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La signalisation par l’estrogène a longtemps été considérée comme jouant un rôle critique dans le développement et la progression des cancers hormono-dépendants tel que le cancer du sein. Deux tiers des cancers du sein expriment le récepteur des estrogènes (ER) qui constitue un élément indiscutable dans cette pathologie. L’acquisition d’une résistance endocrinienne est cependant un obstacle majeur au traitement de cette forme de cancer. L’émergence de cancers hormono-indépendants peut est produite par l’activation de ER en absence d’estrogène, l’hypersensibilité du récepteur aux faibles concentrations plasmique d’estrogène ainsi que l’activation de ER par des modulateurs sélectifs. L’activité du ER est fortement influencée par l’environnement cellulaire tel que l’activation de voie de signalisation des facteurs de croissances, la disponibilité de protéines co-régulatrices et des séquences promotrices ciblées. Présentement, les études ont principalement considérées le rôle de ERα, cependant avec la découverte de ERβ, notre compréhension de la diversité des mécanismes potentiels impliquant des réponses ER-dépendantes s’est améliorée. L’activation des voies des kinases par les facteurs de croissance entraîne le développement d’un phénotype tumoral résistant aux traitements actuels. Nos connaissances des voies impliquées dans l’activation de ER sont restreintes. ERα est considéré comme le sous-type dominant et corrèle avec la plupart des facteurs de pronostic dans le cancer du sein. Le rôle de ERβ reste imprécis. Les résultats présentés dans cette thèse ont pour objectif de mieux comprendre l’implication de ERβ dans la prolifération cellulaire par l’étude du comportement de ERβ et ERα suite à l’activation des voies de signalisation par les facteurs de croissance. Nous démontrons que l’activation des récepteurs de surfaces de la famille ErbB, spécifiquement ErbB2/ErbB3, inhibe l’activité transcriptionnelle de ERβ, malgré la présence du coactivateur CBP, tout en activant ERα. De plus, l’inhibition de ERβ est attribuée à un résidu sérine (Ser-255) situé dans la région charnière, absente dans ERα. Des études supplémentaires de ErbB2/ErbB3 ont révélé qu’ils activent la voie PI3K/Akt ciblant à son tour la Ser-255. En effet, cette phosphorylation de ERβ par PI3K/Akt induit une augmentation de l’ubiquitination du récepteur qui promeut sa dégradation par le système ubiquitine-protéasome. Cette dégradation est spécifique pour ERβ. De façon intéressante, la dégradation par le protéasome requiert la présence du coactivateur CBP normalement requis pour l’activité transcriptionnelle des récepteurs nucléaires. Malgré le fait que l’activation de la voie PI3K/Akt corrèle avec une diminution de l’expression des gènes sous le contrôle de ERβ, on observe une augmentation de la prolifération des cellules cancéreuses. L’inhibition de la dégradation de ERβ réduit cette prolifération excessive causée par le traitement avec Hrgβ1, un ligand de ErbB3. Un nombre croissant d’évidences indique que les voies de signalisations des facteurs de croissance peuvent sélectivement réguler l’activité transcriptionnelle de sous-types de ER. De plus, le ratio ERα/ERβ dans les cancers du sein devient un outil de diagnostique populaire afin de déterminer la sévérité d’une tumeur. En conclusion, la caractérisation moléculaire du couplage entre la signalisation des facteurs de croissance et la fonction des ERs permettra le développement de nouveaux traitements afin de limiter l’apparition de cellules tumorales résistantes aux thérapies endocriniennes actuelles. / It has long been appreciated that estrogenic signaling plays a critical role in the development of hormone-dependent cancers such as breast cancer. Two-thirds of breast cancers express estrogen receptor (ER) which has been demonstrated to play an irrefutable role in tumour development and progression. However the acquisition of endocrine resistance has become a major obstacle in the treatment of hormone-dependent cancers that have acquired a hormone-independent state. Hormone-independent cancers emerge from an array of pathways involving ER activation in the absence of estrogen, hypersensitivity of ER to low serum levels of estrogen and activation by estrogen antagonists. The activity of ER is critically influenced by the cellular environment such as growth factor signaling pathways, availability of coregulatory proteins and the promoter sequence of target genes. The mechanisms studied have mostly considered the role of ERα, however with the discovery of the second subtype, ERβ, the understanding on the diversity of potential mechanisms involving ER-dependent responses have improved. Hormonal-independent activation of ER can occur in estrogen-dependent breast tumours, with concomitant rise in kinase signaling pathways, resulting in the acquisition of a therapeutic resistant phenotype in treated women. Our knowledge is relatively limited on which pathways trigger ER signaling and how these phosphorylation-coupled events affect ER activity. ERα is considered the dominant subtype and correlates with most of the prognostic factors in breast cancers. Conversely the role of ERβ remains unclear. The results presented in this thesis were carried out with the objective of gaining a better understanding of ERβ’s role in cellular proliferation by examining the behavior of ERβ and ERα during the activation of growth factor signaling pathways by cell-surface receptor-tyrosine kinases. We demonstrate here that the activation of cell surface receptors of the ErbB family, specifically ErbB2/ErbB3, inhibits the transcriptional activity of ERβ despite the presence of the coactivator CBP, yet activated ERα. Furthermore the inhibition of ERβ was attributed to a specific serine residue located within the hinge region, not present in ERα. Additional studies of ErbB2/ErbB3-initiated signaling revealed that it triggered the activation of the PI3K/Akt pathway which targeted the serine residue within the hinge region of ERβ. In fact, phosphorylation of ERβ by the PI3K/Akt pathway led to an increase in receptor ubiquitination which promoted its degradation by the ubiquitin-proteasome system which was subtype specific. Interestingly, proteasomal degradation required the presence of the coactivator CBP, which is normally involved in assisting nuclear receptor transcriptional activity. Although the activation of the PI3K/Akt pathway correlated with a decrease in the expression of ERβ target genes it led to an increase in the proliferation of breast cancer cells. Inhibiting the degradation of ERβ reduced the enhanced proliferation of breast cancer cells brought about by the treatment of ErbB3’s ligand, Hrgβ1. Increasing evidence indicates that growth factor signaling pathways can selectively regulate the transcriptional activity of ER subtypes, and the ratio of ERα/ERβ expression in breast tumours is becoming a popular prognostic factor to evaluate the severity of the tumour. Therefore the molecular characterization of the coupling between growth factor signaling and ER function should provide improved therapeutical approaches to overcome or delay the onset of resistance to endocrine therapy in hormone-dependent cancers.

Introdução: A atresia congênita de orelha constitui uma deformidade presente ao nascimento, de prevalência unilateral, decorrente da alteração no desenvolvimento das estruturas das orelhas externa e média. Geralmente, provoca perda auditiva condutiva, e pode ser acompanhada por componente sensorioneural. Dentre as formas de tratamento disponíveis, encontra-se o implante de orelha média Vibrant Soundbridge (VSB), que tem se mostrado eficaz no tratamento deste tipo de alteração. A literatura mostra melhora nos limiares tonais e nos resultados dos testes de percepção auditiva da fala, realizados com o uso do processador de fala após a cirurgia. Considerando que os indivíduos com este tipo de malformação podem passar por um período de privação sensorial auditiva anterior à reabilitação, torna-se interessante avaliar o estágio maturacional das estruturas auditivas corticais e o processamento das informações auditivas em nível central, bem como, verificar o benefício da indicação do VSB unilateral em situação de escuta difícil. Não foram encontrados estudos que abordam este aspecto e o emprego dos potenciais evocados auditivos corticais (PEAC) e do P300 em usuários de VSB. Objetivo: Analisar o impacto da perda auditiva condutiva e mista nos PEAC e P300 em usuários de VSB unilateral, com atresia de orelha bilateral, e verificar as habilidades auditivas, em situação de escuta difícil, considerando a indicação do VSB unilateral. Casuística e método: Vinte indivíduos, divididos em dois grupos, pareados em idade, sexo e grau de escolaridade. G1: dez indivíduos com perda auditiva condutiva ou mista bilateral, usuários de VSB unilateral, atendidos na Instituição de realização da pesquisa. Todos fizeram uso de aparelhos auditivos convencionais antes do VSB. G2: Dez indivíduos normo-ouvintes. Realização de audiometria em campo livre com o uso do VSB (apenas o G1), avaliação das habilidades auditivas pelo Hearing in Noise Test, pesquisa dos componentes P1, N1, P2, N2 e P300, em campo calibrado. Resultados: A média dos limiares tonais nas frequências de 500 a 3000 Hz, de 20 a 36 dB NA, mostrou que o VSB possibilitou o acesso aos sons da fala. Não foi observada diferença estatisticamente significante entre os valores de latência dos PEAC e P300 entre os grupos. Foi observada diferença estatisticamente significante entre o limiar de reconhecimento de sentenças e a relação sinal/ruído entre os grupos, sendo os melhores resultados apresentados pelo G2. Conclusão: Indivíduos com atresia de orelha e perda auditiva condutiva ou mista bilateral, quando adequadamente reabilitados, podem atingir a maturação das vias auditivas centrais e o processamento da informação auditiva em nível cortical. As habilidades de reconhecimento auditivo, sem e com ruído competitivo, mostraram-se defasadas quanto à normalidade, apontando para a indicação do VSB bilateral / Introduction: Congenital aural atresia is a congenital deformity. It is unilaterally prevalent due to alterations in the development of the external and middle ear structures. Congenital aural atresia causes conductive hearing loss and can be accompanied by sensorineural component. Among the available forms of treatment is the middle ear implant, Vibrant Soundbridge (VSB), which has been shown to be effective in treating this type of alteration. The literature shows improvement in tonal thresholds and in the results of tests of auditory perception of speech that were performed using the speech processor after surgery. Individuals with this type of malformation often experience a period of auditory sensory deprivation prior to rehabilitation. Hence, it is important to evaluate the maturation stage of the cortical auditory structures, the processing of auditory information at the central level, and to verify the benefit of unilateral VSB in difficult listening situations. There are no previous data on this aspect and with the use of cortical auditory evoked potentials (CAEP) and event-related potential (P300) in users of VSB. Aim: To analyze the impact of conductive and mixed hearing loss on CAEP and P300 in unilateral VSB users with bilateral ear atresia. To verify the auditory abilities in a difficult listening situation considering the indication for unilateral VSB. Materials and methods: Twenty individuals were divided into two groups matched for age, sex, and educational level. G1 comprised ten individuals with bilateral conductive or mixed hearing loss and users of unilateral VSB, who visited the research institution. All subjects used conventional hearing aids prior to VSB. G2 comprised ten normal hearing individuals. Audiometry in the free field was performed with the use of VSB (G1 only) and evaluation of hearing skills by the Hearing in Noise Test was conducted; components P1, N1, P2, N2, and P300 in a calibrated field were recorded. Results: Evaluation of the mean tonal thresholds in the frequencies between 500 and 3000 Hz, from 20 to 36 dB HL, demonstrated that VSB allowed access to speech sounds. There was no statistically significant difference in the CAEP and P300 latency values between the two groups. A statistically significant difference was observed in the sentence recognition threshold and the signal-to-noise ratio between the groups, with best results presented by G2. Conclusion: Individuals with congenital aural atresia and bilateral conductive or mixed hearing loss may reach maturation of the central auditory pathway and achieve adequate processing of auditory information at the cortical level, when rehabilitated. The auditory recognition skills, with and without competitive noise, were shown to be out of phase with normality, indicating the need for a bilateral VSB

INTRODUÇÃO: O Autismo é um distúrbio que tem início na infância, cujas principais características são a presença de um desenvolvimento anormal ou prejudicado na interação social e comunicação, e um repertório restrito de atividades e interesses. Algumas teorias consideram o autismo como um distúrbio do desenvolvimento causado por uma alteração do sistema nervoso central, e salientam a presença do déficit cognitivo nessa população. Estudos demonstram também a presença de anormalidades eletrofisiológicas nos potenciais evocados auditivos de curta, média e longa latências. Considerando a importância da integridade do sistema auditivo periférico e central na aquisição e desenvolvimento de fala, linguagem e aprendizado, mostra-se imprescindível que anormalidades auditivas tanto periféricas como centrais sejam identificadas e tratadas em indivíduos autistas. OBJETIVO: caracterizar os achados das avaliações comportamentais, eletroacústicas e eletrofisiológicas da audição em indivíduos com autismo, bem como compará-los aos obtidos em indivíduos normais da mesma faixa etária. MÉTODOS: foram realizadas anamnese, audiometria tonal, logoaudiometria, medidas de imitância acústica, potencial evocado auditivo de tronco encefálico, potencial evocado auditivo de média latência e potencial cognitivo em 16 indivíduos com autismo (grupo pesquisa) e 25 normais (grupo controle), com idades entre oito e 20 anos. RESULTADOS: Na comparação entre os resultados normais e alterados (análise qualitativa), não foram encontradas alterações na avaliação comportamental da audição para os dois grupos. Na comparação dos resultados das avaliações comportamentais e eletroacústicas entre os grupos, não ocorreram diferenças estatisticamente significantes. O grupo controle apresentou alterações apenas no resultado do potencial evocado auditivo de média latência, sendo que o tipo de alteração mais freqüentemente encontrada foi ambas (efeito eletrodo e efeito orelha ocorrendo concomitantemente). O grupo pesquisa apresentou resultados alterados em todos os potenciais evocados auditivos, havendo diferença estatisticamente significante quando comparado ao grupo controle. Com relação aos tipos de alterações encontradas no grupo pesquisa, foi observada uma maior ocorrência de alteração em tronco encefálico baixo no potencial evocado auditivo de tronco encefálico, alteração do tipo ambas (efeito eletrodo e efeito orelha ocorrendo concomitantemente) no potencial evocado auditivo de média latência e ausência de resposta no potencial cognitivo. Na análise quantitativa dos resultados dos potenciais evocados auditivos, verificou-se que apenas para o potencial evocado auditivo de tronco encefálico ocorreu diferença estatisticamente significante entre os grupos, com relação às latências das ondas III e V e interpicos I-III e I-V. CONCLUSÃO: Indivíduos com autismo não apresentam alterações nas avaliações comportamentais e eletroacústicas da audição, e apresentam alterações nos potenciais evocados auditivos de tronco encefálico e potencial cognitivo, sugerindo comprometimento da via auditiva em tronco encefálico e regiões corticais. / INTRODUCTION: Autism is a disorder, which begins in the infancy, and the main characteristics are the presence of an abnormal or impaired development of social interaction and communication, and restrict range of activities and interest. Some theories consider autism as a developmental disorder caused by a central nervous system alteration, and stress the presence of a cognitive deficit in this population. Studies also demonstrate the presence of electrophysiological abnormalities in the auditory evoked potentials of short middle and long latencies. Considering the importance of the peripheral and central auditory system integrity for the speech and language acquisition and development and for learning, it becomes important to identify and treat hearing abnormalities, either peripheral or central, in autistic individuals. AIM: to characterize the findings of behavioral, electroacoustic and electrophysiological assessments of autistic individuals, as well as to compare those findings with the ones of normal individuals of the same age. METHOD: 16 individuals with autism (study group) and 25 normal ones (control group), ranging in age from eight and 20 years underwent anamnesis, pure tone audiometry, speech audiometry, acoustic immitance measures, brainstem auditory evoked potential, middle latency response and cognitive potential. RESULTS: Comparing the normal and altered results (qualitative analysis), no alterations were found in the behavioral assessment of hearing in both groups. Comparing the results of the behavioral and electroacoustic evaluations between the two groups, there were no statistical differences. The control group presented altered results only in the middle latency auditory evoked potential and the most common type of alteration was both electrode effect and ear effect occurring simultaneously. The study group presented altered results in all auditory evoked potentials with a significant statistical difference when compared to the control group. Concerning the types of alterations found in the study group it was verified higher occurrence of lower brainstem alteration in the brainstem auditory evoked potential, both electrode and ear effect occurring simultaneously in the middle latency auditory evoked potential, and absence of response in the cognitive potential. The quantitative analysis of the auditory evoked potentials results showed a significant statistical difference between the groups only in the brainstem auditory evoked potential, concerning the latencies of waves III and V and interpeaks I-III and I-V. CONCLUSION: autistic individuals do not present altered behavioral and electroacoustic evaluations, and present altered brainstem auditory evoked potential and cognitive potential, suggesting prejudice in the brainstem auditory pathway and cortical regions.

Introdução: O considerável aumento da população idosa no Brasil e no mundo tem motivado pesquisas acerca da qualidade de vida do idoso. Distúrbios auditivos e a diminuição da capacidade de processar os sons são comuns no processo de envelhecimento, o que provoca dificuldades na compreensão de fala e na comunicação do idoso. A pesquisa do Processamento Auditivo (Central) em adultos e idosos pretende compreender as mudanças que ocorrem nas funções auditivas centrais durante o processo de envelhecimento, assim contribuindo para a melhor compreensão deste processo e facilitando a elaboração de estratégias para melhoria na comunicação destes indivíduos. Objetivo: Avaliar e comparar o desempenho de grupos de diferentes faixas etárias em testes logoaudiométricos, comportamentais do processamento auditivo (central) e eletrofisiológicos da audição. Método: O estudo analisa o desempenho de 131 adultos e idosos, com idade entre 50 e 79 anos, divididos em três grupos, compostos por três faixas etárias: G1 (50-59 anos) com 63 participantes, G2 (60-69 anos) com 47 participantes e G3 (70-79 anos) com 21 participantes, os quais realizaram testes logoaudiométricos (Limiar de Reconhecimento de Fala e Índice Percentual de Reconhecimento de Fala), comportamentais do Processamento Auditivo (Central) (Fala com Ruído Branco, Dicótico de Dígitos e Teste do Padrão de Frequência) e testes eletrofisiológicos da audição (PEATE e P300). Resultados: Os resultados mostram que houve diferença estatisticamente significante no desempenho dos grupos nas respostas dos testes do Limiar de Reconhecimento de Fala, Índice Percentual de Reconhecimento de Fala e Fala com Ruido Branco nas orelhas direita e esquerda e no teste Dicótico de Dígitos na orelha esquerda. Houve também diferença estatisticamente significante nos valores de latência das ondas I, III e V no PEATE na orelha direita e latência das ondas III e V no PEATE na orelha direita. Na análise dos resultados do teste Padrão de Frequência e P300 não houve diferença estatisticamente significante entre os grupos. Conclusões: O estudo mostra que com o processo de envelhecimento houve o aumento do Limiar de Reconhecimento de Fala nas orelhas direita e esquerda; a diminuição das porcentagens de acerto no teste de Índice Percentual de Reconhecimento de Fala e Fala com Ruído Branco nas orelhas direita e esquerda, e no teste Dicótico de Dígitos na orelha esquerda. Nos potenciais eletrofisiológicos, o envelhecimento provocou o aumento dos valores de latência do PEATE, nas ondas I, III e V na orelha direita, e III e V na orelha esquerda, e no P300 na orelha direita / Introduction: The considerable increase of the elderly population in Brazil and worldwide has motivated research on the quality of life of the elderly. Hearing disorders and the decrease in the ability to process sounds are common in the aging process, which provoke difficulties in speech comprehension and in the communication of the elderly. The research on central auditory processing in adults and elderly people aims at understanding the changes which occur in the central auditory functions during the aging process, thus contributing to the better understanding of the process and facilitating the development of strategies to improve these subjects\' communication.Objectives: To evaluate and compare the performance of groups of different ages in speech recognition and behavioral and electrophysiological evaluation of the central auditory system. Methods: The study analyses the performance of 131 adults and elderly people, ranging from 50 to 79 years of age, divided in three groups, formed by the age groups: G1 (50-59 years of age) with 63 members, G2 (60-69 years of age) with 47 members and G3 (70-79 years of age) with 21 members, who did speech audiometry (Speech Reception Threshold and Speech Recognition Test), behaviral evaluation of the central auditory process (Speech in Noise, Dichotic Digit Test and Pitch Pattern Sequence Test) and auditory electrophysiological tests (ABR and P300. Results: The results show that was a statistically significant difference in the performance of the groups on the Speech Recognition Threshold Test, Speech Recognition Test, and Speech in Noise Tests in the right and left ears and the Dichotic Digit Test in the left ear. There was also a statistically significant difference in the latency values of the I, III and V waves in the ABR of the right ear and Latency of the III and V waves in the ABR in the left ear and in the latency values of the 300 of the right ear. In the analysis of the Frequency Pattern Test and in the amplitude values P300 there was no significant difference in the groups\' performances. Conclusions: The study shows that, with the aging process, there was a decrease in the Speech Reception Threshold, Speech Recognitiontion Test and Speech in Noise in the right and left ears, and in the Dichotic Digit Test in the left ear. In the electrophysiological evaluation, the aging process led to an increase in the latency values of the ABR in the I, III and V waves in the right ear, and III and V in the left ear and in the latency of the P300 of the right ear

INTRODUÇÃO: A Síndrome da Imunodeficiência Adquirida é causada pelo vírus da imunodeficiência humana, um retrovírus específico que afeta o sistema imunológico, propiciando a ocorrência de diversas infecções oportunistas e podendo afetar também o sistema nervoso auditivo central. OBJETIVO: Avaliar as vias periférica e central do sistema auditivo em indivíduos adultos com HIV/AIDS. MÉTODOS: Foram avaliados 25 indivíduos com HIV/AIDS e 25 indivíduos do grupo controle, sendo estes submetidos à avaliação audiológica convencional, audiometria em altas frequências, emissões otoacústicas por transiente, supressão das emissões otoacústicas, potenciais evocados auditivos de tronco encefálico, média latência e Potencial Cognitivo (P300). RESULTADOS: O grupo estudo apresentou alterações em todas as avaliações realizadas, enquanto que o grupo controle apresentou alterações na audiometria em altas frequências, supressão das emissões otoacústicas, potencial evocado auditivo de média latência e P300. A comparação dos resultados normais e alterados obtidos entre os grupos apresentou diferença estatisticamente significante para a audiometria tonal convencional, audiometria em altas frequências, timpanometria, pesquisa dos reflexos acústicos, emissões otoacústicas, supressão das emissões otoacústicas e potencial evocado auditivo de tronco encefálico, sendo também possível observar uma tendência à diferença estatisticamente significante no P300. Com relação aos tipos de alteração, o grupo estudo apresentou maior ocorrência de perda auditiva neurossensorial na avaliação audiológica convencional, alterações sugestivas de comprometimento de orelha média e tronco encefálico concomitantemente no potencial evocado auditivo de tronco encefálico, alteração do tipo ambas (efeito eletrodo e efeito orelha ocorrendo concomitantemente) no potencial evocado auditivo de média latência e alterações por aumento de latência no P300. Com relação à análise quantitativa pode-se verificar que na comparação dos resultados obtidos entre os grupos houveram diferenças estatisticamente significantes para todos os limiares obtidos na audiometria tonal convencional, bem como na audiometria em altas frequências; no potencial evocado auditivo de tronco encefálico para a latência das ondas I, III, V, e interpicos I-V e III-V; no potencial evocado auditivo de média latência para a latência da onda Pa nas modalidades C4-A1 e C4-A2 e no P300 para a latência dessa onda. CONCLUSÃO: Indivíduos com HIV/AIDS apresentam alterações na avaliação audiológica convencional, audiometria em altas frequências, emissões otoacústicas, supressão das emissões otoacústicas e nos potenciais evocados auditivos, sugerindo comprometimento tanto da via auditiva periférica como da via auditiva central. / INTRODUCTION: The Acquired Immunodeficiency Syndrome is caused by the human immunodeficiency virus, a specific retrovirus that affects the immunological system allowing the emergence of several opportunistic infections, and that may also affect the central auditory nervous system. AIM: To assess the peripheral and central auditory pathways of the auditory system of individuals with HIV/AIDS. METHOD: 25 individuals with HIV/AIDS and 25 individuals from a control group were evaluated by conventional audiological assessment, high-frequency audiometry, transient otoacoustic emissions, suppression of otoacoustic emissions, brainstem auditory evoked potential, middle latency auditory evoked potential, and Cognitive Potential (P300). RESULTS: The study group presented abnormal results in all evaluations while the control group presented abnormal results in high-frequency audiometry, otoacoustic emission suppression, middle latency auditory evoked potential and P300. The comparison of normal and abnormal results between the groups showed statistically significant difference in conventional pure tone audiometry, high-frequency audiometry, tympanometry, acoustic reflexes, otoacoustic emissions, otoacoustic emissions suppression, and brainstem auditory evoked potential; it was also observed a tendency to statistically significant difference in P300. Concerning the types of alterations, the study group presented higher incidence of sensorineural hearing loss in the conventional audiological assessment; alterations suggestive of concomitant middle ear and brainstem disorders in the brainstem auditory evoked potential; concomitant electrode effect and ear effect in the middle latency auditory evoked potential; and increased latency in P300. In the quantitative analysis it was verified that in the comparison of results between the groups there were statistically significant differences for all thresholds obtained in the conventional pure tone audiometry as well as in the high-frequency audiometry; in the brainstem auditory evoked potential for the latency of waves I, III, V, and interpeaks I-V and III-V; in the middle latency for the latency of wave Pa in modalities C4-A1 and C4- A2; and in P300 latency. CONCLUSION: Individuals with HIV/AIDS present alteration in conventional audiological assessment, high-frequency audiometry, otoacoustic emission, otoacoustic emission suppression, and in auditory evoked potentials suggesting abnormalities of both, the peripheral and the central auditory pathways.

La signalisation par l’estrogène a longtemps été considérée comme jouant un rôle critique dans le développement et la progression des cancers hormono-dépendants tel que le cancer du sein. Deux tiers des cancers du sein expriment le récepteur des estrogènes (ER) qui constitue un élément indiscutable dans cette pathologie. L’acquisition d’une résistance endocrinienne est cependant un obstacle majeur au traitement de cette forme de cancer. L’émergence de cancers hormono-indépendants peut est produite par l’activation de ER en absence d’estrogène, l’hypersensibilité du récepteur aux faibles concentrations plasmique d’estrogène ainsi que l’activation de ER par des modulateurs sélectifs. L’activité du ER est fortement influencée par l’environnement cellulaire tel que l’activation de voie de signalisation des facteurs de croissances, la disponibilité de protéines co-régulatrices et des séquences promotrices ciblées. Présentement, les études ont principalement considérées le rôle de ERα, cependant avec la découverte de ERβ, notre compréhension de la diversité des mécanismes potentiels impliquant des réponses ER-dépendantes s’est améliorée. L’activation des voies des kinases par les facteurs de croissance entraîne le développement d’un phénotype tumoral résistant aux traitements actuels. Nos connaissances des voies impliquées dans l’activation de ER sont restreintes. ERα est considéré comme le sous-type dominant et corrèle avec la plupart des facteurs de pronostic dans le cancer du sein. Le rôle de ERβ reste imprécis. Les résultats présentés dans cette thèse ont pour objectif de mieux comprendre l’implication de ERβ dans la prolifération cellulaire par l’étude du comportement de ERβ et ERα suite à l’activation des voies de signalisation par les facteurs de croissance. Nous démontrons que l’activation des récepteurs de surfaces de la famille ErbB, spécifiquement ErbB2/ErbB3, inhibe l’activité transcriptionnelle de ERβ, malgré la présence du coactivateur CBP, tout en activant ERα. De plus, l’inhibition de ERβ est attribuée à un résidu sérine (Ser-255) situé dans la région charnière, absente dans ERα. Des études supplémentaires de ErbB2/ErbB3 ont révélé qu’ils activent la voie PI3K/Akt ciblant à son tour la Ser-255. En effet, cette phosphorylation de ERβ par PI3K/Akt induit une augmentation de l’ubiquitination du récepteur qui promeut sa dégradation par le système ubiquitine-protéasome. Cette dégradation est spécifique pour ERβ. De façon intéressante, la dégradation par le protéasome requiert la présence du coactivateur CBP normalement requis pour l’activité transcriptionnelle des récepteurs nucléaires. Malgré le fait que l’activation de la voie PI3K/Akt corrèle avec une diminution de l’expression des gènes sous le contrôle de ERβ, on observe une augmentation de la prolifération des cellules cancéreuses. L’inhibition de la dégradation de ERβ réduit cette prolifération excessive causée par le traitement avec Hrgβ1, un ligand de ErbB3. Un nombre croissant d’évidences indique que les voies de signalisations des facteurs de croissance peuvent sélectivement réguler l’activité transcriptionnelle de sous-types de ER. De plus, le ratio ERα/ERβ dans les cancers du sein devient un outil de diagnostique populaire afin de déterminer la sévérité d’une tumeur. En conclusion, la caractérisation moléculaire du couplage entre la signalisation des facteurs de croissance et la fonction des ERs permettra le développement de nouveaux traitements afin de limiter l’apparition de cellules tumorales résistantes aux thérapies endocriniennes actuelles. / It has long been appreciated that estrogenic signaling plays a critical role in the development of hormone-dependent cancers such as breast cancer. Two-thirds of breast cancers express estrogen receptor (ER) which has been demonstrated to play an irrefutable role in tumour development and progression. However the acquisition of endocrine resistance has become a major obstacle in the treatment of hormone-dependent cancers that have acquired a hormone-independent state. Hormone-independent cancers emerge from an array of pathways involving ER activation in the absence of estrogen, hypersensitivity of ER to low serum levels of estrogen and activation by estrogen antagonists. The activity of ER is critically influenced by the cellular environment such as growth factor signaling pathways, availability of coregulatory proteins and the promoter sequence of target genes. The mechanisms studied have mostly considered the role of ERα, however with the discovery of the second subtype, ERβ, the understanding on the diversity of potential mechanisms involving ER-dependent responses have improved. Hormonal-independent activation of ER can occur in estrogen-dependent breast tumours, with concomitant rise in kinase signaling pathways, resulting in the acquisition of a therapeutic resistant phenotype in treated women. Our knowledge is relatively limited on which pathways trigger ER signaling and how these phosphorylation-coupled events affect ER activity. ERα is considered the dominant subtype and correlates with most of the prognostic factors in breast cancers. Conversely the role of ERβ remains unclear. The results presented in this thesis were carried out with the objective of gaining a better understanding of ERβ’s role in cellular proliferation by examining the behavior of ERβ and ERα during the activation of growth factor signaling pathways by cell-surface receptor-tyrosine kinases. We demonstrate here that the activation of cell surface receptors of the ErbB family, specifically ErbB2/ErbB3, inhibits the transcriptional activity of ERβ despite the presence of the coactivator CBP, yet activated ERα. Furthermore the inhibition of ERβ was attributed to a specific serine residue located within the hinge region, not present in ERα. Additional studies of ErbB2/ErbB3-initiated signaling revealed that it triggered the activation of the PI3K/Akt pathway which targeted the serine residue within the hinge region of ERβ. In fact, phosphorylation of ERβ by the PI3K/Akt pathway led to an increase in receptor ubiquitination which promoted its degradation by the ubiquitin-proteasome system which was subtype specific. Interestingly, proteasomal degradation required the presence of the coactivator CBP, which is normally involved in assisting nuclear receptor transcriptional activity. Although the activation of the PI3K/Akt pathway correlated with a decrease in the expression of ERβ target genes it led to an increase in the proliferation of breast cancer cells. Inhibiting the degradation of ERβ reduced the enhanced proliferation of breast cancer cells brought about by the treatment of ErbB3’s ligand, Hrgβ1. Increasing evidence indicates that growth factor signaling pathways can selectively regulate the transcriptional activity of ER subtypes, and the ratio of ERα/ERβ expression in breast tumours is becoming a popular prognostic factor to evaluate the severity of the tumour. Therefore the molecular characterization of the coupling between growth factor signaling and ER function should provide improved therapeutical approaches to overcome or delay the onset of resistance to endocrine therapy in hormone-dependent cancers.

INTRODUÇÃO: A Síndrome da Imunodeficiência Adquirida é causada pelo vírus da imunodeficiência humana, um retrovírus específico que afeta o sistema imunológico, propiciando a ocorrência de diversas infecções oportunistas e podendo afetar também o sistema nervoso auditivo central. OBJETIVO: Avaliar as vias periférica e central do sistema auditivo em indivíduos adultos com HIV/AIDS. MÉTODOS: Foram avaliados 25 indivíduos com HIV/AIDS e 25 indivíduos do grupo controle, sendo estes submetidos à avaliação audiológica convencional, audiometria em altas frequências, emissões otoacústicas por transiente, supressão das emissões otoacústicas, potenciais evocados auditivos de tronco encefálico, média latência e Potencial Cognitivo (P300). RESULTADOS: O grupo estudo apresentou alterações em todas as avaliações realizadas, enquanto que o grupo controle apresentou alterações na audiometria em altas frequências, supressão das emissões otoacústicas, potencial evocado auditivo de média latência e P300. A comparação dos resultados normais e alterados obtidos entre os grupos apresentou diferença estatisticamente significante para a audiometria tonal convencional, audiometria em altas frequências, timpanometria, pesquisa dos reflexos acústicos, emissões otoacústicas, supressão das emissões otoacústicas e potencial evocado auditivo de tronco encefálico, sendo também possível observar uma tendência à diferença estatisticamente significante no P300. Com relação aos tipos de alteração, o grupo estudo apresentou maior ocorrência de perda auditiva neurossensorial na avaliação audiológica convencional, alterações sugestivas de comprometimento de orelha média e tronco encefálico concomitantemente no potencial evocado auditivo de tronco encefálico, alteração do tipo ambas (efeito eletrodo e efeito orelha ocorrendo concomitantemente) no potencial evocado auditivo de média latência e alterações por aumento de latência no P300. Com relação à análise quantitativa pode-se verificar que na comparação dos resultados obtidos entre os grupos houveram diferenças estatisticamente significantes para todos os limiares obtidos na audiometria tonal convencional, bem como na audiometria em altas frequências; no potencial evocado auditivo de tronco encefálico para a latência das ondas I, III, V, e interpicos I-V e III-V; no potencial evocado auditivo de média latência para a latência da onda Pa nas modalidades C4-A1 e C4-A2 e no P300 para a latência dessa onda. CONCLUSÃO: Indivíduos com HIV/AIDS apresentam alterações na avaliação audiológica convencional, audiometria em altas frequências, emissões otoacústicas, supressão das emissões otoacústicas e nos potenciais evocados auditivos, sugerindo comprometimento tanto da via auditiva periférica como da via auditiva central. / INTRODUCTION: The Acquired Immunodeficiency Syndrome is caused by the human immunodeficiency virus, a specific retrovirus that affects the immunological system allowing the emergence of several opportunistic infections, and that may also affect the central auditory nervous system. AIM: To assess the peripheral and central auditory pathways of the auditory system of individuals with HIV/AIDS. METHOD: 25 individuals with HIV/AIDS and 25 individuals from a control group were evaluated by conventional audiological assessment, high-frequency audiometry, transient otoacoustic emissions, suppression of otoacoustic emissions, brainstem auditory evoked potential, middle latency auditory evoked potential, and Cognitive Potential (P300). RESULTS: The study group presented abnormal results in all evaluations while the control group presented abnormal results in high-frequency audiometry, otoacoustic emission suppression, middle latency auditory evoked potential and P300. The comparison of normal and abnormal results between the groups showed statistically significant difference in conventional pure tone audiometry, high-frequency audiometry, tympanometry, acoustic reflexes, otoacoustic emissions, otoacoustic emissions suppression, and brainstem auditory evoked potential; it was also observed a tendency to statistically significant difference in P300. Concerning the types of alterations, the study group presented higher incidence of sensorineural hearing loss in the conventional audiological assessment; alterations suggestive of concomitant middle ear and brainstem disorders in the brainstem auditory evoked potential; concomitant electrode effect and ear effect in the middle latency auditory evoked potential; and increased latency in P300. In the quantitative analysis it was verified that in the comparison of results between the groups there were statistically significant differences for all thresholds obtained in the conventional pure tone audiometry as well as in the high-frequency audiometry; in the brainstem auditory evoked potential for the latency of waves I, III, V, and interpeaks I-V and III-V; in the middle latency for the latency of wave Pa in modalities C4-A1 and C4- A2; and in P300 latency. CONCLUSION: Individuals with HIV/AIDS present alteration in conventional audiological assessment, high-frequency audiometry, otoacoustic emission, otoacoustic emission suppression, and in auditory evoked potentials suggesting abnormalities of both, the peripheral and the central auditory pathways.