Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.10.1 (ERK)
95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The management and prognosis of breast cancer nowadays require the evaluation of Estrogen (ER), Progesterone Receptors (PR) and HER2/neu. Ethnic variation in the expression of these receptors is well documented. The aim of this study is to determine the prevalence of ER, PR and HER2/neu among Jordanian women with breast cancer of ductal and lobular types. A retrospective analysis was performed on 267 cases of breast cancer referred for treatment at King Hussein Cancer Center, Jordan between the period of June 2003 and June 2004. Standard immune stains were used for evaluation of hormone receptors and HER2/neu. In addition, evaluation of HER2/neu was done by FISH in selected cases. Of these 267 cases, 240 (89.9%) were ductal carcinomas of various histological grades, 122 (50.8%) of which were ER-positive, 138 (57.5%) PRpositive and 42 (17.5%) HER2/neu-positive. Twentytwo (8.2%) of all cases were lobular carcinomas, 15 (68%) of which were ER-positive, 20 (90.9%) PRpositive and 3 (13.6%) HER2/neu-positive. Five (1.9%) of the total cases were of mixed lobular and ductal types, 4 (80%) of which were ER-positive, 3 (60%) PR-positive and none were positive for HER2/neu. The prevalence of hormone receptor positivity in breast cancer of Jordanian women is lower than that of the western populations and close to other populations such as the Chinese and the minor ethnic groups of Northern America (African Americans).
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PMID:Prevalence of hormone receptors and HER2/neu in breast cancer cases in Jordan. 1679 8

The objective of the study was to understand how estrogen modulates the rigidity of the cytoskeleton in epithelial cells. Estrogen depletion decreased, and treatment with 17beta-estradiol increased deformability of cervical-vaginal epithelial cells. Estrogen also induced redistribution of nonmuscle myosin II-B (NMM-II-B); lesser interaction of NMM-II-B with actin; increased phosphorylation of NMM-II-B-heavy chains at threonine and serine residues; and decreased filamentation of NMM-II-B in vitro. The effects of 17beta-estradiol were time and dose related and could be mimicked by diethylstilbestrol. The effects of estrogen were blocked by cotreatment with antisense oligonucleotide for the estrogen receptor-alpha and inhibited by ICI-182,780 and tamoxifen; omission of epithelial growth factor (EGF) from the culture medium; and cotreatments with the EGF receptor inhibitor AG1478, the ERK-MAPK inhibitor PD98059, the casein kinase-II (CK2) inhibitor 5,6-dichloro-1-beta-(D)-ribofuranosylbenzimidazole, the Rho-associated kinase inhibitor Y-27632, and the nonspecific phosphatase inhibitor okadaic acid. Coadministration of 5,6-dichloro-1-beta-(D)-ribofuranosylbenzimidazole plus okadaic acid blocked the 17beta-estradiol effect. H-89 or LY294002 did not significantly affect estrogen effects. Treatment with estrogen increased activation of ERK1/2 and CK2 activity. These data suggest a novel pathway of estrogen regulation of the cytoskeleton in epithelial cells. The effect is mediated by estrogen receptor-alpha and involves in part the EGF-EGF receptor and ERK-MAPK cascades as proximal signaling networks and the CK2 and Rho-associated kinase-regulated myosin heavy chain phosphatase as terminal effectors. Augmented phosphorylation of NMM-II-B can block filamentation and induce disassociation of the myosin from the cortical actin, and disruption of the actomyosin ring can increase cell deformability. This mechanism can explain estrogen regulation of paracellular permeability in cervical-vaginal epithelia in vivo.
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PMID:Estrogen regulates epithelial cell deformability by modulation of cortical actomyosin through phosphorylation of nonmuscle myosin heavy-chain II-B filaments. 1690 65

Although crosstalk between cell-surface and nuclear receptor signaling pathways has been implicated in the development and progression of endocrine-regulated cancers, evidence of direct coupling of these signaling pathways has remained elusive. Here we show that estrogen promotes an association between extranuclear estrogen receptor alpha (ER) and the epidermal growth factor receptor (EGFR) family member ERBB4. Ectopically expressed as well as endogenous ERBB4 interacts with and potentiates ER transactivation, indicating that the ERBB4/ER interaction is functional. Estrogen induces nuclear translocation of the proteolytic processed ERBB4 intracellular domain (4ICD) and nuclear translocation of 4ICD requires functional ligand-bound ER. The nuclear ER/4ICD complex is selectively recruited to estrogen-inducible gene promoters such as progesterone receptor (PgR) and stromal cell-derived factor 1 (SDF-1) but not to trefoil factor 1 precursor (pS2). Consistent with 4ICD-selective promoter binding, suppression of ERBB4 expression by interfering RNA shows that 4ICD coactivates ER transcription at the PgR and SDF-1 but not the pS2 promoter. Significantly, ERBB4 itself is an estrogen-inducible gene and the ERBB4 promoter harbors a consensus estrogen response element (ERE) half-site with overlapping activator protein-1 elements that bind ER and 4ICD in response to estrogen. Using a cell proliferation assay and a small interfering RNA approach, we show that ERBB4 expression is required for the growth-promoting action of estrogen in the T47D breast cancer cell line. Our results indicate that ERBB4 is a unique coregulator of ER, directly coupling extranuclear and nuclear estrogen actions in breast cancer. We propose that the contribution of an autocrine ERBB4/ER signaling pathway to tumor growth and therapeutic response should be considered when managing patients with ER-positive breast cancer.
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PMID:Coregulation of estrogen receptor by ERBB4/HER4 establishes a growth-promoting autocrine signal in breast tumor cells. 1691 74

Estrogen reduces brain injury after experimental cerebral ischemia in part through a genomic mechanism of action. Using DNA microarrays, we analyzed the genomic response of the brain to estradiol, and we identified a transcript, cocaine- and amphetamine-regulated transcript (CART), that is highly induced in the cerebral cortex by estradiol under ischemic conditions. Using in vitro and in vivo models of neural injury, we confirmed and characterized CART mRNA and protein up-regulation by estradiol in surviving neurons, and we demonstrated that i.v. administration of a rat CART peptide is protective against ischemic brain injury in vivo. We further demonstrated binding of cAMP response element (CRE)-binding protein to a CART promoter CRE site in ischemic brain and rapid activation by CART of ERK in primary cultured cortical neurons. The findings suggest that CART is an important player in estrogen-mediated neuroprotection and a potential therapeutic agent for stroke and other neurodegenerative diseases.
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PMID:Role of cocaine- and amphetamine-regulated transcript in estradiol-mediated neuroprotection. 1697 88

The role of hormones in the determination of sexual characteristics has been known for several decades. It has been shown, for example, that several products, including sex steroids, may influence the body development pattern, metabolic pathways, fat and muscle distribution and vocal cord anatomy, thus producing an overall outcome consistent with a masculine or feminine phenotypic pattern. These qualities are usually described as secondary sexual traits, so as to be distinguished from primary sex traits, usually referring to the gonads and external genitalia. However, it must be noted that hormonal regulation may not explain the full range of the sexual phenotype, since the central nervous system retains a significant role in the establishment of sexual identity, thus giving rise to a higher sex determination stage exclusively described in humans, namely behavioral or psychological sex. Recently, it has been suggested that differences among the sexes are not limited to brain function but they may also refer to anatomical differences and different biochemical profiles, including a distinct pattern of AR and ER distribution. This new aspect of sexual dimorphism suggests a whole system of meta-hormonal regulation, recently described as the sexual brain model. The role of local androgen and/or estrogen concentrations in the initial establishment of brain sexual dimorphism is still under evaluation, since the first results are relatively inconclusive and no direct cause and effect relationship has been proven so far. On the other hand, sex hormones have recently been found to participate in processes well beyond their initially suggested spectrum of action. For instance, ER interacts with EGFR in a number of ways, affecting development of a number of epithelial structures. Estrogen receptors have also been detected in a number of non-classic targets of steroids, such as the brain and the lungs. This observation may imply that sexual dimorphism goes a lot deeper than previously estimated, affecting virtually every organic system, suggesting, in essence, the existence of two different functional models for the whole human body, formulated and conserved throughout the evolutionary progress.
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PMID:Hormonal and meta-hormonal determinants of sexual dimorphism. 1705 40

Antisense oligonucleotides (oligos) against transforming growth factor-alpha (TGF-alpha; MR(1)) and its binding site, the epidermal growth factor receptor (EGFR; MR(2)), have proven efficacious against PC-3 and LNCaP prostate tumors when evaluated in both in vitro and in vivo models. To enhance their activity, and also to introduce a significantly different type of multifunctional agent into this field, "bispecific" oligos were constructed containing truncated sequences (derived from MR(1) and MR(2)) recognizing both TGF-alpha and EGFR mRNA internal binding sites, located about their respective AUG initiation codons. Two bispecifics were constructed, each having complementary sequences for TGF-alpha and EGFR mRNA, but differing in their 5' to 3' tandem orientation (TGF-alpha/EGFR [MR(12)] and EGFR/TGF-alpha [MR(21)] sequences). These bispecifics were tested in an in vitro system against PC-3 and LNCaP prostate tumor cells, with comparisons made to the original monospecific oligos from which they were derived. Efficacy was also compared when administered either alone or in combination with conventional chemotherapeutic agents. The purpose of this study was: 1) to validate the concept that these newly developed bispecific oligos have antitumor activity; 2) to enhance their efficacy through combination therapy; 3) to identify differences in effectiveness dependent upon binding site orientation; 4) identification of a dominant binding site that can be used to design other bispecifics that target additional tumor regulatory pathways. When fully evaluated against PC-3 cells in a series of experiments, newly developed bispecific oligos are at least as effective as their monospecific counterparts from which they were derived, and the bispecific with the MR(21) orientation is notably more effective than the MR(1) monospecific by 64% (p = 0.014 by Student t-test and p = 0.068 by the more stringent Mann-Whitney U test). Bispecifics were more effective when administered with chemotherapeutics (producing inhibition of 52.1% and 61.2% for MR(12) and MR(21), respectively, with Cytoxan (cyclophosphamide) inhibition of 59.0% and 65.1% for MR(12) and MR(21), respectively, with Taxol (paclitaxel) and 63.0% and 69.4% for MR(12) and MR(21), respectively, with DES [diethylstilbestrol]). Increasing the oligo concentration above 6.25 microM with cyclophosphamide had no additional effect. The sequence directed against EGFR was dominant and contributed most to bispecific activity, particularly when inserted 5' to the TGF-alpha binding sequence (MR(21) orientation). Bispecific oligos are a significant advance in the design of antisense compounds and could play a role in treating prostate cancer, particularly when they are administered with traditional chemotherapeutics. The truncated portion of the MR(2) oligo used here should be included when constructing second-generation bispecifics that target proteins associated with other regulatory pathways, such as apoptosis.
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PMID:Bispecific antisense oligonucleotides with multiple binding sites for the treatment of prostate tumors and their applicability to combination therapy. 1713 30

Pertuzumab (Omnitarg, rhuMab 2C4) is a humanized monoclonal antibody, which inhibits HER2 dimerization. Because it has shown some clinical activity in ovarian cancer, this study sought to identify predictors of response to this agent in a model of ovarian cancer. A panel of 13 ovarian cancer cell lines was treated with heregulin beta1 (HRGbeta1) or transforming growth factor-alpha, and cell proliferation was assessed. Both agents increased cell number in the majority of cell lines studied, the response to both being similar (r = 0.83; P = 0.0004, Pearson test). HRGbeta1 stimulation could be partially reversed by pertuzumab in 6 of 13 cell lines, with complete reversal in PE04 and PE06 cells. Addition of pertuzumab to transforming growth factor-alpha-stimulated cells produced growth inhibition in 3 of 13 cell lines (PE01, PE04, and PE06). The magnitude of HRGbeta1-driven growth stimulation correlated significantly with an increase in extracellular signal-regulated kinase 2 (P = 0.037) but not Akt (P = 0.99) phosphorylation. Such HRGbeta1-driven phosphorylation of extracellular signal-regulated kinase 1/2 and Akt could be reduced with pertuzumab, accompanied by changes in cell cycle distribution. In cell lines responsive to pertuzumab, HRGbeta1-enhanced phosphorylation of HER2 (Tyr(877)) was reduced. Estrogen-stimulated changes in growth, cell cycle distribution, and signaling were reversed by pertuzumab, indicating cross-talk between HER2 and estrogen signaling. These data indicate that there is a subset of ovarian cancer cell lines sensitive to pertuzumab and suggest possible predictors of response to identify patients who could benefit from this therapy. Furthermore, we have identified an interaction between HER2 and estrogen signaling in this disease.
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PMID:Sensitivity to pertuzumab (2C4) in ovarian cancer models: cross-talk with estrogen receptor signaling. 1723 69

Lung cancer is the most common cause of cancer mortality in male and female patients in the US. The etiology of non-small cell lung cancer (NSCLC) is not fully defined, but new data suggest that estrogens and growth factors promote tumor progression. In this work, we confirm that estrogen receptors (ER), both ERalpha and ERbeta, occur in significant proportions of archival NSCLC specimens from the clinic, with receptor expression in tumor cell nuclei and in extranuclear sites. Further, ERalpha in tumor nuclei was present in activated forms as assessed by detection of ER phosphorylation at serines-118 and -167, residues commonly modulated by growth factor receptor as well as steroid signaling. In experiments using small interfering RNA (siRNA) constructs, we find that suppressing expression of either ERalpha or ERbeta elicits a significant reduction in NSCLC cell proliferation in vitro. Estrogen signaling in NSCLC cells may also include steroid receptor coactivators (SRC), as SRC-3 and MNAR/PELP1 are both expressed in several lung cell lines, and both EGF and estradiol elicit serine phosphorylation of SRC-3 in vitro. EGFR and ER also cooperate in promoting early activation of p42/p44 MAP kinase in NSCLC cells. To assess new strategies to block NSCLC growth, we used Faslodex alone and with erlotinib, an EGFR kinase inhibitor. The drug tandem elicited enhanced blockade of the growth of NSCLC xenografts in vivo, and antitumor activity exceeded that of either agent given alone. The potential for use of antiestrogens alone and with growth factor receptor antagonists is now being pursued further in clinical trials.
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PMID:Estrogen receptor signaling pathways in human non-small cell lung cancer. 1727 70

Estrogen has been demonstrated to promote therapeutic reendothelialization after vascular injury by bone marrow (BM)-derived endothelial progenitor cell (EPC) mobilization and phenotypic modulation. We investigated the primary hypothesis that estrogen regulates physiological postnatal vasculogenesis by modulating bioactivity of BM-derived EPCs through the estrogen receptor (ER), in cyclic hormonally regulated endometrial neovascularization. Cultured human EPCs from peripheral blood mononuclear cells (PB-MNCs) disclosed consistent gene expression of ER alpha as well as downregulated gene expressions of ER beta. Under the physiological concentrations of estrogen (17beta-estradiol, E2), proliferation and migration were stimulated, whereas apoptosis was inhibited on day 7 cultured EPCs. These estrogen-induced activities were blocked by the receptor antagonist, ICI182,780 (ICI). In BM transplanted (BMT) mice with ovariectomy (OVX) from transgenic mice overexpressing beta-galactosidase (lacZ) regulated by an endothelial specific Tie-2 promoter (Tie-2/lacZ/BM), the uterus demonstrated a significant increase in BM-derived EPCs (lacZ expressing cells) incorporated into neovasculatures detected by CD31 immunohistochemistry after E2 administration. The BM-derived EPCs that were incorporated into the uterus dominantly expressed ER alpha, rather than ER beta in BMT mice from BM of transgenic mice overexpressing EGFP regulated by Tie-2 promoter with OVX (Tie-2/EGFP/BMT/OVX) by ERs fluorescence immunohistochemistry. An in vitro assay for colony forming activity as well as flow cytometry for CD133, CD34, KDR, and VE-cadherin, using human PB-MNCs at 5 stages of the female menstrual-cycle (early-proliferative, pre-ovulatory, post-ovulatory, mid-luteal, late-luteal), revealed cycle-specific regulation of EPC kinetics. These findings demonstrate that physiological postnatal vasculogenesis involves cyclic, E2-regulated bioactivity of BM-derived EPCs, predominantly through the ER alpha.
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PMID:Estrogen-mediated endothelial progenitor cell biology and kinetics for physiological postnatal vasculogenesis. 1765 79

Estrogen is a known immunomodulator with pleiotropic effects on macrophage function that partly accounts for the gender bias observed in numerous autoimmune, cardiovascular, and neurodegenerative disorders. The effect of estrogen on the survival of human macrophages is largely unknown, and in this study we demonstrate that 17beta-estradiol (E2) provokes a death response in human THP-1 macrophages by initiating Bax translocation from cytosol to the mitochondria; however, a concomitant up-regulation of Bcl-2 creates a Bax to Bcl-2 ratio favorable for Bcl-2, thus ensuring cell survival. Both Bcl-2 up-regulation and Bax translocation are estrogen receptor-dependent events; however, Bcl-2 augmentation but not Bax translocation is dependent on Ca(2+) increase, activation of protein kinase C, and ERK phosphorylation. This estrogen-induced Bcl-2 increase is crucial for the survival of THP-1 macrophages as well as that of human peripheral blood monocyte-derived macrophages, which is evident from E2-induced cell death under small interfering RNA-mediated Bcl-2 knockdown conditions. Hence, this study demonstrates that E2-induced Bcl-2 up-regulation is a homeostatic survival mechanism necessary for the manifestation of immunomodulatory effect of estrogen on human macrophages.
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PMID:Up-regulation of Bcl-2 through ERK phosphorylation is associated with human macrophage survival in an estrogen microenvironment. 1767 94


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