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)

Therapy directed against specific biologic targets has long been used in the treatment of breast cancer; the estrogen receptor is a validated prognostic and therapeutic target, and antiestrogen therapy has been used effectively for decades. Recently, scientific progress and increased comprehension of mechanisms of breast cancer pathogenesis have led to the proliferation of both potential molecular targets and new therapeutic agents. The success of traztuzumab (Herceptin, Genentech, South San Francisco, CA), an anti-HER2 antibody, has spurred the development of other biologically directed therapeutics. In this overview, I discuss three targets relevant to breast cancer (the epidermal growth factor receptor family, angiogenesis, and NF-kappa B), and therapeutic approaches directed against these targets are discussed.
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PMID:Molecular targets as therapeutic strategies in the management of breast cancer. 1238 92

To increase the local concentration of tamoxifen in estrogen receptor (ER) positive breast cancer, we have developed and characterized nanoparticle formulation using poly(epsilon -caprolactone) (PCL). The nanoparticles were prepared by solvent displacement method using acetone-water system. Particle size analysis, scanning electron microscopy, zeta potential measurements, and differential scanning calorimetry (DSC) were used for nanoparticle characterization. Biodegradation studies were performed in the presence and absence of Pseudomonas lipase in phosphate-buffered saline (PBS, pH 7.4) at 37 degrees C. Tamoxifen loading over different concentrations was analyzed by high-performance liquid chromatography (HPLC) and the optimum loading concentration was determined. In vitro release studies were performed in 0.5% (w/v) sodium lauryl sulfate (SLS) containing PBS at 37 degrees C. Cellular uptake and distribution of fluorescent-labeled nanoparticles was examined in MCF-7 breast cancer cells. SEM micrographs and Coulter analysis showed nanoparticles with spherical shape and uniform size distribution (250-300 nm), respectively. Zeta potential analysis revealed a positive surface charge of +25 mV on the tamoxifen-loaded formulation. Being hydrophobic crystalline polyester, PCL did not degrade in PBS alone, but the degradation was enhanced by the presence of lipase. The maximum tamoxifen loading efficiency was 64%. Initial burst release of tamoxifen was observed, probably due to significant surface presence of the drug on the nanoparticles. A large fraction of the administered nanoparticle dose was taken up by MCF-7 cells through non-specific endocytosis. The nanoparticles were found in the perinuclear region after 1 h. Results of the study suggest that nanoparticle formulations of selective ER modulators, like tamoxifen, would provide increased therapeutic benefit by delivering the drug in the vicinity of the ER.
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PMID:Biodegradable poly(epsilon -caprolactone) nanoparticles for tumor-targeted delivery of tamoxifen. 1243 41

Estrogen 17beta-estradiol (E2) rapidly modulates several signaling pathways related to cell growth, preservation, and differentiation. The physiological role of these nongenomic effects with regard to downstream outcomes, and the relationship with transcriptional estrogen activity are unclear. Furthermore, the ability of selective estrogen receptor modulators (SERMs) to trigger nongenomic actions is largely unknown. To determine whether estrogen receptor (ER) ligands exert nongenomic activity in endometrial adenocarcinoma cells, and whether this activity affects transcription and DNA synthesis, we challenged human Ishikawa cells with E2 or partial ER agonists 4-hydroxytamoxifen (OHT) and raloxifene (ral). Serum-starved Ishikawa cells exposed for 5 min to 0.1 nM E2 showed induced phosphorylation of MAPK (ERK1/2). Ral and 4-OHT each at 1 nM also stimulated ERK in a rapid transient manner. E2 and 4-OHT induced proto-oncogene c-fos mRNA expression in Ishikawa cells within 30 min, but ral had no effect. In contrast to nongenomic action, only E2 stimulated expression of an estrogen response element (ERE)-driven luciferase (LUC) reporter gene. To examine DNA synthesis, [(3)H]-thymidine incorporation was measured in serum-starved cultures exposed to E2 or partial agonists for 2 d. E2 at 1 nM stimulated thymidine uptake in an ERK-dependent manner, but 1 nM 4-OHT, 1 nM ral, and 0.1-nM concentrations of E2 had no significant effects. Taken together, these data indicate that both nongenomic and direct transcriptional ER effects are likely required to promote DNA synthesis.
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PMID:Nongenomic activity and subsequent c-fos induction by estrogen receptor ligands are not sufficient to promote deoxyribonucleic acid synthesis in human endometrial adenocarcinoma cells. 1248 37

Estrogens play a crucial role in the development of breast cancer. Estradiol can be produced in the breast tissue in situ, and one of the enzymes involved in this process is 17beta-hydroxysteriod dehydrogenase (17beta-HSD) type 1 that catalyzes the interconversion of estrone (E1) to the biologically more potent estradiol (E2). The gene coding for 17beta-HSD type 1 (HSD17B1) is located at 17q12-21, close to the more studied ERBB2 and BRCA1. The aim of this study was to investigate if HSD17B1 shows an altered gene copy number in breast cancer. We used real-time PCR and examined 221 postmenopausal breast tumors for amplification of HSD17B1 and ERBB2. In all, 32 tumors (14.5%) showed amplification of HSD17B1 and 21% were amplified for ERBB2. Amplification of the two genes was correlated (P=0.00078) and in 14 tumors (44%) with amplification of HSD17B1, ERBB2 was co amplified. The patients with amplification in at least one of the genes had a significantly worse outcome than patients without (P=0.0059). For estrogen receptor (ER)-positive patients who received adjuvant tamoxifen, amplification of HSD17B1 was related to decreased breast cancer survival (P=0.017), whereas amplification of ERRB2 was not. Amplification of HSD17B1 might be an indicator of adverse prognosis among ER-positive patients, and possibly a mechanism for decreased benefit from tamoxifen treatment.
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PMID:Amplification of HSD17B1 and ERBB2 in primary breast cancer. 1252 5

Endocrine therapy remains an important approach to the treatment of metastatic breast cancer because of its effectiveness and excellent tolerability. In the last 10 years, a number of new endocrine therapies have been introduced. These include the luteinizing hormone-releasing hormone agonists, which produce menopausal changes in premenopausal women; the aromatase inhibitors, which prevent production of estrogen in postmenopausal women; and the estrogen receptor down-regulator fulvestrant (Faslodex), which is effective in postmenopausal women whose tumors have progressed following response to other selective estrogen receptor modulators. The endocrine cascade for the treatment of premenopausal women with metastatic disease now involves the concurrent or sequential combination of a luteinizing hormone-releasing hormone analogue and tamoxifen, whereas the cascade for the treatment of postmenopausal women can begin with tamoxifen followed by an aromatase inhibitor or with an aromatase inhibitor followed by tamoxifen. The optimal cascade following the use of an aromatase inhibitor and tamoxifen in postmenopausal women remains unclear, but fulvestrant and megestrol acetate or the use of an aromatase inactivator (exemestane) following an aromatase inhibitor are all available options with some activity. Over the next few years, clinical trials will clarify the optimal sequence of endocrine therapy for postmenopausal women. The use of estrogen and progesterone receptor status to select for endocrine therapy is undeniably crucial. HER2/neu overexpression may also predict response to endocrine therapy, but this remains controversial.
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PMID:Endocrine therapy of advanced disease: analysis and implications of the existing data. 1253 1

It has been reported that overexpression of the epidermal growth factor receptor (erbB1) or its homologous receptor, HER2 (erbB2), can confer antiestrogen resistance to estrogen receptor (ER)-positive human breast cancer cells. Aberrant signaling by receptors of the erbB network up-regulates a number of signaling pathways, which include phospholipase C-gamma1, Ras-Raf-mitogen-activated protein/extracellular signal-regulated kinase kinase-mitogen-activated protein kinase, phosphatidylinositol 3'-kinase and its target, the serine/threonine kinase Akt, stress-activated protein kinases, signal transducers and activators of transcription, and c-Jun-NH(2)-terminal kinase (JNK). Akt has been reported to induce estrogen-independent transcription of ER. Here we show that transfection of ER-positive, HER2 gene-amplified BT-74 cells with an expression vector encoding dominant-negative (K179M) Akt1 partially restored the ability of tamoxifen to inhibit estradiol-stimulated ER reporter activity. Infection of MCF-7 cells with an adenovirus encoding myristoylated, constitutively active Akt induced ER reporter activity in the absence of estradiol and resulted in tamoxifen resistance of these cells in culture. Data will be presented to suggest that, in addition to mitogen-activated protein kinase, Akt is an important mediator of HER2-mediated antiestrogen resistance in human breast cancer cells.
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PMID:ErbB (HER) receptors can abrogate antiestrogen action in human breast cancer by multiple signaling mechanisms. 1253 8

Recent evidence suggests that common molecular adaptations occur during resistance to both tamoxifen and estrogen deprivation that use various signal transduction pathways, often involving cross-talk with a retained and functional estrogen receptor (ER) protein. There appear to be several different levels at which this cross-talk may occur, including peptide growth factor signaling via the type 1 tyrosine kinase growth factor receptor family [epidermal growth factor receptor (EGFR) and HER2], which may become up-regulated during endocrine treatment, ultimately being harnessed by cells to allow them hormone-independent growth. ER may remain involved in cell growth with ligand-independent phosphorylation and activation via different intracellular mitogen-activated protein kinases. ER may also become involved in non-nuclear estrogen-dependent signaling via interaction with the phosphatidylinositol 3'-kinase/Akt cell survival pathway or may interact with the stress-activated protein kinase/c-Jun-NH(2)-terminal kinase pathway. Understanding these mechanisms will permit the optimal integration of new signal transduction inhibitors (STIs) into breast cancer therapy. Preclinical approaches that have shown promise include the use of EGFR tyrosine kinase inhibitors for hormone-resistant breast cancer cells that are dependent on either EGFR or HER2 signaling. Likewise, farnesyl transferase inhibitors, mitogen-activated protein kinase inhibitors, and cell cycle inhibitors have all shown activity in experimental breast cancer models. Emerging data suggest that STIs may be more effective when given in combination with endocrine therapy either to overcome resistance or to prevent/delay emergence of the resistance phenotype. Clinical trials are in progress to determine the safety and optimal schedule for each of the various STIs, and studies of STIs in combination with aromatase inhibitors have commenced in breast cancer to see whether the therapeutic response to endocrine therapy can be enhanced further.
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PMID:Integration of signal transduction inhibitors with endocrine therapy: an approach to overcoming hormone resistance in breast cancer. 1253 10

Insulin-like growth factors (IGFs) stimulate breast cancer proliferation, motility, and survival. The type I IGF receptor (IGF1R) mediates the effects of IGF-I. Thus, inhibition of IGF1R activation could inhibit IGF action in breast cancer cells. A single-chain antibody directed against IGF1R (IGF1R scFv-Fc) has been shown to partially inhibit xenograft growth of MCF-7 cells in athymic mice. In this study, we have examined the effects of scFv-Fc on IGF1R signaling in the estrogen receptor-positive (ER+) MCF-7 breast cancer cells in vitro and in vivo. The antibody stimulated IGF1R activation in vitro in MCF-7 cells and was unable to block IGF-I effects. The antibody also stimulated proliferation of MCF-7 cells in monolayer growth assays. To determine how scFv-Fc could stimulate in vitro growth yet inhibit in vivo tumor growth, we examined the effect of scFv-Fc on IGF1R expression. In MCF-7 cells, scFv-Fc down-regulated IGF1R levels after 2 h, and the levels were greatly reduced after 24 h. In contrast, IGF-I treatment over the same time period did not affect IGF1R levels. Twenty-four-h pretreatment of cells with scFv-Fc blocked IGF-I mediated phosphorylation of insulin receptor substrate-1 and subsequent extracellular signal-regulated kinase 1/extracellular signal-regulated kinase 2 and phosphatidylinositol 3'-kinase activation. In contrast, cells treated with 5 nM IGF-I for 24 h still retained the ability to further activate downstream signaling pathways in response to IGF-I. Moreover, pretreatment of MCF-7 cells with scFv-Fc rendered them refractory to further proliferation induced by additional IGF-I. Twenty-four-h pretreatment of cells with scFv-Fc also inhibited IGF-I stimulated anchorage-independent growth. scFv-Fc did not enhance antibody-dependent cell-mediated cytotoxicity. In vivo, treatment of mice bearing MCF-7 xenograft tumors with scFv-Fc resulted in near complete down-regulation of IGF1R. Our data show that scFv-Fc stimulates biochemical activation of IGF1R, then causes receptor down-regulation, making MCF-7 cells refractory to additional IGF-I exposure. These results indicate that such chimeric single-chain antibodies against IGF1R have future potential in breast cancer therapy by causing down-regulation of receptor.
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PMID:A chimeric humanized single-chain antibody against the type I insulin-like growth factor (IGF) receptor renders breast cancer cells refractory to the mitogenic effects of IGF-I. 1256 6

The ability of estrogen to rapidly initiate a variety of signal transduction cascades is increasingly recognized as playing an important role in a number of tissue-specific transcriptional actions of the hormone. In vivo, estrogen rapidly elicits phosphorylation of cAMP response element-binding protein (CREB). We have previously shown that both ER alpha and ER beta are capable of activating the MAPK pathway in response to a low dose of 17beta-estradiol. In the present study, the ability of estrogen to act through both ER alpha and ER beta to increase CREB phosphorylation was evaluated in an immortalized hippocampal cell line stably expressing either receptor. Estrogen treatment promoted rapid CREB phosphorylation, reaching a maximum by 15 min. This activation is completely blocked by the antiestrogen ICI 182,780, suggesting an estrogen receptor-dependent mechanism. The addition of the mitogen/ERK kinase-1 inhibitor, PD98059, also blocked the ability of estrogen to signal to CREB phosphorylation. Estrogen also caused an increase in p90Rsk activity, a critical mediator of MAPK effects. Surprisingly, blockade of the protein kinase A pathway in cells treated with estrogen did not affect estrogen-mediated CREB phosphorylation. Thus, MAPK and p90Rsk appear to be the primary mediators of estrogen-induced gene transcription through ER alpha and ER beta.
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PMID:Estrogen activation of cyclic adenosine 5'-monophosphate response element-mediated transcription requires the extracellularly regulated kinase/mitogen-activated protein kinase pathway. 1258 59

We examined the effects of maternal exposure to estrogens on platelet-derived growth factor (PDGF) receptor (PDGFR) expression in newborn rat testis. Pregnant rats were treated from gestation Day 14 to birth with corn oil containing diethylstilbestrol, bisphenol A, genistein, or coumestrol by gavage or subcutaneous injection. These treatments induced a dose-dependent increase in the expression of PDGFR alpha and beta mRNAs, determined by semiquantitative reverse transcription polymerase chain reaction, though diethylstilbestrol had a biphasic effect on both mRNAs. In situ hybridization analysis showed that PDGFRalpha mRNA increased mostly in the interstitium, while PDGFRbeta mRNA increased both in the interstitium and seminiferous cords. Immunohistochemical studies of PDGFRalpha and beta proteins revealed that both receptors were present in testis before and after birth and that they were upregulated upon treatment with estrogens in 3-day-old rats, with PDGFRbeta increasing dramatically in gonocytes. PDGFRalpha and beta mRNAs and proteins were also found in purified gonocytes. Our previous finding that PDGF and 17beta-estradiol induce gonocyte proliferation in vitro, together with the present finding that in vivo exposure to estrogens upregulates PDGF receptors in testis, suggest that PDGF pathway is a target of estrogens in testis. In addition, these data identify PDGFRbeta in gonocytes as a major target of gestational estrogen exposure, suggesting that estrogen may have a physiological interaction with PDGF during gonocyte development. These results, however, do not exclude the possibility that the effects of the compounds examined in this study might be due to estrogen receptor-independent action(s).
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PMID:Prenatal exposure to estrogenic compounds alters the expression pattern of platelet-derived growth factor receptors alpha and beta in neonatal rat testis: identification of gonocytes as targets of estrogen exposure. 1260 37


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