potential predicitive biomarkes of tamoxifen efficacy and benefit of breast cancer patients could be a high protein expression of AIB1, a low expression of the HOXB13 protein and a high expression of CXCL10 and CXCR3. Moreover, predicitve markers of tamoxifen benefit could also be a CYP2C19*2 variant allel. A reduced response to treatment could be predicted with the positive expression of p-mTOR-s2448, p-ER-s167/s305 and p-Akt. HER2-positivity could be a marker for identifying patients who will not respond to tamoxifen and may benefit greater from other treatments. These results, however, needs to be verified in bigger cohorts of breast cancer patients, e.g. in meta-analyses or prospective randomized studies.

Dietary components potentially influence breast cancer risk factors, including breast density (BD) and estrogen metabolism (EM). Tamoxifen (TAM) is a commonly prescribed anti-estrogen adjuvant cancer treatment to reduce breast cancer risk, partially through modulation of BD and EM. Epidemiological evidence has suggested a potential protective effect from dietary intakes of fiber and vegetables in breast cancer recurrence in women on TAM as well as an independent influence on BD and EM. The relationship between dietary intake BD and EM in women prescribed TAM is not fully understood. A cross-sectional analysis using baseline data collected from 130 pre- and post-menopausal women taking TAM and enrolled in the Diindolylmethane Efficacy (DIME) Study was conducted. Participants completed the Arizona Food Frequency Questionnaire to assess dietary intake. TAM metabolites were analyzed through HPLC. BD was measured from digital mammograms and urinary EM was analyzed using LC/MS. Unadjusted linear regression between diet and four TAM metabolites indicated significant association between endoxifen and caffeine. 4-hydroxyTAM had significant inverse associations with fat intake, including monounsaturated, polyunsaturated and saturated fats. Linear regression adjusted for BMI revealed a statistically significant positive association with caffeine intake and BD, with no other dietary associations observed. The highest amount of correlations was observed between 2OHE and energy, total fat, MUFA, PUFA, protein and carbohydrate intake, though weak. Correlations were seen between 4OHE, 16αOHE and total isoflavones. Cholesterol was weakly positively correlated with 2mOHE, E1 and approached significance with E2. Dietary intake shows little association with BD or EM in women taking TAM therapy. Alternate preventive mechanisms for diet in women on TAM therapy should be investigated.

<p>Funding: Magnus Bergvall Cancer Foundation; Percy Falk foundation for research in breast and prostate cancer; Nyckelfonden; Örebro University Hospital; Lions cancer research foundation, Region Uppsala-Örebro</p>

Estrogen signalling pathway plays crucial role in carcinogenesis of breast cancer. Estrogen receptor (ER) is a prototypical hormone receptor that upon binding its ligand, estradiol, translocates into the nucleus and turns on target genes related to cellular proliferation and survival. Although estrogen signalling physiologically supports normal breast tissue development, deregulations of this pathway contribute to development of breast tumours that are estrogen receptor dependent. One of the main obstacles in breast cancer treatment is acquired resistance to common anticancer drugs also known as multidrug resistance (MDR). The switch between chemotherapy responsive to chemotherapy resistant cell phenotype is usually accompanied by increased expression of ABC transporters, special membrane proteins responsible for export of various kinds of commonly used anticancer drugs from the intracellular to extracellular space and is also linked to the existence of cancer stem cells (CSCs). ABC transporters can not only export chemotherapeutic drugs but may modulate tumour microenvironment through the transport of endogenous intracellular substrates such as leukotrienes (LTs), sphingolipids and prostaglandins PGs). This function may also play important role in carcinogenesis. The aim of the thesis was to...

A enzima indoleamina 2,3 dioxigenase - IDO desempenha um importante papel na regulação do sistema imunológico, impedindo o estabelecimento de uma resposta imunológica no microambiente em que é expressa. Quando ativada, é responsável por catabolizar o aminoácido triptofano, privando células em proliferação deste componente e gerando metabólitos que as induzem a apoptose. Hormônios, como o estrógeno e a progesterona são capazes de alterar as funções imunológicas nas células, podendo levar à alteração na expressão da IDO, contudo, os mecanismos responsáveis por este efeito, ainda não são claros. Sabe-se que diversas células tumorais e leucócitos adjacentes à região do tumor podem expressar IDO e são sensíveis à ação desses hormônios. Os carcinomas mamários são os mais comuns nos cães, apresentando grande expressão de IDO. Em face destas informações, este trabalho buscou investigar a influência do estrógeno e da progesterona na expressão da IDO em cultura de células provenientes do carcinoma mamário de cadelas tratadas com os referidos hormônios e seus respectivos antagonistas de receptor (tamoxifeno estrógeno e mifepristone progesterona). A expressão da enzima foi analisada pela imuno-histoquímica, citometria de fluxo e quantificada pela técnica de western blot, enquanto os mRNA foram analisados por Real time-PCR. Os resultados da quantificação da enzima (citometria de fluxo e Western blot) seguiram o mesmo padrão da expressão de mRNA. Perante a suplementação das células com estrógeno, houve a elevação da expressão da enzima e do respectivo mRNA que, após a adição de tamoxifeno, antagonista do receptor do estrógeno, reduziu a referida expressão. A suplementação com progesterona, resultou numa discreta diminuição na expressão da IDO e respectivo mRNA, a qual foi revertida após a adição do inibidor de progesterona (mifepristone). Com estes achados, conclui-se que os hormônios esteroides, devido às modificações nos padrões de citocinas expressas pelas células PR e ER positivas no microambiente tumoral, provocam alterações na expressão de IDO. / The indoleamine 2,3 dioxygenase - IDO enzyme plays an important role in the regulation of the immune system, preventing the establishment of an immune response in the microenvironment in which it`s expressed. When activated, it`s responsible for catabolizing the amino acid tryptophan, depriving cells in proliferation of this component generating metabolites that induce apoptosis. Hormones such as estrogen and progesterone are capable of alter immune functions in cells and may lead to altered expression of IDO, but the mechanisms responsible for this effect are still unclear. It is known that several tumor cells and leucocytes adjacent to the tumor region are able to express IDO and are sensitive to the action of these hormones. Breast carcinomas are the most common in female dogs, presenting a great expression of IDO. Bearing this information, this study aimed to investigate the influence of estrogen and progesterone on the expression of IDO in culture of mammary carcinoma cells from bitches treated with these hormones and their respective receptor antagonists (tamoxifen - estrogen and mifepristone - progesterone). The expression of the enzyme was analyzed by immunohistochemistry, flow cytometry and quantified by the western blot technique, while the mRNA was analyzed by Real-time PCR. The results of enzyme quantification (flow cytometry and Western blot) followed the same pattern of mRNA expression. There was an increase of the enzyme expression and mRNA in the estrogen treated group, in contrast to the decrease observed in the progesterone group. When the cells were subjected to the hormonal inhibitors, an evident decrease of IDO expression percentage and the respective mRNA was verified following the supplementation of tamoxifen and a restoration of IDO expression values and the mRNA after the addition of the progesterone inhibitor, mifepristone. With these findings, we conclude that steroid hormones due to the modifications in the cytokine patterns expressed by PR and ER positive cells in the tumor microenvironment alters IDO expression.

Submitted by Angela Maria de Oliveira (amolivei@uepg.br) on 2018-11-27T13:38:37Z No. of bitstreams: 2 license_rdf: 811 bytes, checksum: e39d27027a6cc9cb039ad269a5db8e34 (MD5) Felipe Biscaia.pdf: 705544 bytes, checksum: d29d4058c2971e1453c934610a2e4d2b (MD5) / Made available in DSpace on 2018-11-27T13:38:37Z (GMT). No. of bitstreams: 2 license_rdf: 811 bytes, checksum: e39d27027a6cc9cb039ad269a5db8e34 (MD5) Felipe Biscaia.pdf: 705544 bytes, checksum: d29d4058c2971e1453c934610a2e4d2b (MD5) Previous issue date: 2018-08-22 / Câncer é um conjunto de doenças causadas por uma lesão gênica associada a uma expansão clonal com crescimento desproporcional. O melanoma é o câncer de pele com menor perspectiva de sobrevida e com alta capacidade de metástase. O câncer de mama é um dos mais abundantes entre as mulheres, com alta incidência de morte. Estudos relatam que todas as células do corpo humano são capazes de secretar microvesículas e, que os tecidos tumorais secretam micropartículas com mais abundancia. Essas micelas desempenham um papel importante na comunicação celular. Assim, a comunicação entre as células tumorais possui uma função essencial para o desenvolvimento do câncer. Neste trabalho, as linhagens de melanoma B16F10 e adenocarcinoma 4T1 foram cultivadas e submetidas ao tratamento dos fármacos Dexametasona e tamoxifeno, bem como microvesículas extraídas dos sobrenadante de B16F10 tratado com dexametasona. Como resultados, observamos redução da viabilidade celular de ambas as linhagens ocasionada pelos três tratamentos isolados, assim como pelos tratamentos combinados do compostos utilizados. Os fármacos e as microvesículas desencadearam efeitos citotóxicos sobre as linhagens tumorais, mostrando-se potenciais alternativas para tratamento. / Cancer is a set of diseases caused by a simple gene injury associated with a clonal expansion with disproportionate growth. Melanoma is a skin cancer with a lower survival prospect and high metastatic capacity. Breast cancer is one of the most abundant among women, with a high incidence of death. Several studies report that all human cells are able to secrete microvesicles, and that tumor tissues secrete microparticles with high abundance. These micelles play an important role in cellular communication. Thus, communication between tumor cells has an essential function for the development of cancer. In this work, the B16F10 melanoma and 4T1 adenocarcinoma cell lines were cultured and treated with the drugs Dexamethasone and tamoxifen, as well as microvesicles extracted from the B16F10 supernatant treated with dexamethasone. The results shows a reduction in the cell viability of both strains caused by the three isolated treatments, as well as by the combined treatments of the compounds used. Drugs and microvesicles triggered cytotoxic effects on tumor lines, showing potential treatment alternatives.