The Experts below are selected from a list of 10032 Experts worldwide ranked by ideXlab platform
Salman M Hyder - One of the best experts on this subject based on the ideXlab platform.
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natural and synthetic Progestins enrich cancer stem cell like cells in hormone responsive human breast cancer cell populations in vitro
Breast Cancer: Targets and Therapy, 2017Co-Authors: Sandy Goyette, Yayun Liang, Benford Mafuvadze, Matthew Cook, Moiz Munir, Salman M HyderAbstract:Clinical trials and studies have shown that combination estrogen/Progestin hormone replacement therapy, but not estrogen therapy alone or placebo, increases breast cancer risk in postmenopausal women. Using animal models, we have previously shown that both natural and synthetic Progestins (including medroxyprogesterone acetate [MPA], a synthetic Progestin used widely in the clinical setting) accelerate the development of breast tumors in vivo and increase their metastasis to lymph nodes. Based on these observations, we have hypothesized that Progestin-induced breast cancer tumor growth and metastasis may be mediated by an enrichment of the cancer stem cell (CSC) pool. In this study, we used T47-D and BT-474 hormone-responsive human breast cancer cells to examine the effects of Progestin on phenotypic and functional markers of CSCs in vitro. Both natural and synthetic Progestins (10 nM) significantly increased protein expression of CD44, an important CSC marker in tumor cells. MPA increased the levels of both CD44 variants v3 and v6 associated with stem cell functions. This induction of CD44 was blocked by the antiProgestin RU-486, suggesting that this process is progesterone receptor (PR) dependent. CD44 induction was chiefly Progestin dependent. Because RU-486 can bind other steroid receptors, we treated PR-negative T47-DCO-Y cells with MPA and found that MPA failed to induce CD44 protein expression, confirming that PR is essential for Progestin-mediated CD44 induction in T47-D cells. Further, MPA treatment of T47-D cells significantly increased the activity of aldehyde dehydrogenase (ALDH), another CSC marker. Finally, two synthetic Progestins, MPA and norethindrone, significantly increased the ability of T47-D cells to form mammospheres, suggesting that enrichment of the CD44high, ALDHbright subpopulation of cancer cells induced by MPA exposure is of functional significance. Based on our observations, we contend that exposure of breast cancer cells to synthetic Progestins leads to an enrichment of the CSC pool, supporting the development of Progestin-accelerated tumors in vivo.
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proliferation of endothelial and tumor epithelial cells by Progestin induced vascular endothelial growth factor from human breast cancer cells paracrine and autocrine effects
Endocrinology, 2005Co-Authors: Yayun Liang, Salman M HyderAbstract:Angiogenesis, the formation of new blood vessels, is essential for tumor expansion, and vascular endothelial growth factor (VEGF) is one of the most potent angiogenic growth factors known. We have previously shown that natural and synthetic Progestins, including those used in hormone replacement therapy and oral contraception, induce the synthesis and secretion of VEGF in a subset of human breast cancer cells in a progesterone receptor-dependent manner. We now report that conditioned medium from Progestin-treated breast tumor cells can induce the proliferation of endothelial cells in a paracrine manner and induce the proliferation of tumor epithelial cells in a paracrine and an autocrine manner. The use of an anti-VEGF antibody and SU-1498, an inhibitor of VEGF receptor-2 (VEGFR-2 or flk/kdr) tyrosine kinase activity, demonstrated that these effects involve interactions between VEGF and VEGFR-2. Also, blockage of Progestin-induced VEGF by the antiProgestin RU-486 (mifepristone) eliminated VEGF-induced proliferative effects. The ability of VEGF to increase the proliferation of endothelial cells and tumor cells, including those that do not release VEGF in response to Progestins, suggests that these effects are mediated by amplification of the Progestin signal, which culminates in angiogenesis and tumor growth. These novel findings suggest that targeting the release of VEGF from tumor epithelial cells as well as blocking interactions between VEGF and VEGFR-2 on both endothelial and tumor epithelial cells may facilitate the development of new antiangiogenic therapies for Progestin-dependent breast tumors. Furthermore, these data indicate that it would be useful to develop selective progesterone receptor modulators that prevent the release of angiogenic growth factors from breast cancer cells.
Yayun Liang - One of the best experts on this subject based on the ideXlab platform.
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natural and synthetic Progestins enrich cancer stem cell like cells in hormone responsive human breast cancer cell populations in vitro
Breast Cancer: Targets and Therapy, 2017Co-Authors: Sandy Goyette, Yayun Liang, Benford Mafuvadze, Matthew Cook, Moiz Munir, Salman M HyderAbstract:Clinical trials and studies have shown that combination estrogen/Progestin hormone replacement therapy, but not estrogen therapy alone or placebo, increases breast cancer risk in postmenopausal women. Using animal models, we have previously shown that both natural and synthetic Progestins (including medroxyprogesterone acetate [MPA], a synthetic Progestin used widely in the clinical setting) accelerate the development of breast tumors in vivo and increase their metastasis to lymph nodes. Based on these observations, we have hypothesized that Progestin-induced breast cancer tumor growth and metastasis may be mediated by an enrichment of the cancer stem cell (CSC) pool. In this study, we used T47-D and BT-474 hormone-responsive human breast cancer cells to examine the effects of Progestin on phenotypic and functional markers of CSCs in vitro. Both natural and synthetic Progestins (10 nM) significantly increased protein expression of CD44, an important CSC marker in tumor cells. MPA increased the levels of both CD44 variants v3 and v6 associated with stem cell functions. This induction of CD44 was blocked by the antiProgestin RU-486, suggesting that this process is progesterone receptor (PR) dependent. CD44 induction was chiefly Progestin dependent. Because RU-486 can bind other steroid receptors, we treated PR-negative T47-DCO-Y cells with MPA and found that MPA failed to induce CD44 protein expression, confirming that PR is essential for Progestin-mediated CD44 induction in T47-D cells. Further, MPA treatment of T47-D cells significantly increased the activity of aldehyde dehydrogenase (ALDH), another CSC marker. Finally, two synthetic Progestins, MPA and norethindrone, significantly increased the ability of T47-D cells to form mammospheres, suggesting that enrichment of the CD44high, ALDHbright subpopulation of cancer cells induced by MPA exposure is of functional significance. Based on our observations, we contend that exposure of breast cancer cells to synthetic Progestins leads to an enrichment of the CSC pool, supporting the development of Progestin-accelerated tumors in vivo.
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proliferation of endothelial and tumor epithelial cells by Progestin induced vascular endothelial growth factor from human breast cancer cells paracrine and autocrine effects
Endocrinology, 2005Co-Authors: Yayun Liang, Salman M HyderAbstract:Angiogenesis, the formation of new blood vessels, is essential for tumor expansion, and vascular endothelial growth factor (VEGF) is one of the most potent angiogenic growth factors known. We have previously shown that natural and synthetic Progestins, including those used in hormone replacement therapy and oral contraception, induce the synthesis and secretion of VEGF in a subset of human breast cancer cells in a progesterone receptor-dependent manner. We now report that conditioned medium from Progestin-treated breast tumor cells can induce the proliferation of endothelial cells in a paracrine manner and induce the proliferation of tumor epithelial cells in a paracrine and an autocrine manner. The use of an anti-VEGF antibody and SU-1498, an inhibitor of VEGF receptor-2 (VEGFR-2 or flk/kdr) tyrosine kinase activity, demonstrated that these effects involve interactions between VEGF and VEGFR-2. Also, blockage of Progestin-induced VEGF by the antiProgestin RU-486 (mifepristone) eliminated VEGF-induced proliferative effects. The ability of VEGF to increase the proliferation of endothelial cells and tumor cells, including those that do not release VEGF in response to Progestins, suggests that these effects are mediated by amplification of the Progestin signal, which culminates in angiogenesis and tumor growth. These novel findings suggest that targeting the release of VEGF from tumor epithelial cells as well as blocking interactions between VEGF and VEGFR-2 on both endothelial and tumor epithelial cells may facilitate the development of new antiangiogenic therapies for Progestin-dependent breast tumors. Furthermore, these data indicate that it would be useful to develop selective progesterone receptor modulators that prevent the release of angiogenic growth factors from breast cancer cells.
Wenxin Zheng - One of the best experts on this subject based on the ideXlab platform.
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mechanisms involved in the evolution of Progestin resistance in human endometrial hyperplasia precursor of endometrial cancer
Gynecologic Oncology, 2003Co-Authors: S A Wang, Jeffery Pudney, Joon Song, Gil Mor, Peter E Schwartz, Wenxin ZhengAbstract:Abstract Background Successful treatment of endometrial hyperplasia with Progestins is commonly accompanied by the finding of an inactive or suppressed endometrium after therapy. However, approximately 30% of the endometrial hyperplasia cases do not respond to Progestins and hyperplastic glands persist. The Fas/FasL system is known to play a role in tissue remodeling as a result of changes in menstrual hormone levels. The aims of this study are to examine Fas/FasL expression in endometrial hyperplasia of pre- and postProgestin treatment samples and to study the Fas/FasL regulation in vitro with Ishikawa cells after Progestin stimulation. Design Pre- and posttreatment paraffin-embedded endometrial hyperplasia tissue samples from 26 women were examined by immunohistochemistry for changes in Fas/FasL expression related to the administration of Progestins. Among 26 patients, 18 were successfully treated with Progestins and 8 failed treatment. Fas/ FasL positivity was defined by the presence of 10% or more immunoreactive epithelial cells in each specimen. In positive cases, a percentage or an immunoscore of immunoreactive cells was given by counting 500 cells. Cell viability was evaluated by the MTT assay. The in vitro effects of progesterone on Fas/FasL expression and apoptosis in Ishikawa cells were examined by using Western blot and TUNEL assays, respectively. Results Fas immunoreactivity was present in 4/26 (15%) preProgestin cases with an average of 16% of the epithelial cells expressing Fas. FasL was expressed in 21/26 (80%) pretreatment cases with an average of 42% of the hyperplastic glandular cells being positive. In postProgestin cases, an increase of Fas expression (14/18, 77%) with an average of 47% stained cells was seen in responders ( P P = 0.587). In nonresponders, no significant changes in Fas/FasL expression were detected compared to pretreatment samples. With in vitro Ishikawa cells, a slight increase (10–20%) of Fas and FasL protein expression was detected after 24 h of progesterone treatment, but a more significant increase (220–343%) of both Fas and FasL expression was found after 48 h of withdrawing progesterone, which parallels apoptotic activity. Conclusions The Fas/FasL system may be involved in the development of endometrial hyperplasia. Part of the molecular mechanisms of Progestin therapy for endometrial hyperplasia is through upregulation of Fas/FasL expression. Dysregulation of Fas/FasL expression in hyperplastic endometrium may be part of the molecular mechanisms for nonresponders to Progestin treatment. Intermittent, rather than continuous, Progestin treatment may be more effective clinically for the treatment of endometrial hyperplasia.
Tea Lanisnik Rižner - One of the best experts on this subject based on the ideXlab platform.
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expression of human aldo keto reductase 1c2 in cell lines of peritoneal endometriosis potential implications in metabolism of progesterone and dydrogesterone and inhibition by Progestins
The Journal of Steroid Biochemistry and Molecular Biology, 2012Co-Authors: Natasa Beranic, Petra Brožic, Boris Brus, Izidor Sosic, Stanislav Gobec, Tea Lanisnik RižnerAbstract:Abstract The human aldo-keto reductase AKR1C2 converts 5α-dihydrotestosterone to the less active 3α-androstanediol and has a minor 20-ketosteroid reductase activity that metabolises progesterone to 20α-hydroxyprogesterone. AKR1C2 is expressed in different peripheral tissues, but its role in uterine diseases like endometriosis has not been studied in detail. Some Progestins used for treatment of endometriosis inhibit AKR1C1 and AKR1C3, with unknown effects on AKR1C2. In this study we investigated expression of AKR1C2 in the model cell lines of peritoneal endometriosis, and examined the ability of recombinant AKR1C2 to metabolise progesterone and Progestin dydrogesterone, as well as its potential inhibition by Progestins. AKR1C2 is expressed in epithelial and stromal endometriotic cell lines at the mRNA level. The recombinant enzyme catalyses reduction of progesterone to 20α-hydroxyprogesterone with a 10-fold lower catalytic efficiency than the major 20-ketosteroid reductase, AKR1C1. AKR1C2 also metabolises Progestin dydrogesterone to its 20α-dihydrodydrogesterone, with 8.6-fold higher catalytic efficiency than 5α-dihydrotestosterone. Among the Progestins that are currently used for treatment of endometriosis, dydrogesterone, medroxyprogesterone acetate and 20α-dihydrodydrogesterone act as AKR1C2 inhibitors with low μM Ki values in vitro. Their potential in vivo effects should be further studied.
Gustavo C Rodriguez - One of the best experts on this subject based on the ideXlab platform.
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phase ii trial of chemopreventive effects of levonorgestrel on ovarian and fallopian tube epithelium in women at high risk for ovarian cancer an nrg oncology group gog study
Cancer Prevention Research, 2019Co-Authors: Gustavo C Rodriguez, Jessica Hunn, James Kauderer, Larry G Thaete, William G Watkin, Samantha RussellAbstract:A large body of epidemiologic evidence has shown that use of Progestin-containing preparations lowers ovarian cancer risk. The purpose of the current study was to gather further preclinical evidence supporting Progestins as cancer chemopreventives by demonstrating Progestin-activation of surrogate endpoint biomarkers pertinent to cancer prevention in the genital tract of women at increased risk of ovarian cancer. There were 64 women enrolled in a multi-institutional randomized trial who chose to undergo risk-reducing bilateral salpingo-oophorectomy (BSO) and to receive the Progestin levonorgestrel or placebo for 4 to 6 weeks prior to undergoing BSO. The ovarian and fallopian tube epithelia (FTE) were compared immunohistochemically for effects of levonorgestrel on apoptosis (primary endpoint). Secondary endpoints included TGFβ isoform expression, proliferation, and karyometric features of nuclear abnormality. In both the ovary and fallopian tube, levonorgestrel did not confer significant changes in apoptosis or expression of the TGFβ1, 2, or 3 isoforms. In the ovarian epithelium, treatment with levonorgestrel significantly decreased the proliferation index. The mean ovarian Ki-67 value in the placebo arm was 2.027 per 100 cells versus 0.775 per 100 cells in the levonorgestrel arm (two-sided P value via Mann-Whitney U test = 0.0114). The karyometric signature of nuclei in both the ovarian and FTE deviated significantly from normal controls (women at average risk of ovarian cancer), but was significantly less abnormal in women treated with levonorgestrel. These karyometric data further support the idea that Progestins may clear genetically abnormal cells and act as chemopreventive agents against ovarian and fallopian tube cancer.
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Progestins inhibit calcitriol induced cyp24a1 and synergistically inhibit ovarian cancer cell viability an opportunity for chemoprevention
Gynecologic Oncology, 2016Co-Authors: Gustavo C Rodriguez, Jane Turbov, R Rosales, Jennifer Yoo, Jessica Hunn, Katherine J Zappia, Kaarin Lund, Catherine P BarryAbstract:Abstract Objectives Previously we have shown in endometrial cells that progesterone (P4) and calcitriol (CAL, 1,25(OH) 2 D 3 ) synergistically promote apoptosis and that Progestins induce expression of the vitamin D receptor. In the current study we examined the Progestin/vitamin D combination in ovarian cells and searched for other Progestin-related effects on vitamin D metabolism that may underlie the novel interaction between Progestins and vitamin D, including whether Progestins inhibit CYP24A1 , the enzyme that renders CAL inactive. Methods We investigated the impact of P4 on CAL-induced CYP24A1 expression in cancer cell lines expressing progesterone receptors (PRs), [OVCAR-5, OVCAR-3-PGR (PR-transfected OVCAR-3 ovarian line), and T47D-WT, T47D-A and T47D-B (breast lines expressing PRs or individual PR isoforms)] or lines that do not express PRs (OVCAR-3 and T47D-Y). We examined CYP24A1 expression using RT-PCR and western blotting, and apoptosis by TUNEL. We also investigated P4 inhibition of Cyp24a1 in ovaries from CAL-treated mice. Results CAL treatment induced CYP24A1 expression. When co-treated with P4, cell lines expressing PRs showed marked inhibition of CYP24A1 expression (p Cyp24a1 mRNA (p Conclusions We show for the first time that Progestins and vitamin D synergistically reduce cell viability and induce apoptosis in ovarian cells and that Progestins PR-dependently inhibit CAL-induced CYP24A1 , thus extending CAL activity. The combination of Progestins and vitamin D deserves further consideration as a strategy for inhibiting ovarian carcinogenesis.
