共查询到11条相似文献,搜索用时 0 毫秒
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Romero IL Lee W Mitra AK Gordon IO Zhao Y Leonhardt P Penicka CV Mui KL Krausz TN Greene GL Lengyel E 《Gynecologic oncology》2012,124(1):134-141
Objective
To test if estrogen promotes carcinogenesis in vitro and in a genetic mouse model of ovarian cancer and whether its effects can be inhibited by a novel selective estrogen receptor modulator (SERM), bazedoxifene.Methods
Bazedoxifene was synthesized and it was confirmed that the drug abrogated the uterine stimulatory effect of 17β-estradiol in mice. To determine if hormones alter tumorigenesis in vivo LSL-K-rasG12D/+PtenloxP/loxP mice were treated with vehicle control, 17β-estradiol or bazedoxifene. Hormone receptor status of a cell line established from LSL-K-rasG12D/+PtenloxP/loxP mouse ovarian tumors was characterized using Western blotting and immunohistochemistry. The cell line was treated with hormones and invasion assays were performed using Boyden chambers and proliferation was assessed using MTT assays.Results
In vitro 17β-estradiol increased both the invasion and proliferation of ovarian cancer cells and bazedoxifene reversed these effects. However, in the genetic mouse model neither treatment with 17β-estradiol nor bazedoxifene changed mean tumor burden when compared to treatment with placebo. The mice in all treatment groups had similar tumor incidence, metastatic nodules and ascites.Conclusion
While 17β-estradiol increases the invasion and proliferation of ovarian cancer cells, these effects do not translate into increased tumor burden in a genetic mouse model of endometrioid ovarian cancer. Likewise, while the SERM reversed the detrimental effects of estrogen in vitro, there was no change in tumor burden in mice treated with bazedoxifene. These findings demonstrate the complex interplay between hormones and ovarian carcinogenesis. 相似文献2.
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De Stefano I Zannoni GF Prisco MG Fagotti A Tortorella L Vizzielli G Mencaglia L Scambia G Gallo D 《Gynecologic oncology》2011,122(3):573-579
Objective
In this study we investigated the prognostic value of estrogen receptor α (ERα), ERβ and progesterone receptor (PR) expression in 58 untreated advanced serous ovarian cancer patients. The study also included 12 macroscopically and histopathologically normal ovaries.Materials and methods
Protein expression was evaluated by immunohistochemistry, and antibody staining detected in both the nuclear and cytoplasmic compartments was taken into account. Immunopositivity was analyzed in relation to tumor clinicopathological variables, disease-free survival (DFS), and overall survival (OS).Results
Epithelial cells in ovarian cancer tissue showed significantly lower levels of nuclear ERβ and PR, but not ERα, than in normal ovarian tissue. In the case of ERβ, however, while normal ovarian epithelium exhibited almost exclusively strong nuclear staining, ovarian cancer tissue mostly showed cytoplasmic immunopositivity. Nuclear ERα and ERβ expression were not associated with clinical outcome. Conversely, any cytoplasmic ERβ expression was an independent unfavorable prognostic factor for DFS, a finding approaching statistical significance also for OS. These data suggest that, in advanced serous ovarian cancer, cytoplasmic ERβ signaling may be more important for patient survival than its nuclear signaling. In the case of PR, positivity was an independent favorable prognostic factor for DFS.Conclusions
These novel findings, that need to be confirmed in a large prospective trial, suggest that additional prognostic, and possibly therapeutic opportunities may be available in advanced serous ovarian cancer. 相似文献4.
《Gynecological endocrinology》2013,29(8):618-624
AbstractStriatin, an estrogen receptor (ER)-interacting protein, plays an important role in estrogen’s nongenomic actions in vascular endothelial cells. However, the role of striatin in VSMCs is unknown. Here, we investigated the role of striatin in estrogen-regulated VSMCs migration. 17β-Estradiol (E2) at 10?nM largely inhibited VSMCs migration, which was reversed by the silencing of striatin expression. E2 increased striatin protein expression in a dose- and time-dependent manner. ERα agonist PPT, but not ERβ agonist DPN, mimicked the regulatory effect of E2. The regulatory effect of E2 on striatin protein expression was blocked by the pure ER antagonist ICI 182,780 or the mitogen-activated protein kinase inhibitor PD98059, but not by the phosphatidylinositol-3 kinase inhibitor wortmannin or Src inhibitor PP2, suggesting that E2 increased striatin protein expression via extracellular-signal regulated kinase 1/2 (ERK1/2). E2 resulted in phosphorylation of ERK1/2 in a time-dependent manner. The silencing of ERK1/2 largely abolished E2-enhanced striatin expression. Finally, the inhibitory effect of E2 on VSMC migration was reversed by ICI 182,780 or PD98059. Taken together, our results indicate that E2 inhibits VSMC migration by increasing striatin expression via ERα to ERK1/2 pathway, which maybe helpful to understand estrogen’s anti-atherogenic effect in VSMCs. 相似文献
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Objective. Growing evidence indicates that estrogen's non-genomic effects play important roles in cellular functions and backs up the hypothesis of the existence of a membrane estrogen receptor (mER) in a number of cell types, but little is known about the complementary effects between traditional genomic and novel non-genomic effects of estrogen. The aim of the present study was to explore the non-genomic activation of ERK1/2 mitogen-activated protein kinase (MAPK) by 17β-estradiol (E2) through mER and its role in cell proliferation.Methods. On cultured bovine artery endothelial cells (BAECs) we used the [3H]thymidine incorporation assay to evaluate the influence of E2 on cell proliferation and fluorescence microscopy to show the presence of mER on the cell membrane. Scatchard analysis was performed to identify and characterize the mER on a purified membrane fraction of BAECs.Results. E2 upregulated cyclin D1 protein expression and enhanced cell proliferation. Inhibition of the MAPK cascade with PD98059 or of G protein with pertussis toxin (PTX) completely abolished the above effects, while the estrogen receptor antagonist tamoxifen attenuated E2-dependent upregulation of cyclin D1 and cell proliferation. Accordingly, E2 rapidly led to ERK1/ERK2 activation, which was prevented by tamoxifen or PTX and was entirely reproduced by membrane-impermeable estradiol–bovine serum albumin conjugate (E2coBSA). Immunofluorescent staining with E2coBSA–fluorescein isothiocyanate resulted in a punctuate staining pattern of the plasma membrane and Scatchard analysis of the E2-binding protein in a purified membrane fraction of BAECs showed that E2 binds to the membrane fraction with a dissociation constant of 0.2394 nmol/l.Conclusion. Our findings showed that E2 induces cell proliferation through upregulation of cyclin D1 via non-genomic activation of the ERK1/ERK2 pathway mediated by mER and G protein. 相似文献
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Yoshio Yoshida Tetsuji Kurokawa Tetuya Tsujikawa Hidehiko Okazawa Fumikazu Kotsuji 《Journal of ovarian research》2009,2(1):1-10
The most frequently used molecular imaging technique is currently 18F-deoxy-glucose (FDG) positron emission tomography (PET). FDG-PET holds promise in the evaluation of recurrent or residual ovarian cancer when CA125 levels are rising and conventional imaging, such as ultrasound, CT, or MRI, is inconclusive or negative. Recently, integrated PET/CT, in which a full-ring-detector clinical PET scanner and a multidetector helical CT scanner are combined, has enabled the acquisition of both metabolic and anatomic imaging data using one device in a single diagnostic session. This can also provide precise anatomic localization of suspicious areas of increased FDG uptake and rule out false-positive PET findings. FDG-PET/CT is an accurate modality for assessing primary and recurrent ovarian cancer and may affect management. FDG-PET/CT may provide benefits for detection of recurrent of ovarian cancer and improve surgical planning. And FDG-PET has been shown to predict response to neoadjuvant chemotherapy and survival in advanced ovarian cancer. This review focuses on the role of FDG-PET and FDG-PET/CT in the management of patients with ovarian cancer. Recently, we have evaluated 16α-18F-fluoro-17β-estradiol (FES)-PET, which detects estrogen receptors. In a preliminary study we reported that FES-PET provides information useful for assessing ER status in advanced ovarian cancer. This new information may expand treatment choice for such patients. 相似文献
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Alessandra Ciucci Gian Franco Zannoni Daniele Travaglia Marco Petrillo Giovanni Scambia Daniela Gallo 《Gynecologic oncology》2014
Objective
In the present study we have examined the pattern of expression of the full length estrogen receptor β (ERβ1) and two ERβ splice variant isoforms (ERβ2, ERβ5) in well-characterized advanced serous ovarian cancers.Methods
Immunohistochemistry was performed with ERβ1, ERβ2, and ERβ5 antibodies and results were correlated with pathological and clinical follow-up data. Expression of ERβ isoforms in a panel of ovarian cancer cell lines and human tumor xenografts was also assessed.Results
Immunohistochemical staining revealed cellular compartment-specific distribution for each isoform in malignant ovarian tissues exhibiting both nuclear staining and cytoplasmic staining. Patients with cytoplasmic ERβ2 expression had significantly worse outcome (p = 0.006 at the multivariate analysis), the 5-year survival rate being nearly 28% for patients who did express cytoplasmic ERβ2, and 60% in negative patients. Cytoplasmic ERβ2 expression was also found to be significantly associated with chemoresistance. In concordance with clinical results both nuclear and cytoplasmic expressions were observed for the three isoforms in the cancer cell lines and human tumor xenografts tested.Conclusions
This is the first study to uncover an unfavorable prognostic role of ERβ2 in advanced serous ovarian cancer. If anomalies of ERβ2 cytoplasmic expression could be demonstrated to represent an independent unfavorable prognostic marker and/or a marker predicting chemoresistance in advanced serous ovarian cancer, its immunohistochemical assessment at the time of surgery, could help to recognize candidates for clinical trials of new interventions. 相似文献11.