The mammary gland cell growth and differentiation are under the control of both systemic hormones and locally produced growth factors. Among all these important hormones and growth factors, estrogen plays a central role in mammary gland development. The biological function of estrogen is mediated by estrogen receptor α (ERα) and estrogen receptor β (ERβ). Both ERα and ERβ are expressed in the mammary gland, but with distinct expression patterns. In the mammary gland, ERα has been proved to be the estrogen receptor that mediates the mitogenic function of estrogen. However the function of ERβ in mammary cell proliferation is less understood and there remains some controversy. Accumulating evidence indicates that ERβ, unlike ERα, is a negative regulator of mammary epithelial cell proliferation. In this dissertation, ERα and ERβ were evaluated for their expression patterns in the mammary gland. In the proestrus phase, ERα was detected in about 20% of mammary epithelial cells; in the diestrus phase, no ERα staining was detected in the mammary gland. ERβ was expressed in more than 50% of mammary epithelial cells and ERβ staining was detected in some stromal cells in the proestrus phase. In the diestrus phase, ERβ staining cells were very limited and the staining intensity was very weak. These data suggest that the expression levels of both ERα and ERβ undergo dynamic changes during the estrous cycle. In the ovariectomised (OVX) rats, both ERα and ERβ were detected in more than 50% of mammary epithelial cells. Compared with the ovary-intact rats, the mammary gland of the OVX rats showed more cells with ERα expression, but the staining intensity was weaker. Taken together, the expression of ERα and ERβ is regulated by estrogen in normal mammary gland, while without estrogen stimulation in the OVX rats, more mammary cells showed ERα expression, but at a lower level in these cells. The effects of ERα and ERβ on mammary cell proliferation were studied by two different approaches, activation of endogenous ERα and ERβ via selective agonists, and overexpression of ERα and ERβ via lentiviral infection. In the first approach, we used ERα and ERβ selective agonists, propylpyrazole-triol (PPT) and diarylpropionitrile (DPN) respectively, to activate endogenous ERα and ERβ in the OVX rats. We found that ERβ selective agonist DPN counteracts the proliferative effect of ERα selective agonist PPT in the mammary gland. In the second approach, ERα and ERβ were ectopically overexpressed in the mammary gland of mature virgin rats by lentivirus infection. We found that ERβ overexpression significantly decreased mammary cell proliferation rate in both the proestrus and diestrus phases, indicating that ERβ, unlike ERα, is a negative regulator for mammary cell proliferation. Collectively, these data supports that in contrast to ERα, ERβ activation or overexpression is able to inhibit mammary cell proliferation.

Hormonal therapy is a common part of breast carcinoma treatment in patients whose tumors express estrogen and progesterone receptors. The aim of hormonal therapy is to prevent proliferative effect of hormones througt their receptor proteins in order to inhibit tumor growth. However, certain number of tumors is resistant to hormonal therapy despite expression of hormonal receptors. Presently, the reasons of this resistance are not fully understood. Oxysterols are hydroxylated cholesterol derivates, which may play some role in development of the resistance. They may interfere with hormonal therapy effect and influence some signal pathways leading to cancer progression. This study comes with results of gene expression of proteins influenced by oxysterol action, metabolic and transport proteins, transcription factors and members of signaling pathways that may be related to oxysterol effect. This thesis identifies some candidate genes for future analysis on the basis of comparison of gene expression between estrogen receptor positive and negative tumors and correlation with clinopathological data. The final goal should lead to discovery of new diagnostic markers for breast cancer therapy. Powered by TCPDF (www.tcpdf.org)

Os estrógenos exercem importantes efeitos fisiológicos através dos dois subtipos dos receptores de estrógeno humanos (hERs), alfa (hER?) e beta (hER?). Enquanto hER? é um importante alvo macromolecular no desenvolvimento de fármacos para o tratamento do câncer de mama, hER? é um alvo promissor no desenvolvimento de agentes terapêuticos para a terapia de reposição hormonal. O progresso no planejamento de moduladores apresentando maior potência, afinidade e seletividade, entretanto, requer a otimização múltipla de interações intermoleculares fármaco-receptor. A Química Medicinal moderna, de forte caráter multidisciplinar, fornece um arsenal de alternativas e estratégias úteis no processo de planejamento de novos fármacos. As ferramentas de modelagem molecular e de estudos das relações quantitativas entre a estrutura e atividade (QSAR) estão integradas a esse processo, sendo de extremo valor na busca por moléculas bioativas com propriedades múltiplas otimizadas. Para a realização deste trabalho, conjuntos padrões de dados foram organizados para diferentes classes químicas de potentes moduladores dos ERs. Esses conjuntos padronizados para os subtipos do hER, contendo a informação qualificada sobre a estrutura química dos ligantes associada a medida da propriedade farmacológica correspondente, estabeleceram as bases para o desenvolvimento de modelos empregando os métodos holograma QSAR, CoMFA e GRID/PCA. Os modelos finais de HQSAR e CoMFA possuem elevada consistência interna e externa, apresentando bom poder de correlação e predição das propriedades alvo. Juntamente com as informações obtidas pelos mapas de contribuição 2D e de contorno 3D, os modelos de QSAR e GRID/PCA construídos são guias químico-medicinais úteis no planejamento de novos moduladores seletivos do ER possuindo maior afinidade e potência. / Estrogens exert important physiological effects through two human estrogen receptor subtypes (hERs), alpha (hER?) and beta (hER?). While hER? is a macromolecular target of great importance for breast cancer therapy, hER? is an attractive drug target for the development of novel therapeutic agents for hormone replacement therapy. Progress towards the design of modulators having improved potency, affinity and selectivity requires the optimization of multiple ligand-receptor interactions. The strong multidisciplinary character of modern Medicinal Chemistry supplies a rich arsenal of useful rational strategies for the design of new drug candidates. Molecular modeling tools and quantitative structure-activity relationships (QSAR) are integrated into the drug design process in the search of bioactive molecules having optimized properties. In this study, standard data sets were organized for different chemical classes of ER modulators, integrating the qualified information about chemical structure associated to the corresponding pharmacological property. The data sets established the scientific basis for the development of models employing the hologram QSAR, CoMFA and GRID/PCA methods. The final HQSAR and CoMFA models possess high internal and external consistency, with good correlative and predictive power. The generated QSAR and GRID/PCA models as well as the information gathered from the 3D contour maps provide useful guidelines for the design of new selective ER modulators having improved affinity and potency.

La relative immunité des femmes vis-à-vis du risque cardiovasculaire a longtemps été attribuée aux hormones sexuelles. Néanmoins, le rôle protecteur des estrogènes dans le développement de l’athérosclérose et de ses complications a été récemment remis en cause chez les femmes ménopausées. A partir de la cohorte française des Trois Cités incluant environ 10.000 sujets de plus de 65 ans, j’ai évalué l’association entre les estrogènes endogènes et le risque de maladies cardiovasculaires chez des femmes n’utilisant pas de traitement hormonal. J’ai montré pour la première fois que des taux élevés d’estradiol plasmatique étaient associés à une augmentation du risque artériel ischémique à 4 ans, indépendamment des facteurs de risque cardiovasculaire traditionnels, notamment l’obésité ou le diabète. Dans une deuxième partie, j’ai étudié le rôle modulateur des polymorphismes génétiques des récepteurs des estrogènes α (ESR1) et β (ESR2). J’ai montré que le risque cardiovasculaire augmentait avec les taux élevés d’estradiol chez les femmes porteuses du génotype rs9340799-AA mais pas chez celles avec le génotype rs9340799-AG/GG. Des analyses complémentaires m’ont également permis de suggérer que l’effet des estrogènes était lié en partie à une hypercoagulabilité et un état inflammatoire. Dans une dernière étape, j’ai évalué le rôle prédicteur à long terme des estrogènes endogènes. J’ai confirmé la relation indépendante entre les taux élevés d’estrogènes et la survenue d’un évènement cardiovasculaire après 10 ans de suivi. Globalement, ces résultats suggèrent un effet délétère des estrogènes dans le développement des maladies artérielles ischémiques chez les femmes ménopausées après 65 ans . Si ces résultats étaient confirmés, une meilleure stratification du risque artériel pourrait être proposée chez les femmes ménopausées avec des implications potentielles dans la prévention des maladies cardiovasculaires. / The low incidence of coronary heart disease among women has often been attributed to sex hormones. However, adverse effects of estrogens on arterial disease have been recently reported in older postmenopausal women. In the French Three-City prospective cohort study of subjects over 65 years of age, I investigated the association of endogenous estradiol with cardiovascular risk among postmenopausal women who did not use any hormone therapy. In a first part, I showed that high levels of plasma estradiol were related to the 4-year incidence of ischemic arterial disease (IAD), independently of traditional cardiovascular risk factors such as obesity or diabetes. Then, I reported that the relation between estrogens and IAD risk could be modulated by estrogen receptor-α (ESR1) polymorphisms. Indeed, endogenous estrogens were positively associated with IAD risk in women carrying the ESR1 rs9340799-AA genotype but not in those carrying the ESR1 rs9340799-AG/GG genotype. Further analyses revealed that both hypercoagulability and inflammatory state might act as mediators. Finally, I assessed the long-term predictor role of endogenous estrogens in arterial disease. I showed a positive and independent association of estrogens levels with the 10-year incidence of cardiovascular disease. Overall, high plasma levels of endogenous estradiol emerge as a new significant predictor of cardiovascular disease in older postmenopausal women. If confirmed, these findings could have the potential to improve the stratification of IAD risk in postmenopausal women.

by Cheung Tak Chi. / Thesis (M.Phil.)--Chinese University of Hong Kong, 1998. / Includes bibliographical references (leaves 117-123). / Abstract also in Chinese. / Acknowledgeements --- p.i / Abbreviations --- p.ii / Abstract --- p.v / List of Figures --- p.viii / List of Tables --- p.xiv / Contents --- p.xv / Contents / Chapter 1. --- Introduction --- p.1 / Chapter 1.1 --- Epidemiological Risk Factors --- p.1 / Chapter 1.1.1 --- Age --- p.1 / Chapter 1.1.2 --- Race --- p.2 / Chapter 1.1.3 --- Environmental or Migratory Factor --- p.2 / Chapter 1.1.4 --- Diet --- p.2 / Chapter 1.1.5 --- Genetics --- p.3 / Chapter 1.2 --- Regulation of Normal Prostate Development and Function --- p.4 / Chapter 1.3 --- Biochemistry and Development of Prostate Cancer --- p.6 / Chapter 1.3.1 --- Androgen-Dependent Prostate Cancer --- p.6 / Chapter 1.3.2 --- Androgen-Independent Prostate Cancer --- p.8 / Chapter 1.4 --- Classification of Prostate Cancer --- p.9 / Chapter 1.4.1 --- Stage A Prostate Cancer --- p.10 / Chapter 1.4.2 --- Stage B Prostate Cancer --- p.10 / Chapter 1.4.3 --- Stage C Prostate Cancer --- p.11 / Chapter 1.4.4 --- Stage D Prostate Cancer --- p.11 / Chapter 1.5 --- Methods for Early Detection of Prostate Cancer --- p.12 / Chapter 1.6 --- Clinical Treatment of Prostate Cancer --- p.12 / Chapter 1.6.1 --- Surgery --- p.12 / Chapter 1.6.2 --- Radiotherapy --- p.13 / Chapter 1.6.3 --- Chemotherapy --- p.13 / Chapter 1.6.4 --- Hormonal Therapy --- p.13 / Chapter 1.7 --- Objective --- p.14 / Chapter 1.8 --- Estrogen and Its Related Compounds --- p.16 / Chapter 1.8.1 --- 17β-Estradiol --- p.16 / Chapter 1.8.2 --- Tamoxifen --- p.18 / Chapter 1.8.3 --- Aromatase Inhibitor --- p.20 / Chapter 1.9 --- Anticancer Drugs --- p.23 / Chapter 1.9.1 --- Doxorubicin --- p.23 / Chapter 1.9.2 --- cis-Platinum --- p.24 / Chapter 1.10 --- Apoptotic Pathways --- p.25 / Chapter 1.10.1 --- BCL-2 /BAD Pathway --- p.26 / Chapter 1.10.2 --- FADD Pathway --- p.27 / Chapter 1.10.3 --- CAS Pathway --- p.27 / Chapter 2. --- Materials and Methods --- p.28 / Chapter 2.1 --- Materials --- p.28 / Chapter 2.2 --- Cell Lines --- p.32 / Chapter 2.3 --- Preparation of Drugs --- p.32 / Chapter 2.4 --- Drug Sensitivity Assay --- p.33 / Chapter 2.5 --- Cell Cycle Analysis --- p.35 / Chapter 2.6 --- DNA Fragmentation Assay --- p.36 / Chapter 2.7 --- Annexin Binding Assay --- p.37 / Chapter 2.8 --- Western Blot Analysis --- p.38 / Chapter 2.9 --- Data Analysis --- p.41 / Chapter 3. --- Results --- p.42 / Chapter 3.1 --- Response of Human Androgen-Independent Prostate Cancer Cells to Doxorubicin and cis-Platinum --- p.42 / Chapter 3.2 --- The Effect of 17p-Estradiol on the Growth and Anticancer Drug Sensitivity of Human Androgen-Independent Prostate Cancer Cells --- p.45 / Chapter 3.2.1 --- 17β-Estradiol on Cell Growth --- p.45 / Chapter 3.2.2 --- 17β-Estradiol on Anticancer Drug Sensitivity --- p.45 / Chapter 3.2.3 --- 17β-Estradiol and Doxorubicin on Cell Cycle Progression --- p.51 / Chapter 3.2.4 --- 17β-Estradiol and Doxorubicin Induced DNA Fragmentation --- p.57 / Chapter 3.2.5 --- 17β-Estradiol and Doxorubicin on Annexin Staining --- p.59 / Chapter 3.2.6 --- 17β-Estradiol and Doxorubicin on Apoptotic Protein Expression --- p.62 / Chapter 3.3 --- The Effect of Tamoxifen on the Growth and Anticancer Drug Sensitivity of Human Androgen-Independent Prostate Cancer Cells --- p.64 / Chapter 3.3.1 --- Tamoxifen on Cell Growth of Human --- p.65 / Chapter 3.3.2 --- Tamoxifen on Anticancer Drug Sensitivity --- p.65 / Chapter 3.3.3 --- Tamoxifen and Doxorubicin on Cell Cycle Progression --- p.71 / Chapter 3.3.4 --- Tamoxifen and Doxorubicin Induced DNA Fragmentation --- p.76 / Chapter 3.3.5 --- Tamoxifen and Doxorubicin on Annexin Staining --- p.78 / Chapter 3.3.6 --- Tamoxifen and Doxorubicin on Apoptotic Protein Expression --- p.79 / Chapter 3.4 --- The Effect of Aromatase Inhibtiors on the Growth and Anticancer Drug Sensitivity of Human Androgen-Independent Prostate Cancer Cells --- p.81 / Chapter 3.4.1 --- Aromatase Inhibitors on Cell Growth --- p.81 / Chapter 3.4.2 --- Aromatase Inhibitors on Anticancer Drug Sensitivity --- p.83 / Chapter 3.4.3 --- 4-AcA and Doxorubicin on Cell Cycle Progression --- p.93 / Chapter 3.4.4 --- 4-AcA and Doxorubicin Induced DNA Fragmentation --- p.99 / Chapter 3.4.5 --- 4-AcA and Doxorubicin on Annexin Staining --- p.100 / Chapter 3.4.6 --- 4-AcA and Doxorubicin on Apoptotic Protein Expression --- p.102 / Chapter 4. --- Discussion --- p.105 / Chapter 4.1 --- 17 β-Estradiol and Anticancer Drug Sensitivity --- p.106 / Chapter 4.2 --- Tamoxifen and Anticancer Drug Sensitivity --- p.109 / Chapter 4.3 --- Aromatase Inhibitors and Anticancer Drug Sensitivity --- p.112 / Chapter 4.4 --- DU145 Cells vs PC3 Cells --- p.115 / Chapter 5. --- Conclusion and Perspectives --- p.116 / Chapter 6. --- References --- p.117

Background and aims of the study. Prostate cancer (PCa) is one of the most common hormone-dependent cancers in men in Western and also Asian countries. The standard treatment options for localized PCa include surgery and androgen-deprivation therapy (ADT). However, most patients upon ADT therapy invariably relapse and progress to a more aggressive and metastatic stage termed as castration-resistant PCa (CRPC). Accumulating studies indicate that androgen receptor (AR) transcriptional activity is dysregulated during the advanced progression of CRPC. One important mechanism responsible for the growth of CRPC includes increased intra-tumoral androgen synthesis in PCa. Recently, a novel androgen-responsive fusion gene TMPRSS2:ERG formed by fusion between the transmembrane protein TMPRSS2 and transcription factor ERG, has been identified in approximately 50% PCa samples, which results in the aberrant expression of ERG function as oncogenic factor in PCa. Currently, TMPRSS2:ERG is regarded as a significant potential diagnostic and prognostic biomarker for PCa. Estrogen-related receptor alpha-ERRα, the first identified ligand-independent orphan nuclear receptor, is characterized to be up-regulated in advanced cancers, suggesting that ERRα might play important regulatory roles in the malignant progression of PCa. Previous studies showed that ERRα can functionally cross-talk with AR signaling via co-targeting to AR targets and regulate the expression of some steroidogenic enzymes in breast cancer. Based on this background, it is hypothesized that ERRα could functionally regulate the TMPRSS2:ERG fusion gene and play a regulatory role in the development and progression of CRPC through activation of the intracellular androgen synthesis pathway. / Results. 1) The results obtained in this study showed that suppression of ERRα by its specific inverse agonist XCT790 or shRNA-knockdown could induce down-regulation of TMPRSS2:ERG and also its target genes in AR-positive VCaP PCa cells. 2) Ectopic expression of ERRα and/or its coactivator PGC-1α could increase the expression of TMPRSS2:ERG in AR-negative NCI-H660 PCa cells. 3) Two ERRα-DNA binding elements were identified by ChIP assay and sequence analysis in the promoter of TMPRSS2:ERG and both of these two elements could be transactivated by ERRα and PGC-1α. 4) Ectopic expression of TMPRSS2:ERG under the regulation of ERRα enhanced the prostatic cell invasion capacity as shown in the TMPRSS2:ERG infectants of BPH-1 and PC-3 prostatic cells. 5) ERG expressed by the TMPRSS2:ERG fusion could directly transactivate the ERRα gene in prostatic cells. 6) A positive correlation on the expressions between TMPRSS2:ERG and ERRα was demonstrated in a xenograft model of CRPC (VCaP-CRPC). 7) The expression of TMPRSS2:ERG and ERRα showed significant up-regulation and the transactivation activity of ERRα was also enhanced in castration-resistant VCaP-CRPC cells. 8) Ectopic expression of ERRα could promote resistant growth capacity to androgen-deprivation condition in LNCaP PCa cells, whereas shRNA-mediated silence of ERRα could weaken this resistant capacity. Furthermore, ectopic expression of ERRα in LNCaP-ERRα infectants could promote their in vivo growth resistance to castration in SCID mice. 9) Expression of several androgenic enzyme genes, including CYP11A1, CYP17A1 and ARK1C3, were detected to be up-regulated in castration-resistant VCaP-CRPC cells. Moreover, ectopic expression of ERRα could induce the increased expression of these enzyme genes in LNCaP-ERRα infectants, whereas knockdown of ERRα by shRNA could decrease their expression. 10) ERRα could directly transactivate the gene promoters of CYP11A1, CYP17A1 and ARK1C3 which contain ERRE elements prediction by sequence analysis. These results suggested that ERRα could play a role in de novo or intra prostatic androgen synthesis in the PCa cells. / Conclusions. The results obtained in this study suggested that ERRα and TMPRSS2:ERG could form a positive reciprocal loop in PCa cells, and ERRα could also promote the resistant growth capacity of PCa cells resistant to the androgen-deprivation condition in vitro and also castration-resistant growth in vivo via a mechanism of up-regulation of androgenic enzyme genes. The results also suggested that ERRα might play a significant regulatory role in the development and progression of PCa, particularly the advanced CRPC, and also ERRα could be a potential therapeutic target for the treatment of PCa, particularly the advanced PCa-CRPC. / 研究背景與研究目的：前列腺癌作為激素依賴的一種癌症，經常出現在西方和亞洲國家的男性人群中。對於局限性前列腺癌多採用外科手術和去勢的治療。但是大多數病人經過去勢治療后會再次復發並且形成更加惡心幾轉移的前列腺癌，稱之為去勢難治性前列腺癌（CRPC）。越來越多的研究表明在去勢難治性前列腺癌發病過程中，雄激素受體轉錄活性異性增強。其中一個重要機理解釋為前列腺癌細胞自身合成的雄激素增多。進來，在大約50%的前列腺癌病人中新檢測到一個受雄激素受（AR）體調控的融合基因TMPRSS2:ERG，它是由稱為TMPRSS2的一個跨膜蛋白和一個稱為ERG的轉錄因子融合而成，它的出現導致了在前列腺癌中異常的稱為致癌因子的ERG蛋白的高表達。目前，TMPRSS2:ERG已經被作為一個重要的潛在的診斷和預測的標誌物應用在前列腺癌中。作為第一個鑒定的配體不依賴的孤兒受體-ERRα，被證明在晚期的癌症中有很高的表達，預示著ERRα可能在惡性的癌症中起到一個非常重要的調控作用。之前的研究表明通過共同調控AR的下游基因，ERRα同AR信號通路之間有功能性的交叉調控；除此之外，在乳腺癌中，ERRα還可以調控一些類固醇類化合物的合成相關的一些酶的合成。依據上述，我們推定ERRα可能功能性地調控TMPRSS2:ERG融合基因的表達並且通過調控細胞內的雄激素的合成進而在去勢難治性前列腺癌的發生和發展中起到一個非常重要的作用。 / 結果：本論文研究結果總結如下：1）在有AR表達的前列腺癌細胞-VCaP細胞中，通過ERRα特異性的抑制劑XCT790處理或者shRNA介入的干擾ERRα的mRNA的方法來抑制ERRα，下調了TMPRSS2:ERG和它的一些下游調控基因的表達。2）在沒有AR表達的前列腺癌細胞-NCI-H660細胞中，上調ERRα或者它的特異性的共激活因子PGC-1α表達可以提升TMPRSS2:ERG的表達。3）通過ChIP實驗，在TMPRSS2:ERG的啟動子上面，兩個ERRα的DNA結合位點被鑒定出來。並且這兩個位點可以被ERRα和PGC-1α轉錄激活。4）在兩個前列腺細胞BPH-1和PC-3細胞中，在ERRα的調控下高表達TMPRSS2:ERG融合基因可以增強細胞的侵襲能力。5）融合基因TMPRSS2:ERG導致的ERG蛋白的表達可以直接轉錄激活ERRα的表達。6）我們通過VCaP細胞的異種移植建立VCaP-CRPC的體內模型來模擬CRPC過程，在整個過程中，我們發現TMPRSS2:ERG和ERRα有一致性的表達相關性。除此之外，我們根據上述動物模型通建立了VCaP-CRPC細胞系，並且發現在VCaP-CRPC細胞細胞中，TMPRSS2:ERG和ERRα都有被上調並且ERRα的轉錄活性同樣也提升。7）在LNCaP細胞中高表達ERRα可以提升細胞在去除雄激素的環境中生長的能力。但是當在LNCaP細胞中用shRNA干擾掉ERRα可以明顯減弱這種生長的能力。用LNCaP-ERRα穩轉ERRα的細胞異種移植建立SCID老鼠體內腫瘤模型，我們發現和LNCaP-pBABE對照組相比，LNCaP-ERRα細胞生長的更快更大。並且在對老鼠進行睪丸切除術后，LNCaP-ERRα組細胞更快適應這種環境并繼續生長，相比之下，LNCaP-pBABE對照組則持續萎縮減小。8）在上述的VCaP-CRPC細胞中，我們發現一些和雄激素合成相關的關鍵的酶包括CYP11A1，CYP17A1和ARK1C3的表達量有顯著地提升。而且在LNCaP-ERRα細胞中同樣檢測到這些酶的表達量的提升。然而當在LNCaP細胞中用shRNA干擾掉ERRα可以明顯減降低上述酶的表達。9）我們在CYP11A1，CYP17A1和ARK1C3基因的啟動子區域發現有ERRα結合位點，並且發現這些位點可以被ERRα轉錄激活。 / 結論：本論文的研究結果提示在前列腺癌細胞中，ERRα和TMPRSS2:ERG可以形成一個相互正向調控的循環。除此之外，上調ERRα可以促進細胞在去除雄激素的環境中生長的能力，並且在動物體內可以提升細胞在睪丸去除的環境中的適應和生長能力。這種體內和體外的能力的提升是通過一種潛在的上調前列腺癌細胞的雄激素合成相關的關鍵的酶的表達，進而提升雄激素的含量而得以實現的。上述的結果預示著ERRα可能在前列腺癌發生機發展的過程中起到非常重要的調控作用，尤其在晚期的CRPC中。同時，ERRα也可能作為一個潛在的重要的前列腺癌尤其是晚期的CRPC的治療靶點，尤其是一些潛在ERRα的特異性抑制劑，比如XCT790，可能作為將來用以作為治療前列腺癌的特異性靶點藥物。 / Xu, Zhenyu. / Thesis Ph.D. Chinese University of Hong Kong 2014. / Includes bibliographical references (leaves 126-143). / Abstracts also in Chinese. / Title from PDF title page (viewed on 05, October, 2016). / Xu, Zhenyu. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only.

Hot flashes are one of the most bothersome symptoms experienced by women who have undergone breast cancer treatment-induced menopause. This vasomotor symptom has been hypothesized to be responsible for decreased sleep quality. This study further investigated the relationship between hot flashes and sleep quality in this population. The convenience sample consisted of 30 women being seen at an outpatient clinic in a comprehensive cancer center in southwest Florida. All participants were between the ages of 36-65, had a diagnosis of breast cancer and were currently taking a selective estrogen receptor modulator for at least six weeks. The participants completed the Hot Flash Diary, Hot Flash Questionnaire, Hot Flash Related Daily Interference Scale, Pittsburgh Sleep Quality Index and a demographic form. The mean sleep score of the sample was 9.33 (SD= 4.4). Global sleep scores above five are indicative of poor sleep quality, and global sleep scores of eight or more have been linked to cancer-related fatigue. Sleep was strongly correlated with hot flash distress (r = .754, p. = .000) and hot flash severity (r = .718, p. = .000) and moderately correlated with hot flash interference (r = .507, p. = .004) and hot flash frequency while asleep (r = .680, p. = .000). The small sample size was a study limitation. However, study results do support findings from previous studies. This study addresses a symptom management problem that may give nurses better understanding of the experiences of their patients. These findings also may assist patients in helping their providers to understand the frustration they are experiencing with regard to their decreased sleep quality.

Thesis (Ph.D.)--University of Toledo, 2006. / "In partial fulfillment of the requirements for the degree of Doctor of Philosophy in Biomedical Sciences." Major advisor: Brian G. Rowan. Includes abstract. Document formatted into pages: iv, 204 p. Title from title page of PDF document. Title at ETD Web site: Molecular mechanisms of protein kinase a signaling pathway on estrogen receptor action in breast cancer . Bibliography: pages 59-65, 100-104, 137-150, 167-202.

Thesis (M.D) -- University of Texas Southwestern Medical Center at Dallas, 2007. / Vita. Bibliography: pp. 35-37.

WW-domain binding protein-2 (WBP-2) was cloned as an E6-associated protein (E6-AP) interacting protein and its role in steroid hormone receptor (SHR) function was investigated. We show that WBP-2 differs from other SHR coactivators, as it specifically enhanced the transactivation functions of progesterone receptor (PR) and estrogen receptor (ER alpha), whereas it had no significant effect on the androgen receptor, glucocorticoid receptor or the activation functions of p53 or VP-16. We also demonstrated that, like other well characterized coactivators, WBP-2 contains an intrinsic activation domain. Depletion of endogenous WBP-2 with small interfering RNAs indicated that normal physiological protein level of WBP-2 was required for the proper functioning of ER alpha and PR. Moreover, chromatin immunoprecipitation (ChIP) assays demonstrate the hormone-dependent recruitment of WBP-2 onto an estrogen-responsive promoter. As we initially identified WBP-2 as an E6-AP interacting protein, we investigated whether WBP-2 and E6-AP function in concert. Our data shows that WBP-2 and E6-AP each enhance PR function and when co-expressed they additively enhance the transactivation functions of PR. However, WBP-2 was also able to enhance the transactivation functions of ER alpha and PR in mouse embryonic fibroblast cells generated from E6-AP knockout mice lines, suggesting that the coactivation functions of WBP-2 was not dependent on E6-AP. The further elucidate the molecular mechanism of action of WBP-2; we dissected the functional importance of the polyproline (PY) motifs contained within the WBP-2 protein. Mutational analysis suggests that one of three PY motifs, PY3 of WBP-2 was essential for its coactivation and intrinsic activation functions. In this study, we also demonstrate that the WBP-2 binding protein, Yes-kinase associated protein 1 (YAP1) acts as a secondary coactivator of ER alpha and PR. However, the coactivation function of YAP1 is revealed only in the presence of wild-type WBP-2 and not with the PY motif 3 mutant WBP-2. This is consistent with our observations that, unlike the wild-type WBP-2, the PY motif 3 mutant WBP-2 does not interact with YAP1. Our quantitative reChIP assays demonstrates an estrogen-dependent recruitment and association of ER alpha with both WBP-2 and YAP1. The hormone-dependent recruitment of YAP1 to ER alpha responsive promoter is dependent on the physiological expression levels of WBP-2. This is consistent with, our observation that the coactivation functions of YAP1 is dependent on WBP-2, and is also in agreement with other known secondary coactivators that get recruited to SHR responsive promoter via their interaction with primary coactivators. Surprisingly, the association of WBP-2 with ER alpha and its recruitment to the ER alpha target promoter was abrogated by YAP1 knock-down, suggesting that WBP-2 and YAP1 may stabilize each other at the promoter, and consequently, are functionally interdependent. Taken together our data establish the role of WBP-2 and YAP1 as selective coactivators for ER alpha and PR transactivation pathways.