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: UMLS:C0006142 (breast cancer)
160,383 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The insulin receptor (IR) form hybrids with the closely related insulin-like growth factor-I (IGF-I) receptor (IGF-I-R). Because most human breast carcinomas overexpress both the IR and the IGF-I-R, we evaluated whether the insulin/IGF-I hybrid receptor (Hybrid-R) is also overexpressed in these tumors and what role it plays in breast cancer biology. Using specific ELISAs and Western blots, we measured Hybrid-R content and function in 8 human cultured breast cancer cell lines and 39 human breast cancer specimens. Hybrid-R content and function were also compared to the content and function of the IR and the IGF-I-R. Hybrid-R content exceeded the IGF-I-R content in >75% of breast cancer specimens and was directly related to the molar ratio of both the IR and IGF-I-R content, suggesting that Hybrid-R formation occurred by random assembly of IR and IGF-I-R half-receptors. Hybrid-Rs became tyrosine autophosphorylated when breast cancer cells were exposed to IGF-I but not when they were exposed to insulin. In cells with an elevated Hybrid-R content, Hybrid-R autophosphorylation in response to IGF-I exceeded IGF-I-R autophosphorylation, suggesting that most of the IGF-I effect occurred via the Hybrid-R. Furthermore, Hybrid-Rs mediated growth in response to IGF-I, as indicated by experiments with blocking antibodies to the IGF-I-R. These data indicated therefore that: (a) Hybrid-Rs are present and play a major role in mediating the IGF-I signal in breast cancer; (b) their expression is directly related to IR overexpression; and (c) potential therapies designed to block IGF-I actions in breast cancer must take into account the role of these Hybrid-Rs.
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PMID:Insulin and insulin-like growth factor-I (IGF-I) receptor overexpression in breast cancers leads to insulin/IGF-I hybrid receptor overexpression: evidence for a second mechanism of IGF-I signaling. 1043 Jan 1

The epidermal growth factor receptor (EGFR) tyrosine kinase has an essential function for the survival of human breast cancer cells. In a systematic effort to design potent and specific inhibitors of this receptor family protein tyrosine kinase (PTK) as antibreast cancer agents, we recently reported the construction of a three-dimensional homology model of the EGFR kinase domain. In this model, the catalytic site is defined by two beta-sheets that form an interface at the cleft between the NH2-terminal and COOH-terminal lobes of the kinase domain. Our modeling studies revealed a distinct, remarkably planar triangular binding pocket within the kinase domain with approximate dimensions of 15 A x 12 A x 12 A, and the thickness of the binding pocket is approximately 7 A with an estimated volume of approximately 600 A3 available for inhibitor binding. Molecular docking studies had identified alpha-cyano-beta-hydroxy-beta-methyl-N-[4-(trifluoromethoxy)phenyl]-p ropenamide (LFM-A12) as our lead inhibitor, with an estimated binding constant of 13 microM, which subsequently inhibited EGFR kinase in vitro with an IC50 value of 1.7 microM. LFM-A12 was also discovered to be a highly specific inhibitor of the EGFR. Even at very high concentrations ranging from 175-350 microM, this inhibitor did not affect the enzymatic activity of other PTKs, including the Janus kinases JAK1 and JAK3, the Src family kinase HCK, the Tec family member Bruton's tyrosine kinase, SYK kinase, and the receptor family PTK insulin receptor kinase. This observation is in contrast to the activity of a quinazoline inhibitor tested as a control, 4-(3-bromo, 4-hydroxyanilino)-6,7-dimethoxyquinazoline, which was shown to inhibit EGFR and other tyrosine kinases such as HCK, JAK3, and SYK.
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PMID:Specificity of alpha-cyano-beta-hydroxy-beta-methyl-n-[4-(trifluoromethoxy)phe nyl]-propenamide as an inhibitor of the epidermal growth factor receptor tyrosine kinase. 1063 69

The ligands, receptors and related signaling proteins of the insulin-like growth factor family are involved in the regulation of breast-cancer cell growth. We investigated the expression pattern of insulin-like growth factor-I receptor (IGF-IR), insulin receptor (IR) and insulin receptor substrate-1 (IRS-1), a core downstream signaling protein, in 69 primary breast-cancer specimens of different grades and in 21 control tissues by immunohistochemistry. In addition, cell proliferation (percentage of Ki67(+) nuclei) and estrogen receptor (ER) expression were determined. IGF-IR, IRS-1 and IR were expressed mainly in epithelial cells. IRS-1 and IGF-IR were expressed at high levels in control tissues and in well and moderately differentiated carcinomas but at low levels in poorly differentiated breast cancers. IR expression did not show a significant correlation with the differentiation grade of the tissues investigated. Statistical analysis (ROC analysis for tumor grade) demonstrated that down-regulation of IGF-IR and IRS-1 correlated better with tumor progression than reduction of ER expression or increase in cell proliferation, IGF-IR showing the best correlation, followed by IRS-1 and, less significant, ER and Ki67. Our findings clearly show that progression of breast cancer is accompanied by a reduction of IGF-IR/IRS-1 expression and that IGF-IR/IRS-1 expression inversely correlates with high proliferation rate in dedifferentiated breast cancers. The strong correlation of IGF-IR and IRS-1 down-regulation with tumor progression suggests the use of IGF-IR and IRS-1 as a novel set of marker proteins for tumor grading.
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PMID:Down-regulation of insulin-like growth factor-I receptor and insulin receptor substrate-1 expression in advanced human breast cancer. 1110 95

Mitogen-activated protein (MAP) kinase mediates cell proliferation, cell differentiation, and cell survival by regulating signaling pathways activated by receptor protein tyrosine kinases (RPTKs), including the insulin-like growth factor 1 receptor (IGF-IR). We analyzed the upstream signaling components of the MAP kinase pathway, including RPTKs, in human breast cancer cell lines and found that some of those components were overexpressed. Importantly, signaling molecules such as IGF-IR, insulin receptor, and insulin receptor substrate 1, leading to the MAP kinase pathway, were found to be concomitantly overexpressed within certain tumor lines, i.e., MCF-7 and T-47D. When compared with the nonmalignant and other breast tumor lines examined, MCF-7 and T-47D cells displayed a more rapid, robust, and sustained MAP kinase activation in response to insulin-like growth factor I (IGF-I) stimulation. By contrast, IGF-I treatment led to a sustained down-regulation of MAP kinase in those lines overexpressing ErbB2-related RPTKs. Interestingly, blocking the MAP kinase pathway with PD098059 had the greatest antiproliferative effect on MCF-7 and T-47D among the normal and tumor lines tested. Furthermore, addition of an IGF-IR blocking antibody to growth medium attenuated the ability of PD098059 to suppress the growth of MCF-7 and T-47D cells. Thus, our study suggests that concomitant overexpression of multiple signaling components of the IGF-IR pathway leads to the amplification of IGF-I-mediated MAP kinase signaling and resultant sensitization to PD098059. The enhanced sensitivity to PD098059 implies an increased requirement for the MAP kinase pathway in those breast cancer cells, making this pathway a potential target in the treatment of selected breast malignancies.
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PMID:Inhibition of mitogen-activated protein kinase kinase selectively inhibits cell proliferation in human breast cancer cells displaying enhanced insulin-like growth factor I-mediated mitogen-activated protein kinase activation. 1114 1

PS6K, a putative oncogene mapped to chromosome 17q23, encodes a serine/threonine kinase, which phosphorylates ribosomal subunit 6 and is part of the insulin receptor signal transduction pathway involved in the regulation of messenger RNA translation, protein synthesis, cell cycle progression, and cell size. Comparative genomic hybridization studies have detected 17q23 amplifications in a subset of meningiomas, particularly those with aggressive histologic features. PS6K amplifications have been reported in breast cancer, another hormonally driven neoplasm. We assessed PS6K dosage in 94 archival paraffin-embedded meningiomas using dual-color fluorescence in situ hybridization. We found high-level PS6K amplifications in 3 of 22 anaplastic grade III meningiomas. Amplification was confirmed by differential polymerase chain reaction in 1 of these cases. In contrast, no amplifications were identified in 37 benign (grade I) and 35 atypical (grade II) meningiomas. To our knowledge, this represents the first report of gene amplification in primary human meningiomas. Given its exclusive association with anaplastic meningiomas, PS6K amplification likely occurs during the malignant progression of a small subset of anaplastic tumors. Further studies are needed to map the 17q23 amplicon to determine whether additional genes in this region are amplified in high-grade meningiomas.
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PMID:PS6K amplification characterizes a small subset of anaplastic meningiomas. 1121 9

The tumour suppressor gene PTEN encodes a dual-specificity phosphatase that recognizes protein substrates and phosphatidylinositol-3,4,5-triphosphate. PTEN seems to play multiple roles in tumour suppression and the blockade of phosphoinositide-3-kinase signalling is important for its growth suppressive effects, although precise mechanisms are not fully understood. In this study, we show that PTEN plays a unique role in the insulin-signalling pathway in a breast cancer model. Ectopic expression of wild-type PTEN in MCF-7 epithelial breast cancer cells resulted in universal inhibition of Akt phosphorylation in response to stimulation by diverse growth factors and selective inhibition of MEK/extracellular signal-regulated kinase (ERK) phosphorylation stimulated by insulin or insulin-like growth factor 1 (IGF-1). The latter was accompanied by a decrease in the phosphorylation of insulin receptor substrate 1 (IRS-1) and the association of IRS-1 with Grb2/Sos, without affecting the phosphorylation status of the insulin receptor and Shc, nor Shc/Grb2 complex formation. The MEK inhibitor, PD980059, but not the PI3K inhibitor, wortmannin, abolished the effect of PTEN on insulin-stimulated cell growth. Without addition of insulin, wortmannin reduced PTEN-mediated growth suppression, whereas PD980059 had little effect, suggesting that PTEN suppresses insulin-stimulated cell growth by blocking the mitogen-activated protein kinase (MAPK) pathway. Furthermore, PD980059 treatment led to the downregulation of cyclin D1 and the suppression of cell cycle progression. Our data suggest that PTEN blocks MAPK phosphorylation in response to insulin stimulation by inhibiting the phosphorylation of IRS-1 and IRS-1/Grb2/Sos complex formation, which leads to downregulation of cyclin D1, inhibition of cell cycle progression and suppression of cell growth.
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PMID:PTEN inhibits insulin-stimulated MEK/MAPK activation and cell growth by blocking IRS-1 phosphorylation and IRS-1/Grb-2/Sos complex formation in a breast cancer model. 1123 Jan 80

Hyperandrogenism observed in women with a variety of insulin-resistant states is thought to be due to a stimulatory effect of insulin on ovarian steroid hormone production. However, it is not known what mechanisms could allow the ovary to remain sensitive to insulin while classical target organs for insulin action (liver, fat, and muscle) exhibit insulin resistance. One hypothesis proposed to explain this paradox suggests that a postbinding divergence of insulin receptor signaling occurs in the ovary and that signaling pathways for steroid hormone synthesis and other ovarian effects of insulin may be distinct from classical glucose signaling pathways. We now report that activation of phosphatidyl-inositol-3 (PI-3) kinase, which is crucial for glucose transport, is not necessary for the insulin-induced stimulation of progesterone production or for the insulin-induced inhibition of insulin-like growth factor binding protein 1 (IGFBP-1) production in cultured human ovarian cells. Human granulosa cells obtained during in vitro fertilization procedures were cultured with 10, 10(2), 10(3), or 10(4) ng/mL insulin with or without preincubation with 100 nM wortmannin, a specific irreversible inhibitor of PI-3 kinase. IGFBP-1 concentration in the conditioned medium was measured using immunoradiometric assay or by Western blot analysis. Progesterone concentration was measured using RIA. Additional studies were carried out in cultures of human ovarian cells prepared from homogenized whole ovarian tissue of a woman with a family history of breast cancer and a mutation of BRCA-1 gene who underwent bilateral oophorectomy. These cells were cultured with 10(3) ng/mL insulin with or without preincubation with 100 nM wortmannin. Two-way ANOVA was used to compare mean values of IGFBP-1 and progesterone according to insulin dose and the use of wortmannin. In cultured granulosa cell medium, progesterone production was stimulated by insulin in a dose-related manner up to 175% of control (P < 0.0001). In tissue culture medium from ovarian cells obtained from a patient with BRCA-gene mutation, concentration of progesterone in the tissue culture medium increased from 2.5 +/- 0.2 ng/mL for control to 5.4 +/- 0.3 ng/mL for cells incubated with insulin (P < 0.001). IGFBP-1 production in tissue culture medium from human granulosa cells was inhibited by insulin to the nadir of 45% of control (P < 0.0001). Preincubation with wortmannin, despite complete inhibition of PI-3 kinase in both cell systems confirmed by Western blot analysis, failed to significantly alter these results. We conclude that inhibition of PI-3 kinase by wortmannin fails to abolish stimulatory effect of insulin on progesterone production or inhibitory effect of insulin on IGFBP-1 production in cultured human ovarian cells. These findings suggest that activation of PI-3 kinase, an enzyme crucial for insulin-stimulated glucose transport, is not necessary for the above effects of insulin in the ovary. These data provide evidence for the presence of PI-3 kinase-independent insulin signaling pathway(s) in human ovarian cells.
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PMID:Phosphatidyl-inositol-3 kinase-independent insulin action pathway(s) in the human ovary. 1144 75

In this study, we report on the isolation of a PDZ domain protein, here designated as IIP-1, insulin-like growth factor-1 (IGF-1) receptor-interacting protein-1, which binds to the IGF-1 receptor, but not to the related insulin receptor, and which is involved in the regulation of cell motility. The interaction between the IGF-1 receptor and IIP-1 as well as a splice variant IIP-1/p26 was demonstrated in the yeast two-hybrid system. Using co-precipitation experiments, we confirmed the interaction in transfected cells as well as in vitro. Analysis of deletion mutants indicates that the PDZ domain of IIP-1 mediates interaction with the C-terminal tail of the IGF-1 receptor (serine-threonine-cysteine). This finding demonstrates that the C terminus of the IGF-1 receptor acts as novel PDZ domain binding site. Immunofluorescence analysis revealed an overlapping localization of IIP-1 and the IGF-1 receptor in the breast cancer cell line MCF-7. A functional connection between IIP-1 and the IGF-1 receptor is further supported by the finding that the level of expression of IIP-1 and the IGF-1 receptor strongly correlates in different normal and cancer cells. Furthermore, overexpression of IIP-1 resulted in an attenuation of migration of MCF-7 cells, which is one of the biological activities mediated by the IGF-1 signaling system.
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PMID:A PDZ domain protein interacts with the C-terminal tail of the insulin-like growth factor-1 receptor but not with the insulin receptor. 1144 79

The insulin-like growth factor I receptor (IGF-IR) is overexpressed in many diverse tumor types and is a critical signaling molecule for tumor cell proliferation and survival. Therapeutic strategies targeting the IGF-IR may therefore be effective broad-spectrum anticancer agents. Through screening of a Fab phage display library, we have generated a fully human antibody (A12) that binds to the IGF-IR with high affinity (4.11 x 10(-11) M) and inhibits ligand binding with an IC(50) of 0.6-1 nM. Antibody-mediated blockade of ligand binding to the IGF-IR inhibited downstream signaling of the two major insulin-like growth factor (IGF) pathways, mitogen-activated protein kinase and phosphatidylinositol 3'-kinase/Akt, in MCF7 human breast cancer cells. As a result, the mitogenic and proliferative potential of IGF-I and IGF-II were significantly reduced. A12 did not block insulin binding to the insulin receptor but could block binding to atypical IGF-IR in MCF7 cells. In addition, A12 was shown to induce IGF-IR internalization and degradation on specific binding to tumor cells, resulting in a significant reduction in cell surface receptor density. In xenograft tumor models in vivo, IGF-IR blockade by A12 was shown to occur rapidly, resulting in significant growth inhibition of breast, renal, and pancreatic tumors. Histological analysis of tumor sections demonstrated a marked increase in apoptotic tumor cells in antibody-treated animals. These results demonstrate that A12 possesses strong antitumor activity in vitro and in vivo and may therefore be an effective therapeutic candidate for the treatment of cancers that are dependent on IGF-IR signaling for growth and survival.
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PMID:A fully human monoclonal antibody to the insulin-like growth factor I receptor blocks ligand-dependent signaling and inhibits human tumor growth in vivo. 1469 8

Blockade of the estrogen receptor (ER) with antiestrogens and aromatase inhibitors is effective in the treatment of breast cancer. Why ER plays such a dominant role in breast cancer and represents such an excellent target remains to be defined. The ability of ER to respond to multiple inputs and to control expression of multiple downstream genes may be one of the reasons why ER is such a powerful target for breast cancer treatment. The recent modest performance of a number of targeted therapies in breast cancer has raised the question whether we will ever develop therapies that have such success as antiestrogens. Targeted therapies tend to inhibit a single pathway that is probably altered in only a subset of patients. Even within this subset, only a limited number of patients respond. The evidence that virtually all pathways can cross-talk and that they exhibit several layers of redundancy reveals a complexity of signaling networks that may defy the generation of targeted therapies with efficacy similar to antiestrogens. However, there are clearly regulatory nodes that can integrate multiple upstream inputs and elicit diverse downstream outputs. We provide evidence and rationales for integrins, insulin receptor substrates (IRSs), and cyclin D1 as potential therapeutic targets. These proteins, similar to ER, can integrate and coordinate multiple signals in breast cancer cells and thus mediate diverse aspects of breast cancer progression. New treatment targets will emerge in light of more global models of signal transduction that fully integrate all aspects of cell biology such as the role of the extracellular matrix and will hopefully result in the development of targeted therapies that show efficacy similar to antiestrogens.
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PMID:Regulatory nodes that integrate and coordinate signaling as potential targets for breast cancer therapy. 1473 98


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