Diss. (sammanfattning) Uppsala : Univ., 2004. / Härtill 5 uppsatser.

Thesis (Ph. D.)--University of Washington, 1997. / Vita. Includes bibliographical references (leaves 75-85).

Endometrial cancer (EC) is the most common gynaecological cancer affecting women in developed countries. Improving outcomes for women who are unfit for primary surgery or have advanced disease remains a challenge. Metformin use is associated with reduced cancer risk in several observational studies of patients with type 2 diabetes. Pre-clinical studies in EC show that metformin reduces cellular proliferation. The work described in this thesis tests the hypothesis that metformin reduces cellular proliferation in vitro and in vivo in type I EC through actions on the PI3K/AKT/mTOR pro-proliferative pathway. First, an in vitro model of EC using cell lines was established to determine the effect of metformin on cellular proliferation. Metformin was found to be cytostatic in a dose-dependent manner; these effects were potentiated in combination with carboplatin and paclitaxel. Metformin was shown to modulate mTOR phosphorylation proteins by immunoblot. Flow cytometric and metabolic assays found metformin to increase mitochondrial mass, but conversely, reduce mitochondrial function. These in vitro findings varied according to glucose concentration and were attenuated in hypoxia. Next, staining and scoring protocols for Ki-67, a marker of cellular proliferation, were established using semi-automated scoring on archived EC tumours. Ki-67 correlated with age, tumour grade and myometrial invasion; high Ki-67 expression was associated with an increased risk of disease recurrence, and was thus a prognostic marker. Finally, a presurgical window study of metformin versus no drug in women with EC demonstrated a 17% reduction in tumour Ki-67 with short-term metformin. Ki-67 response varied positively with increased average daily dose of metformin and negatively with increased BMI. High grade tumours were more hypoxic, according to baseline HIF-1alpha and the Ki-67 response to metformin was lower in hypoxic tumours. The effect on tumour mTOR phosphorylation events varied, but was not significant after adjusting for changes in controls. In conclusion, these results demonstrated that short-term oral metformin was associated with reduced cellular proliferation in women with EC. The findings from this study require corroboration with a placebo-controlled trial prior to the introduction of metformin as treatment for EC, both as a sole agent and in combination with existing adjuvant therapy. The response to metformin was heterogeneous; tumour hypoxia and metabolic adaptations of cancer cells may lead to metformin-resistance. Future studies should take these modulating effects into account to help identify patients likely to derive clinical benefit from metformin.

E–cadherin (CDH1) is a cell–cell adhesion molecule expressed in the epithelium to coordinate key morphogenetic processes, establish cell polarity, and regulate epithelial differentiation and proliferation. CDH1 forms adherens junctions that mediate intercellular adhesion through dynamic interactions with β–catenin (CTNNB1). To determine the role of CDH1 in the mouse uterus, Cdh1 was conditionally ablated by crossing Pgr–Cre and Cdh1–flox mice. Animals with the resulting genotype of Pgrcre/+Cdh1f/f had Cdh1 conditionally ablated in the Pgr expressing tissue, which includes the uterus (referred to as Cdh1d/d). We characterized the phenotype and found that loss of Cdh1 in the neonatal uterus results in a disorganized cellular structure of the epithelium and ablation of endometrial glands. Cdh1d/d mice lost adherens junction (CTNNB1 and CTNNA1) and tight junction (claudin, occludin and ZO–1) in the neonatal uterus leading to loss of epithelial cell–cell interaction. Ablation of Cdh1 induced abnormal epithelial proliferation and massive apoptosis, and disrupted Wnt and Hox gene expression in the neonatal uterus. Although the uteri of Cdh1d/d mice did not show any defect of myometrium, ablation of Cdh1 inhibited stromal (CD10) markers. In addition, a conditional knockout of Ctnnb1 in the uterus and a double conditional knockout of Cdh1&Ctnnb1 in the uterus were created to determine if the uterine defects were caused by an alteration in CDH1, CTNNB1, or a combination of both. Ctnnb1 and Cdh1&Ctnnb1 were conditionally ablated in the uterus by crossing Pgr–Cre and Ctnnb1–flox mice or Cdh1&Ctnnb1–flox mice. The Ctnnb1d/d mice maintained adhesive epithelial characteristics and did not lose adherens junction or tight junction proteins; however ablation of Ctnnb1 induced epithelial hyperplasia and disrupted Wnt and Hox gene expression in the neonatal uterus. The Cdh1d/dCtnnb1d/d mice carried a similar phenotype to the Cdh1d/d mice. Adult Cdh1d/d mice were infertile due to defects during implantation and decidualization. Collectively, these findings suggest that CDH1 has an important role in structural and functional development of the uterus as well as adult uterine function. CDH1 has a capacity to control cell fate by altering directional cell proliferation and apoptosis.

Made available in DSpace on 2014-06-11T19:33:26Z (GMT). No. of bitstreams: 0 Previous issue date: 2008-04-07Bitstream added on 2014-06-13T21:06:08Z : No. of bitstreams: 1 porto_cd_dr_botfmvz.pdf: 1382971 bytes, checksum: 28cb91b96745b48451d036819e9d1632 (MD5) / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) / Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) / O presente trabalho teve por objetivos avaliar os índices de proliferação celular e apoptótico, nos endométrios sadios, portadores de endometrite crônica e com endometrose por método imunoistoquímico. Ainda, verificou-se a expressão e distribuição do TGF-β1 e das metaloproteinases (MMP) 2 e 9 e sua relação com os índices de proliferação celular e apoptóticos, além da inter-relação entre esse fator de crescimento e as enzimas colagenolíticas estudadas. Os resultados obtidos foram comparados aos diferentes graus de alteração endometrial das éguas, e os tipos de colágeno presentes e sua proporção nas endometrites crônicas, especificados por técnicas histoquímicas. Foram utilizadas 60 biópsias endometriais classificadas histologicamente de acordo com Kenney e Doig (1986) e segundo as definições de Ricketts & Alonso (1991) para endometrite crônica infiltrativa e endometrose. A avaliação do colágeno foi realizada pelos métodos histoquímicos Tricrômico de Masson e Picrosirius Red - Polarização. Estudo morfométrico da fibrose periglandular foi realizado utilizando-se a técnica histoquímica do Picrosirius Red - Polarização. Os resultados mostraram que nos endométrios portadores de endometrite grave há deposição de colágeno do tipo III e do tipo I, sendo este predominante. Não houve diferença significativa na extensão da fibrose periglandular entre as endometrites crônicas infiltrativas e endometroses. A expressão do TGF-β1 foi escassa, presente nos endométrios normais e com alterações inflamatórias e degenerativas, e teve como principal fonte as células inflamatórias, embora tenha mostrado positividade nas células estromais em grande número de amostras, esparsamente. Não foi possível relacionar a presença do TGF-β1... (Acesso ao texto completo, clicar acesso eletrônico abaixo) / The aim of this study was to evaluate the indexes of cellular proliferation and apoptosis in healthy endometrium and with chronical lesions by means of immunohistochemical method. It was also verified the expression and distribution of TGF-β1 and metalloproteinases (MMP) 2 and 9 and its relation with the rates of cellular proliferation and apoptosis, besides the interrelation between that growth factor and the studied collagenolytic enzymes. The results were compared to the different degrees of endometrial alteration of the mares, and the present types of collagen and its proportion in chronical lesions, specified by histochemical techniques. Sixty endometrial biopsies were classified in agreement with Kenney and Doig (1986) and according to the definitions of Ricketts & Alonso (1991) for infiltrative chronic endometritis and endometrosis. The collagen evaluation was made by Masson’s trichrome and Picrosirius Red staining methods. The endometrial periglandular fibrosis morphometric analysis was carried out by using Picrosirius Red stained slides. Deposition of type III collagen and type I collagen was seen in severe endometritis with type I predominance. The chronic infiltrative endometritis and endometrosis didn’t show significant difference in the extension of periglandular fibrosis. The expression of TGF-β1 was scanty, present in normal endometrium and with chronical lesions, and it had as main source the inflammatory cells, although it has shown assertiveness in the stromal cells in a great number of samples, sparsely. It was not possible the correlation of TGF-β1... (Complete abstract click electronic access below)

Failure of the embryo to implant into the uterine lining results in infertility and is also the rate limiting step in FVF. The tethered, glycoprotein MUC1 is a protective cell surface receptor that has been associated with infertility. Evidence suggests MUC1 and other endometrial mucins regulate embryo implantation. Endometrial epithelia must be shielded from infection whilst permitting the recognition and implantation of the embryo. The protein backbone of MUC1 is thought to act as a scaffold for L-selectin ligands and may be integral to the initial tethering of the embryo during early implantation. Objectives The remit of this thesis was to model the expression of MUC1 and other mucins in the human endometrium using endometrial cell lines and to use atomic force microscopy to understand the role played by these proteins in shaping the non-specific and embryo specific adhesive characteristics of endometrial monolayers. If possible the proposed L-selectin implantation mechanism was to be identified and functionally characterised. Methodology This project successfully married the traditional molecular tools of quantitative PCR and immunocytochemistry with novel application of INCELL analyzer high content screening protein analysis, peak force quantitative nano-mechanical mapping atomic force microscopy and single molecule force spectroscopy atomic force microscopy to characterise the specific and non-specific surface adhesion on live endometrial monolayers. Results Firstly, immunocytochemistry and qRTPCR revealed that basal MUC1 expression was significantly higher in Hec-1-B relative to Hec-IA, Ishikawa and Hec50. Secondly, INCELL analysis qualified a distinct heterogeneous expression of MUC1 across the endometrial monolayer and delineated altered patterning following treatment with estradiol and progestins. Thirdly, we have shown a direct and proportional correlation between MUC1 expression and adhesion in live Hec-IA and Hec-IB cell monolayers. Fourthly, this work has confirmed and characterised binding of recombinant L-selectin to the endometrial epithelial cell surface. Fifthly, it is shown that L-selectin surface binding decreases following a reduction in MUC1 surface presentation. Conclusions The results implicate MUC1 as a key component of endometrial adhesion and an initial mediator of implantation with a functional patterned expression suggesting areas of altered receptivity exist across endometrial monolayers. Abnormal MUC1 expression has been shown in endometrial pathologies and unexplained infertility. The current investigation suggests MUC1 protein may assist embryo attachment by retarding it sufficiently through mechanical impedance to allow specific L-selectin binding further securing the embryo. A non-receptive endometrium may contribute towards the infertile phenotype despite repeated IVF treatments, thus novel examination of potential embryo adhesion molecules such as MUC1 may aid understanding of endometrial characteristics which prevent embryo implantation and contribute towards IVF failure.

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No. of bitstreams: 1 abrao_f_dr_bot.pdf: 4863333 bytes, checksum: d5c66d377ec9c9a5af09337fc25585bd (MD5) Previous issue date: 2016-02-19 / Objetivo: Avaliar os pólipos endometriais pela imunoexpressão das proteínas p53 e PTEN como fatores preditivos para riscos de pré-malignidade e malignidade. Pacientes e Métodos: Estudo transversal com amostra por conveniência, cujos dados foram obtidos através de consultas aos prontuários no período de janeiro de 2010 a dezembro 2014 de pacientes com diagnóstico de pólipos endometriais, submetidas a histeroscopias diagnósticas e cirúrgicas/polipectomia no Setor de Endoscopia Ginecológica e Planejamento Familiar da Disciplina de Ginecologia da Faculdade de Medicina de Botucatu (UNESP) e da Clínica “Abrão” de Marília. Os pólipos endometriais foram encaminhados, em bloco de parafina, à Consultoria em Patologia Dr Carlos Bacchi para avaliação imunoistoquímica, identificando os marcadores p53 e PTEN. Todas as pacientes realizaram, previamente, ultrassonografia transvaginal e histeroscopia diagnóstica. O grupo estudado constituiu-se de 159 pacientes (n=159) com diagnóstico de pólipo confirmado pelo exame anátomo patológico. Grupo amostral: as pacientes foram divididas em 2 (dois) grupos, assim denominados: Grupo A=120 (pacientes com pólipos endometriais sem atipias) e Grupo B=39 (pacientes com pólipos endometriais com atipias). O Grupo A foi subdividido em 4 subgrupos, assim denominados: A1- imunoistoquímico p53 negativo e PTEN positivo; A2- imunoistoquímico p53 positivo e PTEN positivo; A3- imunoistoquímico p53 negativo e PTEN negativo e A4- imunoistoquímico p53 positivo e PTEN negativo. O Grupo B foi subdividido em 4 subgrupos, assim denominados: B1- imunoistoquímico p53 negativo e PTEN positivo; B2- imunoistoquímico p53 positivo e PTEN positivo; B3- imunoistoquímico p53 negativo e PTEN negativo e B4 imunoistoquímico p53 positivo e PTEN negativo. Resultados: Os Grupos não apresentaram diferenças nas características clinico-epidemiologicas, demonstrando homogeneidade na amostra estudada. No grupo A: o subgrupo A1, com 80 pacientes (66,6%) apresentou p53 negativo e PTEN positivo, marcadores tumorais normais e 1 (uma) paciente (1,25%) teve neoplasia maligna de endométrio. As demais 40 pacientes (33,4%) dos subgrupos A2, A3, A4 apresentaram marcadores tumorais alterados, destes, 6 (seis) pacientes (15%) tiveram neoplasia maligna de endometrio; O A2 com 20 pacientes (16,6%) apresentou p53 positivo e PTEN positivo; A3 com 14 pacientes (11,6%) apresentou p53 positivo e PTEN negativo e A4 com 6 pacientes (5,1%) apresentou p53 negativo e PTEN negativo . O Grupo A teve, média de idade 57,5 anos, Índice de Massa Corpórea (IMC) 28,45, número médio de gestações 2(duas), índice de Aborto 16,7%, Tabagista 8,3%, Hipertensas 46,7%, Diabeticas 11,7%, amenorreia média 10 anos. Cerca de 5.9% das pacientes do grupo A tiveram neoplasia maligna de endométrio e houve maior incidência de neoplasia nas pacientes com marcadores alterados, em relação aquelas com marcadores normais (15% versus 1,25%, respectivamente; p=0,0089 e OR=13.94). No Grupo B: o subgrupo B1 com 21 pacientes (53,9%) apresentou marcadores tumorais normais (p53 negativo e PTEN positivo) e 1(uma) paciente (4,8%) teve neoplasia maligna de endométrio. As demais 18 pacientes (46,1%) dos subgrupos B2, B3, B4 apresentaram marcadores tumorais alterados, destes 7(sete) pacientes (38,9%) tiveram neoplasia maligna de endométrio. O B2 com 11 pacientes (28,2%) apresentou p53 positivo e PTEN positivo; B3 com 4 pacientes (10,2%) apresentou p53 positivo e PTEN negativo e A4 com 3 pacientes (7,7%) apresentou p53 negativo e PTEN negativo. O Grupo B teve, média de idade 61 anos, Índice de Massa Corpórea (IMC) 27, número médio de Gestações 2 (duas), índice de Aborto 7,7%, Tabagista 8,3%, Hipertensas 64%, Diabeticas 17,9%, com amenorreia média de 10 anos. Cerca de 20,5% das pacientes do grupo B tiveram neoplasia maligna de endométrio e houve maior incidência nas pacientes com marcadores tumorais alterados em relação as pacientes com marcadores normais (38,9 versus 4,8%, respectivamente; p=0,00255 e OR= 12.73). O grupo B teve maior incidência de neoplasia maligna de endometrio em relação ao grupo A (20,5% versus 5,9% respectivamente; p=0,011). No total 159 pacientes (grupo A + Grupo B), 110 pacientes com p53 negativo, 3 pacientes tiveram neoplasia de endométrio; e 49 pacientes com p53 positivo, 11 tiveram neoplasia de endométrio.(p=0,0006,OR=7,67) e 132 pacientes com PTEN positivo, 8 pacientes tiveram neoplasia de endométrio, 27 pacientes com PTEN negativo, 7 tiveram neoplasia de endométrio.(p=0,00043; OR=5,43). Conclusões: 1- O estudo imunoistoquímico nas pacientes portadoras de pólipo endometrial mostrou ser um armamento útil para predizer o risco de malignização do endométrio,2- Estudos complementares devem ser aguardados, principalmente com maior casuística, para corroborar os dados encontrados,3- As pacientes com pólipos endometriais e marcadores tumorais alterados, p53 e PTEN, principalmente, quando associados a obesidade, hipertensão arterial sistêmica e diabetes mellitus II, podem apresentar maior risco de neoplasia maligna de endométrio,4- As neoplasias malignas do endométrio foram encontrados com maior incidências em mulheres de maior idade e no grupo de pólipos com atipias. / Objective: Evaluate the endometrial polyps by immune expression of p53 protein and PTEN as predictive factors for pre malignancy and malignancy risks. Patients and Methods: Transversal study with samples by convenience whose data were obtained by consulting the medical charts from January 2010 to December 2014 of patients diagnosed with endometrial polyps, submitted to a diagnostic and surgical hysteroscopy/polypectomy in the Gynaecological Endoscopy and Familiar Planning Division of the Gynaecology Discipline at Medical School of Botucatu (UNESP) and “Abrão” Clinic of Marília. The endometrial polyps, in paraffin blocks, were sent to Doctor Carlos Bacchi Pathology Advisory for immune hystochemical assessment, identifying the markers p 53 and PTEN. Previously, transvaginal ultrasonography and diagnostic hysteroscopy were done in all the patients. The studied group was made up of 159 patients (n=159) with confirmed diagnosis of polyps by anatomical pathological examination. Sample group: the patients were divided into 2 groups: Group A=120 (patients with endometrial polyps without atypias) and Group B = 39 (patients with endometrial polyps with atypias). Group A was subdivided into 4 sub groups: A1- immune hystochemical p53 negative and PTEN positive; A2- immune hystochemical p53 positive and PTEN positive; A3- immune hystochemical p53 negative and PTEN negative and A4- immune hystochemical p53 positive and PTEN negative. Group B was subdivided into 4 sub groups: B1- immune hystochemical p53 negative and PTEN positive; B2- immune hystochemical p53 positive and PTEN positive; B3- immune hystochemical p53 negative and PTEN negative and B4- immune hystochemical p53 positive and PTEN negative. Results: The groups did not present differences in clinical-epidemiological characteristics, showing homogeneity in the sample studied. In Group A: subgroup A1 with 80 patients (66.6%) presented p53 negative and PTEN positive, normal tumor markers and one patient (1.25%) had endometrium malignant neoplasm. The other 40 patients (33.4%) of subgroups A2, A3 and A4 presented altered tumor markers, being 6 (six) patients (15%) with endometrium malignant neoplasm; A2 with 20 patients(16.6%) presented p53 positive and PTEN positive; A3 with 14 patients (11.6%) presented p 53 positive and PTEN negative and A4 with 6 patients (5.1 %) presented p53 negative and PTEN negative. In Group A, the average age was 57.5 years, the Body Mass Index (BMI) 28.45, the medium number of Pregnancy was 2(two), the Abortion rate was 16.7%, Smoking 8.3%, Hypertensive 46.7%, Diabetics 11.7%, with 10 years average amenorrhea, and around 5.9% of them developed endometrium malignant neoplasm and there was higher incidence of neoplasm on patients with altered markers compared to those with normal markers (15% versus 1.25%, respectively; p=0.0089 and OR=13.94). In Group B: the subgroup B1 with 21 patients (53.9%) presented normal tumor markers (p53 negative and PTEN positive) and 1(one) patient (4.8%) had endometrium malignant neoplasm. The other 18 patients (46.1%) of subgroups B2, B3, B4 presented altered tumor markers, being that 7(seven) patients (38.9%) had endometrium malignant neoplasm. B2 with 11 patients (28.2%) presented p53 positive and PTEN positive; B3 with 4 patients (10.2%) presented p53 positive and PTEN negative and A4 with 3 patients (7.7%) presented p53 negative and PTEN negative. In Group B, the average age was 61 years, the Body Mass Index (BMI) 27, the medium number of Pregnancy was 2 (two) , the Abortion rate was 7.7%, Smoking 8.3%, Hypertensive 64%, Diabetics 17.9%, with 10 years average amenorrhea, and around 20.5% of them developed endometrium malignant neoplasm and there was higher incidence on patients with altered tumor in relation to those with normal markers (38.9 versus 4.8%, respectively; p=0.00255 e OR= 12.73). Group B had higher incidence of endometrium malignant neoplasm than group A (20.5% versus 5.9% respectively; p=0.011). Out of 159 patients (Group A + Group B), 110 patients with p53 negative, 3 patients had endometrium neoplasm; and 49 patients with p53 positive, 11 had endometrium neoplasm.(p=0.0006,OR=7.67) and 132 patients with PTEN positive, 8 patients had endometrium neoplasm, 27 patients with PTEN negative, 7 had endometrium neoplasm.(p=0.00043; OR=5.43). Conclusions:1-Immunohistochemical analysis can be useful to predict malignant transformation in cases of endometrial polyps, 2-Further larger studies to confirm the data obtained are warranted, 3-The risk of malignant endometrial neoplasia is higher in patients with endometrial polyps showing abnormal p53 and PTEN immunohistochemistry in the presence of advanced age, high BMI, systemic arterial hypertension, and type 2 Diabetes Mellitus, 4-The incidence of malignant endometrial neoplasia was higher in women of more advance age with polyps with atypia.

Orientador: Julio Lopes Sequeira / Banca: Noeme Sousa Rocha / Banca: Carlos Alberto Hussni / Banca: Louisiane de Carvalho Nunes / Banca: Anaglória Pontes / Resumo: O presente trabalho teve por objetivos avaliar os índices de proliferação celular e apoptótico, nos endométrios sadios, portadores de endometrite crônica e com endometrose por método imunoistoquímico. Ainda, verificou-se a expressão e distribuição do TGF-β1 e das metaloproteinases (MMP) 2 e 9 e sua relação com os índices de proliferação celular e apoptóticos, além da inter-relação entre esse fator de crescimento e as enzimas colagenolíticas estudadas. Os resultados obtidos foram comparados aos diferentes graus de alteração endometrial das éguas, e os tipos de colágeno presentes e sua proporção nas endometrites crônicas, especificados por técnicas histoquímicas. Foram utilizadas 60 biópsias endometriais classificadas histologicamente de acordo com Kenney e Doig (1986) e segundo as definições de Ricketts & Alonso (1991) para endometrite crônica infiltrativa e endometrose. A avaliação do colágeno foi realizada pelos métodos histoquímicos Tricrômico de Masson e Picrosirius Red - Polarização. Estudo morfométrico da fibrose periglandular foi realizado utilizando-se a técnica histoquímica do Picrosirius Red - Polarização. Os resultados mostraram que nos endométrios portadores de endometrite grave há deposição de colágeno do tipo III e do tipo I, sendo este predominante. Não houve diferença significativa na extensão da fibrose periglandular entre as endometrites crônicas infiltrativas e endometroses. A expressão do TGF-β1 foi escassa, presente nos endométrios normais e com alterações inflamatórias e degenerativas, e teve como principal fonte as células inflamatórias, embora tenha mostrado positividade nas células estromais em grande número de amostras, esparsamente. Não foi possível relacionar a presença do TGF-β1... (Acesso ao texto completo, clicar acesso eletrônico abaixo) / Abstract: The aim of this study was to evaluate the indexes of cellular proliferation and apoptosis in healthy endometrium and with chronical lesions by means of immunohistochemical method. It was also verified the expression and distribution of TGF-β1 and metalloproteinases (MMP) 2 and 9 and its relation with the rates of cellular proliferation and apoptosis, besides the interrelation between that growth factor and the studied collagenolytic enzymes. The results were compared to the different degrees of endometrial alteration of the mares, and the present types of collagen and its proportion in chronical lesions, specified by histochemical techniques. Sixty endometrial biopsies were classified in agreement with Kenney and Doig (1986) and according to the definitions of Ricketts & Alonso (1991) for infiltrative chronic endometritis and endometrosis. The collagen evaluation was made by Masson's trichrome and Picrosirius Red staining methods. The endometrial periglandular fibrosis morphometric analysis was carried out by using Picrosirius Red stained slides. Deposition of type III collagen and type I collagen was seen in severe endometritis with type I predominance. The chronic infiltrative endometritis and endometrosis didn't show significant difference in the extension of periglandular fibrosis. The expression of TGF-β1 was scanty, present in normal endometrium and with chronical lesions, and it had as main source the inflammatory cells, although it has shown assertiveness in the stromal cells in a great number of samples, sparsely. It was not possible the correlation of TGF-β1... (Complete abstract click electronic access below) / Doutor

Endometrial cancer is a common gynaecological cancer. Improving outcomes for women with advanced disease remains a challenge and there is also a need to develop preventative strategies in those women at highest risk of developing disease. Peroxisome proliferator-activated receptors (PPARs) comprise of a group of transcription factors belonging to the nuclear hormone receptor subfamily. PPAR sub-types are involved in metabolic homeostasis and have been implicated in malignancy, particularly breast and colo-rectal malignancies both of which are associated with obesity. Endometrial cancer is also closely associated with both obesity and insulin resistance. The work described in this thesis examined the expression of PPARs in endometrioid endometrial cancer and investigated their effects on key pathways implicated in this disease. Immunoblotting revealed over expression of PPARα and loss of PPARγ in human endometrioid endometrial cancer tissues. Pull-down assays also demonstrated differential selectivity of different PPARs for heterodimerisation with different isoforms of the RXR family of transcription factors. PPARα was localized to tumour cells and vascular endothelium and ELISA demonstrated an increase in VEGF-A in PPARα silenced cells suggesting that PPARα may promote tumour angiogenesis. PPARγ was largely seen in epithelial cells and also macrophages within benign endometrium. Reduction of PPARγ expression in cultured endometrial cells led to increased proliferation and decreased apoptosis. Loss of PPARγ was correlated with a loss of the tumour suppressor PTEN in endometrial tissues. Furthermore, PPARγ silencing led to diminished expression of PTEN and a concomitant increase in phosphorylated AKT suggesting that PPARγ is protective against deregulated growth within the endometrium. Synthetic PPAR-specific ligands reduced proliferation and increased apoptosis in endometrial cell lines. These effects were present in PPAR-silenced cells too although reduced in magnitude, indicating that the actions of specific PPAR ligands are mediated via both receptor dependent and receptor independent pathways.In conclusion, this work has demonstrated the differential expression of PPARs and RXRs in endometrial cancers and identified possible mechanisms, both direct and indirect, by which these may modulate endometrial cancer growth. Different PPAR family members may provide targets for therapeutic intervention in endometrial cancer care and require further study in this regard.

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第22638号 / 医博第4621号 / 新制||医||1044(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 武藤 学, 教授 小川 誠司, 教授 小川 修 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM