Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0006142 (breast cancer)
 160,383 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Repression of nuclear factor (NF)-kappaB-dependent gene expression is one of the key characteristics by which glucocorticoids exert their antiinflammatory and immunosuppressive effects. In vitro studies have shown protein-protein interactions between NF-kappaB and the glucocorticoid receptor, possibly explaining their mutual repression of transcriptional activity. Furthermore, glucocorticoid-induced transcription of IkappaBalpha was presented as a mechanism in mediation of immunosuppression by glucocorticoids. At present, the relative contribution of each mechanism has not been investigated. We show that dexamethasone induced IkappaBalpha gene transcription in human pulmonary epithelial A549 cells. However, this enhanced IkappaBalpha synthesis did not cause repression of NF-kappaB DNA-binding activity. In addition, dexamethasone was still able to inhibit the expression of NF-kappaB target genes (cyclooxygenase-2, intercellular adhesion molecule-1) in the absence of protein synthesis. Furthermore, we show that the antihormone RU486 did not induce IkappaBalpha expression. However, RU486 was still able to induce, albeit less efficiently, both glucocorticoid- and progesterone receptor-mediated repression of endogenous NF-kappaB target gene expression in A549 cells and the breast cancer cell line T47D, respectively. Taken together, these results indicate that induced IkappaBalpha expression accounts for only part of the repression of NF-kappaB activity by glucocorticoids and progestins. In addition, protein-protein interactions between NF-kappaB and the glucocorticoid or progesterone receptor, resulting in repression of NF-kappaB activity, seem also to be involved. We therefore conclude that NF-kappaB activity is repressed via a dual mechanism involving both protein-protein interactions and induction of IkappaBalpha.
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PMID:A dual mechanism mediates repression of NF-kappaB activity by glucocorticoids. 951 53

Progesterone and glucocorticoid receptor levels were assayed in breast tumor. The progesterone levels in tumor were 1.2-2.5 times those in normal tissue sampled from the same patients. The binding of glycyrrhizic acid (GA) to cytoplasmic proteins (GA "receptor" levels) was studied using procedures for glucocorticoid receptor assay. The "receptor" concentrations in tumor tissue were 1.5-5 times that in normal one. The "receptors" were detected only in 5.9% of normal breast tissue samples. The Kd of GA-protein complex was ca.7 x 10(-8) M. GA seems to offer significant advantage as a drug-carrier involved in therapy of glucocorticoid-dependent breast cancer.
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PMID:[Content of progesterone, glucocorticoid and glycyrrhizic acid receptors in normal and tumoral human breast tissue]. 980 99

Estrogens are important for bone homeostasis and are classified as antiresorptive agents. One of the mechanisms for this effect is the inhibition of cytokine-induced bone resorption, which is mediated in part through an interaction between the estrogen receptor (ER) and nuclear factor (NF)-kappaB in osteoblasts. We present evidence that bone-resorbing cytokines that activate NF-kappaB conversely inhibit ligand-dependent ER activity in the conditionally immortalized human osteoblast cell line, HOB-03-CE6. Treatment of HOB-03-CE6 cells with 17beta-estradiol (17beta-E2) up-regulated reporter gene activity [ERE-thymidine kinase (tk)-luciferase] 3- to 5-fold in a dose-dependent manner (EC50 = 1.0 pM). However, cotreatment of the cells with 17beta-E2 and increasing concentrations of either tumor necrosis factor-alpha (TNF alpha), interleukin-1alpha (IL-1alpha), or IL-1beta completely suppressed ERE-tk-luciferase activity in a dose-dependent manner (IC50 = 0.05-5.0 pM). On the other hand, treatment of the cells with growth factors either up-regulated or had no effect on ERE-tk-luciferase expression. Neither TNF alpha, IL-1alpha, nor IL-1beta treatment affected basal reporter gene activity in the cells, and the TNF alpha effect was reversed by a neutralizing antibody to the cytokine. TNF alpha treatment also suppressed ligand-dependent ER activity in MCF-7 human breast cancer cells, but not in Chinese hamster ovary cells that overexpressed human ER alpha, even though both cell lines responded to the cytokine as measured by the up-regulation of NFkappaB-tk-luciferase activity. TNF alpha treatment did not affect the steady state levels of either ER alpha or ER beta messenger RNA expression by the HOB-03-CE6 cells, nor did it reduce [125I]17beta-E2 binding. Moreover, TNF alpha treatment only weakly inhibited ligand-dependent glucocorticoid receptor activity in the HOB-03-CE6 cells. Bone-resorbing cytokines, which do not signal through the NF-kappaB pathway, did not suppress ERE-tk-luciferase activity in HOB-03-CE6 cells. Treatment of the cells with 17beta-E2 partially suppressed the activation of NF-kappaB by TNF alpha, but did not block cytokine-induced IL-6 secretion. Finally, cotreatment of HOB-03-CE6 cells with an antisense oligonucleotide to NF-kappaB p50 partially reversed the suppression of ERE-tk-luciferase activity by TNF alpha. In summary, these data provide evidence for a potent feedback inhibition of estrogen action in human osteoblasts that is at least partly mediated by the activation of NF-kappaB.
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PMID:Suppression of ligand-dependent estrogen receptor activity by bone-resorbing cytokines in human osteoblasts. 1034 28

Local tissue concentrations of glucocorticoids are modulated by the enzyme 11beta-hydroxysteroid dehydrogenase which interconverts cortisol and the inactive glucocorticoid cortisone in man, and corticosterone and 11-dehydrocorticosterone in rodents. The type I isoform (11beta-HSD1) is a bidirectional enzyme but acts predominantly as a oxidoreductase to form the active glucocorticoids cortisol or corticosterone, while the type II enzyme (11beta-HSD2) acts unidirectionally producing inactive 11-keto metabolites. There are no known clinical conditions associated with 11beta-HSD1 deficiency, but gene deletion experiments in the mouse indicate that this enzyme is important both for the maintenance of normal serum glucocorticoid levels, and in the activation of key hepatic gluconeogenic enzymes. Other important sites of action include omental fat, the ovary, brain and vasculature. Congenital defects in the 11beta-HSD2 enzyme have been shown to account for the syndrome of apparent mineralocorticoid excess (AME), a low renin severe form of hypertension resulting from the overstimulation of the non-selective mineralocorticoid receptor by cortisol in the distal tubule of the kidney. Inactivation of the 11beta-HSD2 gene in mice results in a phenotype with similar features to AME. In addition, these mice show high neonatal mortality associated with marked colonic distention, and remarkable hypertrophy and hyperplasia of the distal tubule epithelia. 11Beta-HSD2 also plays an important role in decreasing the exposure of the fetus to the high levels of maternal glucocorticoids. Recent work suggests a role for 11beta-HSD2 in non-mineralocorticoid target tissues where it would modulate glucocorticoid access to the glucocorticoid receptor, in invasive breast cancer and as a mechanism providing ligand for the putative 11-dehydrocorticosterone receptor. While previous homologies between members of the SCAD superfamily have been of the order of 20-30% phylogenetic analysis of a new branch of retinol dehydrogenases indicates identities of > 60% and overlapping substrate specificities. The availability of crystal structures of family members has allowed the mapping of conserved 11beta-HSD domains A-D to a cleft in the protein structure (cofactor binding domain), two parallel beta-sheets, and an alpha-helix (active site), respectively.
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PMID:The type I and type II 11beta-hydroxysteroid dehydrogenase enzymes. 1041 17

Nuclear steroid/thyroid/retinoid receptors and c-erbB membrane receptor tyrosine kinases control epithelial growth and differentiation. Retinoid receptors can dimerize with the vitamin D receptor, the glucocorticoid receptor or the thyroid receptor. Furthermore, multiple c-erbB receptor dimers have been identified. It has been shown that some of these receptor pathways communicate with each other via cross-connected regulatory networks. Molecular interactions between retinoid receptors or estrogen receptors (ER) and c-erbB-2, and between ER and retinoic acid receptor(RAR)-alpha have been reported. Here, we demonstrate the effects of steroids/thyroids/retinoids and of activators of protein kinase A (forskolin, Forsk) and C (12-O-tetradecanoylphorbol-13-acetate, TPA), on growth and expression of c-erbB and RARs in MCF-7 breast cancer cells, which contain high levels of RAR-alpha and -gamma, and which express significant amounts of c-erbB-2 and -3. All trans-retinoic acid (tRA), the anti-estrogen ICI 182 780 (ICI), Forsk and TPA reduced, whereas triiodothyronine and 17beta-estradiol (E2) stimulated cell growth. Flow cytometry revealed that tRA and E2 reduced c-erbB-2 and -3, whereas tamoxifen, Forsk and TPA up-regulated c-erbB-2. c-erbB-3 was co-regulated with c-erbB-2. Northern analysis demonstrated that RAR-alpha was down-regulated by dexamethasone, ICI, and TPA, whereas vitamin D3 and E2 up-regulated RAR-alpha. RAR-gamma expression was less responsive to such treatment, being reduced only by ICI and Forsk. These data indicate that nuclear receptor and protein kinase signaling communicate with each other and control the expression of RARs and c-erbB receptors. Efficient growth control requires the coordinated interplay of both receptor systems.
Breast Cancer Res Treat 1999 Nov
PMID:Involvement of nuclear steroid/thyroid/retinoid receptors and of protein kinases in the regulation of growth and of c-erbB and retinoic acid receptor expression in MCF-7 breast cancer cells. 1067 83

The effect of retinoic acid and dexamethasone on alkaline phosphatase (AP) expression was investigated in human breast cancer MCF-7 cells. Cellular AP activity was induced significantly by retinoic acid or dexamethasone in a time-dependent and dose-dependent fashion. A marked synergistic induction of AP activity was observed when the cells were incubated with both agents simultaneously. Two AP isozymes, tissue-nonspecific (TNAP) and intestinal (IAP), were shown to be expressed in MCF-7 cells as confirmed by the differential rate of thermal inactivation of these isozymes and RT-PCR. Based on the two-isozyme thermal-inactivation model, the specific activities for TNAP and IAP in each sample were analyzed. TNAP activity was induced only by retinoic acid and IAP activity was induced only by dexamethasone. Whereas dexamethasone conferred no significant effect on TNAP activity, retinoic acid was shown to inhibit IAP activity by approximately 50%. Interestingly, TNAP was found to be the only isozyme activity superinduced when the cells were costimulated with retinoic acid and dexamethasone. Northern blot and RT-PCR analysis were then used to demonstrate that the steady-state TNAP mRNA level was also superinduced, which indicates that the superinduction is regulated at the transcriptional or post-transcriptional levels. In the presence of the glucocorticoid receptor antagonist RU486, the dexamethasone-mediated induction of IAP activity was blocked completely as expected. However, the ability of RU486 to antagonize the action of glucocorticoid was greatly compromised in dexamethasone-mediated superinduction of TNAP activity. Furthermore, in the presence of retinoic acid, RU486 behaved as an agonist, and conferred superinduction of TNAP gene expression in the same way as dexamethasone. Taken together, these observations suggest that the induction of IAP activity by dexamethasone and the superinduction of TNAP by dexamethasone were mediated through distinct regulatory pathways. In addition, retinoic acid plays an essential role in the superinduction of TNAP gene expression by enabling dexamethasone to exert its agonist activity, which otherwise has no effect.
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PMID:Expression and regulation of alkaline phosphatases in human breast cancer MCF-7 cells. 1069 70

Steroid hormones regulate the transcription of numerous genes via high affinity receptors that act in concert with chromatin remodeling complexes, coactivators and corepressors. We have compared the activities of a variety of glucocorticoid receptor (GR) antagonists in breast cancer and osteosarcoma cell lines engineered to stably maintain the mouse mammary tumor virus promoter. In both cell types, GR activation by dexamethasone occurs via the disruption of mouse mammary tumor virus chromatin structure and the recruitment of receptor coactivator proteins. However, when challenged with a variety of antagonists the GR displays differential ability to activate transcription within the two cell types. For the breast cancer cells, the antagonists fail to activate the promoter and do not promote the association of the GR with either remodeling or coactivator proteins. In contrast, in osteosarcoma cells, the antiglucocorticoids, RU486 and RU43044, exhibit partial agonist activity. The capacity of these antagonists to stimulate transcription in the osteosarcoma cells is reflected in the ability of the RU486-bound receptor to remodel chromatin and associate with chromatin-remodeling proteins. Similarly, the observation that the RU486-bound receptor does not fully activate transcription is consistent with its inability to recruit receptor coactivator proteins.
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PMID:Selective activation of the glucocorticoid receptor by steroid antagonists in human breast cancer and osteosarcoma cells. 1074 3

We find that prothymosin alpha (PTalpha) selectively enhances transcriptional activation by the estrogen receptor (ER) but not transcriptional activity of other nuclear hormone receptors. This selectivity for ER is explained by PTalpha interaction not with ER, but with a 37-kDa protein denoted REA, for repressor of estrogen receptor activity, a protein that we have previously shown binds to ER, blocking coactivator binding to ER. We isolated PTalpha, known to be a chromatin-remodeling protein associated with cell proliferation, using REA as bait in a yeast two-hybrid screen with a cDNA library from MCF-7 human breast cancer cells. PTalpha increases the magnitude of ERalpha transcriptional activity three- to fourfold. It shows lesser enhancement of ERbeta transcriptional activity and has no influence on the transcriptional activity of other nuclear hormone receptors (progesterone receptor, glucocorticoid receptor, thyroid hormone receptor, or retinoic acid receptor) or on the basal activity of ERs. In contrast, the steroid receptor coactivator SRC-1 increases transcriptional activity of all of these receptors. Cotransfection of PTalpha or SRC-1 with increasing amounts of REA, as well as competitive glutathione S-transferase pulldown and mammalian two-hybrid studies, show that REA competes with PTalpha (or SRC-1) for regulation of ER transcriptional activity and suppresses the ER stimulation by PTalpha or SRC-1, indicating that REA can function as an anticoactivator in cells. Our data support a model in which PTalpha, which does not interact with ER, selectively enhances the transcriptional activity of the ER but not that of other nuclear receptors by recruiting the repressive REA protein away from ER, thereby allowing effective coactivation of ER with SRC-1 or other coregulators. The ability of PTalpha to directly interact in vitro and in vivo with REA, a selective coregulator of the ER, thereby enabling the interaction of ER with coactivators, appears to explain its ability to selectively enhance ER transcriptional activity. These findings highlight a new role for PTalpha as a coregulator activity-modulating protein that confers receptor specificity. Proteins such as PTalpha represent an additional regulatory component that defines a novel paradigm enabling receptor-selective enhancement of transcriptional activity by coactivators.
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PMID:Prothymosin alpha selectively enhances estrogen receptor transcriptional activity by interacting with a repressor of estrogen receptor activity. 1093 99

The estrogen receptor alpha (ER) is a ligand-dependent transcription factor that plays a critical role in the development and progression of breast cancer, in part, by regulating target genes involved in cellular proliferation. To identify novel components that affect the ER transcriptional response, we performed a genetic screen in yeast and identified RDI1, a Rho guanine nucleotide dissociation inhibitor (Rho GDI), as a positive regulator of ER transactivation. Overexpression of the human homologue of RDI1, Rho GDIalpha, increases ERalpha, ERbeta, androgen receptor, and glucocorticoid receptor transcriptional activation in mammalian cells but not activation by the unrelated transcription factors serum response factor and Sp1. In contrast, expression of constitutively active forms of RhoA, Rac1, and Cdc42 decrease ER transcriptional activity, suggesting that Rho GDI increases ER transactivation by antagonizing Rho function. Inhibition of RhoA by expression of either the Clostridium botulinum C3 transferase or a dominant negative RhoA resulted in enhanced ER transcriptional activation, thus phenocopying the effect of Rho GDI expression on ER transactivation. Together, these findings establish the Rho GTPases as important modulators of ER transcriptional activation. Since Rho GTPases regulate actin polymerization, our findings suggest a link between the major regulators of cellular architecture and steroid receptor transcriptional response.
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PMID:Rho GTPases as modulators of the estrogen receptor transcriptional response. 1106 Feb 89

We previously demonstrated that activation of the glucocorticoid receptor (GR) initiates an antiapoptotic signal in the immortalized human mammary epithelial cell line MCF10A that is dependent on the GR's transcriptional activity. In this study, we show that the survival role of GR activation extends to protecting human breast cancer cells undergoing apoptosis after growth factor deprivation. Serum and glucocorticoid-regulated kinase-1 (sgk), a gene previously identified as a direct transcriptional target of the activated GR in a rat mammary tumor cell line, was rapidly induced after GR activation in human mammary epithelial cells. Furthermore, in the absence of all growth factors, ectopic sgk expression inhibited apoptosis, suggesting that SGK is a survival kinase. Finally, kinase-dead SGK expression inhibited the protection from apoptosis usually seen after GR activation. These findings suggest that SGK is an important downstream target of GR-mediated survival signaling and that it is distinct from other survival kinases because it can be primarily regulated at the level of transcription.
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PMID:Glucocorticoid receptor-mediated protection from apoptosis is associated with induction of the serine/threonine survival kinase gene, sgk-1. 1127 64


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