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L’hypertrophie bénigne de la prostate (HBP) est une pathologie qui affecte 50% des hommes dès l’âge de 60 ans et qui conduit à des troubles de la miction. L’HBP se caractérise par une hypertrophie exclusive ou composite de plusieurs compartiments tissulaires de la prostate que sont l’épithélium, le stroma et les fibres musculaires qui définissent respectivement les composantes glandulaire, fibreuse et musculaire de cette pathologie. Il a récemment été montré que les souris dépourvues en récepteurs nucléaires LXR (Liver‐X‐receptor) α (souris lxrα‐/‐) développent une hypertrophie de la prostate dont les signes histologiques évoquent une HBP de type fibreuse. Par ailleurs, un des traitements de l’HBP, vise à éteindre la signalisation androgénique en inhibant la conversion de la testostérone en son métabolite actif, la dihydrotestostérone (DHT). Le phénotype d’hypertrophie de la prostate pourrait donc également s’expliquer par une altération de la signalisation androgénique dans les souris lxrα‐/‐. Dans ce contexte, notre projet de recherche a été centré sur l’étude du rôle des LXR dans l’apparition de l’HBP dans sa composante glandulaire et l’analyse des relations moléculaires associant les signalisations dépendantes de LXRα et du récepteur des androgènes (AR) au sein de la prostate. Le phénotype d’HBP observé dans les souris lxrα‐/‐ résulte d’altérations importantes de l’homéostasie de l’épithélium qui miment la composante glandulaire : 1) une activité sécrétoire accrue ; 2) une altération des processus de sécrétion associée à une altération de l’expression des gènes codant des protéines du transport vésiculaire ; 3) une réponse altérée de certains gènes androgéno‐dépendants associée à une hypersensibilité aux androgènes ; 4) des modifications du réseau paracrine reliant le stroma et l’épithélium. Au final, ces travaux définissent LXRα comme un acteur clé de l’homéostasie prostatique et ouvrent des pistes intéressantes pour la compréhension de l’étiologie de l’HBP chez l’homme. Ces résultats montrent qu’il est possible de moduler la réponse androgénique de la prostate en ciblant LXRα. Ainsi, à plus long terme, l’activation pharmacologique de LXRα constitue une piste potentielle dans le traitement de l’HBP. / Benign prostate hyperplasia (BPH) is a very common prostatic disorder that affects 50% of men after 60 years. In BPH, prostate enlargement causes urinary disorders. BPH is characterized by a hypertrophy of several tissue compartments such as the epithelium, stroma and/or muscle fibers. Hence, three main forms of BPH have been described : glandular, fibrous and muscular form. It has been recently shown that LXR (Liver‐X‐receptor) α (lxrα‐/‐) mice develop a prostate enlargement with histological signs of fibrous BPH. Inhibition of testosterone conversion into DHT is one the most effective pharmacological treatment of BPH. Thus, the lxrα‐/‐ prostate phenotype could be in part due to an alteration of androgen signaling. In this context, the aim of this work was to study the role of LXR in glandular BPH development and to understand the relationships between LXRα and the androgen receptor (AR) dependent signaling pathway in prostate. The prostate enlargement observed in lxrα‐/‐ mice results from major alterations in epithelium homeostasis mimicking the glandular alteration of BPH : 1) increase of secretory activity ; 2) alteration of the secretory process associated with altered expression of vesicular transport protein encoding genes ; 3) a disruption in the response of androgen‐dependent genes associated with androgen hypersensitivity ; 4) changes in the paracrine network between stroma and epithelium. Finally, this work defines LXRα as a key player in prostate homeostasis and opens interesting way to the understanding of BPH etiology. These results show that targeting LXRα modulate the prostate androgenic response. Thus, pharmacological activation of LXRα could constitute a new option for the treatment of BPH.

Orientador: Laura Sterian Ward / Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciencias Medicas / Made available in DSpace on 2018-08-06T20:05:49Z (GMT). No. of bitstreams: 1 LimaJunior_MarioMacielde_M.pdf: 2114915 bytes, checksum: 56c9d6904dd7e0a16ab5565b0d280b7c (MD5) Previous issue date: 2006 / Resumo: O câncer de próstata (CaP) é atualmente a neoplasia maligna mais prevalente no mundo, após os tumores de pele. A incidência dessa enfermidade tem crescido nas últimas décadas devido, principalmente; ao aumento da longevidade da população. Atualmente o CaP tem sido detectado em estágios menos avançados do que no passado. As melhorias dos métodos de diagnóstico contribuem para a detecção precoce dessa neoplasia. Os polimorfismos de genes que codificam enzimas envolvidas na metabolização de drogas e de xenobióticos, como as do sistema Glutationa S-transferase (GST) e Citocromo P450 (CYP), podem estar implicados no risco e prognóstico para neoplasias. Foram avaliados os genótipos de GSTT1, GSTM1, GSTP1, GSTO1 e CYP1A1 em 125 pacientes portadores de câncer de próstata e em 100 indivíduos com hiperplasia prostática benigna. Tempo e atividade ocupacional, tabagismo e outros dados relevantes da história natural da doença foram obtidas por meio de entrevistas. Não foram encontrados quaisquer associações entre os genótipos estudados e o risco de câncer de próstata, tanto avaliando os diferentes genótipos em separado como em combinações, através de análise de regressão logística uni ou multivariada. Não houve associação entre os genótipos estudados e fatores clínicos de risco para câncer de próstata ou quaisquer parâmetros de agressividade do tumor ao diagnóstico ou durante o seguimento. Nossos dados permitem concluir que os genótipos de GST e CYP1A1 não estão associados à susceptibilidade ao câncer de próstata ou à sua evolução na população brasileira estudada / Abstract: Prostate cancer is currently the most common malignancy worldwide, second only to skin tumors. The incidence of prostate cancer has risen dramatically over the last decade, more than can be explained just by the increase in longevity. It is also apparent that prostate cancer is now being detected at less advanced stages than in the past. Increased awareness of the disease and improved detection methods are thought to contribute to this earlier detection. The polymorphic inheritance of human drug-metabolizing enzymes, such as those encoded by the Glutathione-S-Transferase (GST) and the Cytochrome P450 (CYP) systems, may be implicated in both cancer risk and prognostic. We compared GSTT1, GSTM1, GSTO1, GSTP1 e CYP1A1 genotypes of 125 prostate cancer and 100 benign prostatic hyperplasia patients. Lifetime occupational history, cigarette-smoking, and other anamnestic data were obtained through interviews. None of the studied polymorphisms was found associated to prostate cancer risk either considered in separate or in combination, in uni ou multivariate regression logistic analysis. Also, there was no association between genotypes and possible clinical factors of risk, or any parameter of tumor agressiveness at diagnosis or during follow-up. Our data suggest that GST and CYP1A1 genotypes are not associated to the susceptibility to prostate cancer or its outcome in the Brazilian population / Mestrado / Clinica Medica / Mestre em Clinica Medica