1,721,013 research outputs found
17 beta-estradiol-induced growth of triple-negative breast cancer cells is prevented by the reduction of GPER expression after treatment with gefitinib
No full textTriple-negative breast cancers (TNBCs) are neither susceptible to endocrine therapy due to a lack of estrogen receptor a expression nor trastuzumab. TNBCs frequently overexpress epidermal growth factor receptor (EGFR) and membrane bound estrogen receptor, GPER. To a certain extent the growth of TNBCs is stimulated by 17 beta-estradiol via GPER. We analyzed whether inhibition of EGFR by gefitinib reduces the expression of GPER and subsequent signal transduction in TNBC cells. Dependence of proliferation on 17 beta-estradiol was determined using Alamar Blue assay. Expression of GPR30 and activation of c-src, EGFR and cAMP-responsive element binding (CREB) protein by 17 beta-estradiol was analyzed by western blotting. Expression of c-fos, cyclin D1 and aromatase was determined using RT-PCR. Gefitinib reduced GPER expression concentration- and time-dependently. In HCC70 cells, GPER expression was reduced to 15 +/- 11% (p<0.05) after treatment with 200 nM gefitinib for four days, and in HCC1806 cells GPER expression was reduced to 39 +/- 5 (p<0.01) of the control. 17 beta-estradiol significantly increased the percentage of HCC1806 cells within 7 days to 145 +/- 29% of the control (HCC70, 110 +/- 8%). This increase in cell growth was completely prevented in both TNBC cell lines after GPR30 expression was downregulated by treatment with 200 nM gefitinib. In HCC1806 cells, activation of c-src was increased by 17 beta-estradiol to 350 50% (p<0.01), and gefitinib reduced src activation to 110%. Similar results were obtained in the HCC70 cells. Phosphorylation of EGFR increased to 240 +/- 40% (p<0.05) in the HCC1806 cells treated with 17 beta-estradiol (HCC70, 147 +/- 25%). Gefitinib completely prevented this activation. Phosphorylation of CREB and induction of c-fos, cyclin D1 and aromatase expression by 17 beta-estradiol were allGerman Research Foundation [GR 1895/10-1
Hormonal heterogeneity of endometrial cancer
No full textEndometrial cancer is the most common malignant tumor of the female genital tract in the developed world. Increasing evidence suggests that the majority of cases can be divided into two different types of endometrial cancer based on clinico-pathological and molecular characteristics. Type I is associated with an endocrine milieu of estrogen predominance. These tumors are of endometroid histology and develop from endometrial hyperplasia. They have good prognosis and are sensitive to endocrine treatment. Type II endometrial cancers are not associated with a history of unopposed estrogens and develop from the atrophic endometrium of elderly women. Mainly, they are of serous papillary or clear cell morphology, have a poor prognosis and do not react to endocrine treatment. Both types of endometrial cancer probably differ markedly with regard to the molecular mechanisms of transformation. The transition from normal endometrium to a malignant tumor is thought to involve a stepwise accumulation of alterations in cellular mechanisms leading to dysfunctional cell growth. This chapter reviews the current knowledge of the molecular mechanisms commonly associated with development of type I and type II endometrial cancer
Hormonal heterogeneity of endometrial cancer
No full textEndometrial cancer is the most common malignant tumor of the female genital tract in the developed world. Increasing evidence suggests that the majority of cases can be divided into two different types of endometrial cancer based on clinico-pathological and molecular characteristics. Type I is associated with an endocrine milieu of estrogen predominance. These tumors are of endometroid histology and develop from endometrial hyperplasia. They have good prognosis and are sensitive to endocrine treatment. Type II endometrial cancers are not associated with a history of unopposed estrogens and develop from the atrophic endometrium of elderly women. Mainly, they are of serous papillary or clear cell morphology, have a poor prognosis and do not react to endocrine treatment. Both types of endometrial cancer probably differ markedly with regard to the molecular mechanisms of transformation. The transition from normal endometrium to a malignant tumor is thought to involve a stepwise accumulation of alterations in cellular mechanisms leading to dysfunctional cell growth. This chapter reviews the current knowledge of the molecular mechanisms commonly associated with development of type I and type II endometrial cancer
Starving Tumors: Inhibition of Glycolysis Reduces Viability of Human Endometrial and Ovarian Cancer Cells and Enhances Antitumor Efficacy of GnRH Receptor-Targeted Therapies
No full textObjective: Increased glycolysis for energy production is necessary for survival of tumor cells and thus represents a selective therapeutic target. We have analyzed in vitro whether inhibition of glycolysis can reduce the viability of human endometrial and ovarian cancer cells and whether it can enhance the antitumor efficacy of GnRH receptor-targeted therapies. Materials and Methods: Cell viability of ovarian and endometrial cancer cells treated without or with glycolysis inhibitor 2-Deoxy-n-Glucose (2DG) alone or in combination with GnRH-II antagonist [Ac-D2Nal(1), D-4Cpa(2), D-3Pal(3,6),Leu(8), D-Ala(10)]GnRH-II or with cytotoxic GnRH-I agonist AEZS-108 (AN-152) was measured using alamar blue assay. Induction of apoptosis was analyzed using TUNEL assay and quantified by measurement of loss of mitochondrial membrane potential. Apoptotic signaling was measured by quantification of activated caspase-3 by using the Western blot technique. Results: Treatment of endometrial and ovarian cancer cells with glycolysis inhibitor 2DG resulted in a significant decrease of cell viability and a significant increase of apoptosis. Treatment with 2DG in combination with the GnRH-II antagonist or with AEZS-108 resulted in a significant reduced viability compared with single-agent treatments. The observed reduction in viability was due to induction of apoptosis. Also for apoptosis induction, a significant stronger effect in the case of cotreatments compared with single-agent treatments could be observed. These additive effects could be correlated to increased activation of caspase-3. Conclusions: The glycolytic phenotype of human endometrial and ovarian cancer cells can be targeted for therapeutic intervention. In addition, cotreatment of a glycolysis inhibitor with GnRH receptor-targeted therapies might be a suitable therapy for GnRH receptor-positive human endometrial and ovarian cancers.Deutsche Krebshilf
Antiproliferative effects of kisspeptin-10 depend on artificial GPR54 (KISS1R) expression levels
No full textKisspeptins are peptides derived from the metastasis suppressor gene KISS1 interacting with GPR54 as their corresponding receptor. The KISS1/GPR54 system is one regulator of cellular motility mechanisms leading to decreased migration and invasion. Its role in cell proliferation processes is not clearly understood. In this study, breast cancer cell lines, T47D, ZR75-1, MDA-MB-231, MDA-MB-435s, MDA-MB-453, HCC 70, HCC 1806, HCC 1937 and MCF-7, were investigated for their endogenous GPR54 expression by immunocytochemistry, RT-PCR and western blot analysis. The effect of kisspeptin-10 on proliferation was measured in MDA-MB-231, MDA-MB-435s, HCC 1806 and MCF-7 cells. Further experiments on proliferation were carried out with cells transfected with GPR54. All of the tested breast cancer cell lines expressed GPR54 in different amounts. No effects on proliferation were detected in the breast cancer cells expressing the receptor endogenously. In transfected neuronal cells overexpressing GPR54, proliferation was significantly inhibited by kisspeptin-10. The results indicate that the antiproliferative action of kisspeptin depends on the nature of GPR54 expression. The effect was detected in an artificial system of cells transfected with GPR54 and not in cells expressing the receptor endogenously. Thus, the antiproliferative action of kisspeptin seems not to be important for pathophysiological processes.Deutsche Krebshilfe, Dr Mildred Scheel Stiftun
Electromagnetic fields alter the expression of estrogen receptor cofactors in breast cancer cells
No full textBreast cancer is the most common malignancy of women in Western societies. The increasing exposure to electromagnetic fields has been suspected to contribute to the rising incidence of breast cancer in industrialized Countries. The majority of breast tumors is treated with the partial antiestrogen tamoxifen. Most tumors become resistant to tamoxifen in the course of treatment resulting in treatment failure. Electromagnetic fields reduce the efficacy of tamoxifen similar to tamoxifen resistance. In this study we investigated the mechanism by which electromagnetic fields influence the sensitivity to tamoxifen. In cells exposed to 1.2 mu T of a 50 Hz electromagnetic field gene expression of cofactors of the estrogen receptors was compared to sham exposed cells. Using a gene array technology several cofactors were found to be differentially expressed. The expression of the coactivators, SRC-I and AIB 1, and of two corepressors, N-Cor and SMRT, was quantified by RT-PCR. Both coactivators were expressed more strongly in the exposed cells while the expression of two corepressors decreased. The RNA analysis was confirmed by Western blots. The contradirectional changes in gene expression of coactivators and corepressors by electromagnetic fields results in a lower sensitivity to tamoxifen. Electromagnetic fields may contribute to the induction of tamoxifen resistance in vivo. Bioelectromagnetics 29:169-176, 2008. (C) 2007 Wiley-Liss, Inc
GnRH-II agonist [D-Lys(6)]GnRH-II inhibits the EGF-induced mitogenic signal transduction in human endometrial and ovarian cancer cells
No full textThe majority of human endometrial and ovarian cancers express receptors for GnRH type I (GnRH-I). Their proliferation is time- and dose-dependently reduced by GnRH-I and its analogs. GnRH-I analogs activate a phosphotyrosine-phosphatase (PTP) and inhibit EGF-induced mitogenic signal transduction. Recently we found that GnRH type II (GnRH-II) and its agonist [D-Lys(6)]GnRH-II also have antiproliferative effects on these tumor cells which are significantly greater than those of GnRH-I agonists. In a more recent study, we showed that the antiproliferative activity of GnRH-II on human endometrial and ovarian cancer cell lines is not mediated through the GnRH-I receptor. The underlying signal transduction mechanisms of GnRH-III are still unknown. In this study we showed that the mitogenic effects of growth factors in endometrial and ovarian cancer cell lines were counteracted by GnRH-II agonist [D-LyS(6)]GnRH-II, indicating an interaction with the mitogenic signal transduction. We showed that [D-LyS6]GnRH-III reduces EGF-induced auto-tyrosine-phosphorylation of EGF-receptors via activation of a PTP and that EGF-induced activation of mitogen-activated protein kinase was blocked in cells treated with [D-Lys(6)]GnRH-H. Furthermore, EGF-induced expression of the immediate early gene c-fos was inhibited by treatment with [D-Lys(6)]GnRH-II. After knock-out of GnRH-I receptor expression, GnRH-H agonist [D-LyS(6)]GnRH-II still activated PTP and inhibited the EGF-induced mitogenic signal transduction. These data indicate, that the effects of GnRH-H are not due to a cross-reaction with the GnRH-I receptor. In conclusion these data suggest that the si naling of GnRH-II agonist [D-LyS(6)]GnRH-H is comparable to that of GnRH-I analogs
GnRH-II agonist [D-Lys(6)]GnRH-II inhibits the EGF-induced mitogenic signal transduction in human endometrial and ovarian cancer cells
No full textThe majority of human endometrial and ovarian cancers express receptors for GnRH type I (GnRH-I). Their proliferation is time- and dose-dependently reduced by GnRH-I and its analogs. GnRH-I analogs activate a phosphotyrosine-phosphatase (PTP) and inhibit EGF-induced mitogenic signal transduction. Recently we found that GnRH type II (GnRH-II) and its agonist [D-Lys(6)]GnRH-II also have antiproliferative effects on these tumor cells which are significantly greater than those of GnRH-I agonists. In a more recent study, we showed that the antiproliferative activity of GnRH-II on human endometrial and ovarian cancer cell lines is not mediated through the GnRH-I receptor. The underlying signal transduction mechanisms of GnRH-III are still unknown. In this study we showed that the mitogenic effects of growth factors in endometrial and ovarian cancer cell lines were counteracted by GnRH-II agonist [D-LyS(6)]GnRH-II, indicating an interaction with the mitogenic signal transduction. We showed that [D-LyS6]GnRH-III reduces EGF-induced auto-tyrosine-phosphorylation of EGF-receptors via activation of a PTP and that EGF-induced activation of mitogen-activated protein kinase was blocked in cells treated with [D-Lys(6)]GnRH-H. Furthermore, EGF-induced expression of the immediate early gene c-fos was inhibited by treatment with [D-Lys(6)]GnRH-II. After knock-out of GnRH-I receptor expression, GnRH-H agonist [D-LyS(6)]GnRH-II still activated PTP and inhibited the EGF-induced mitogenic signal transduction. These data indicate, that the effects of GnRH-H are not due to a cross-reaction with the GnRH-I receptor. In conclusion these data suggest that the si naling of GnRH-II agonist [D-LyS(6)]GnRH-H is comparable to that of GnRH-I analogs
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