Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P04626 (erbB-2)
 5,251 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Malignant Balb/c mouse lung cell clones related to alveologenic carcinoma exhibited low levels of epidermal growth factor (EGF) receptor activity compared to nonmalignant cell clones. Immunoprecipitation of cell homogenates and immunohistochemistry on urethane-induced lung tumors suggest that the absence of activity reflects decreased amounts of EGF receptor protein. Low levels of EGF receptor alone cannot cause neoplastic transformation, since a nonneoplastic cell cone, B5D3, exhibited low levels of EGF receptor despite its nontransformed phenotype. The reduced levels of EGF receptor in malignant clones have been mimicked by long-term (12 h) treatment of a nontransformed cell clone with 200 nM phorbol dibutyrate. The detection of mutated ras oncogene in the transformed cell lines, taken together with the EGF receptor findings, suggests that more than one alteration in the signal transduction pathway may be necessary for transformation in alveologenic adenoma and carcinoma cell systems. A further phenotypic feature of transformation, reduced expression of the extracellular matrix proteins fibronectin and laminin, may be mediated at the transcriptional level.
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PMID:EGF-receptor and extracellular matrix changes in mouse pulmonary carcinogenesis. 205 35

The effects of 13-cis retinoic acid (RA) and dexamethasone on the levels of epidermal growth factor (EGF) receptor and fibroblast derived proteoglycan core protein (PG40) mRNAs were studied in human skin fibroblasts. The EGF receptor is involved in the regulation of cellular proliferation and the synthesis of matrix proteins, and proteoglycan 40 is important for cell attachment and interaction with collagen and fibronectin. 13-cis-RA at a concentration of 10(-7) M markedly reduced the levels of the EGF receptor and PG40 mRNAs, the decreases being 33 and 56%, respectively. Dexamethasone reduced these mRNAs markedly less. Simultaneous treatment of the fibroblasts with 13-cis-RA and dexamethasone resulted in similar decreases in EGF receptor and PG40 mRNAs as with 13-cis-RA alone. Surprisingly, the proliferation rate of the fibroblasts was increased in the presence of dexamethasone under conditions similar to those which caused slight decrease in the EGF receptor mRNA levels. This indicates that glucocorticoids also affect the cellular growth by mechanisms which do not involve EGF receptors.
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PMID:13-cis retinoic acid and dexamethasone modulate the gene expression of epidermal growth factor receptor and fibroblast proteoglycan 40 core protein in human skin fibroblasts. 257 17

Alterations in the structure and/or expression of oncogenes have been examined to comprehend better the relationship between metastasis and oncogenes. There are reports that amplification and overexpression of N-myc (human neuroblastoma) and erbB-2 (human breast cancer) are closely related to malignant progression. On the other hand, DNA transfer experiments have also been done to assess involvement of oncogenes in metastasis. The active ras oncogenes, which are frequently used, show that transfer of the ras oncogenes endow and/or enhance the metastatic potential of the recipient cells. In addition to the phenomenological studies to determine whether an oncogene alters metastatic potential, increasing attention has been directed to possible phenotypic changes relating to metastasis and affected by oncogenes. It has been clarified that transfer of a certain oncogene, such as ras and fos, alters the expression of biomolecules, for example, metalloproteinases responsible for invasion, autocrine motility factors and cytoskeletal proteins related to cell motility, receptors of fibronectin for cell attachment, and histocompatibility antigens, such as H-2K and H2-D. While further characterization of the biomolecular changes induced by the oncogenes has to be done, the mechanisms of alteration in the expression and function of biomolecules directly involved in the metastatic potential also should be paid attention.
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PMID:[Cancer metastasis and oncogenes]. 267 90

Some human neoplasms show aberrant expression or overexpression of epidermal growth factor (EGF) receptor, and the degree of the receptor expression is correlated with the malignant phenotype in certain epithelial tumors including squamous carcinoma cells. Since phenotypic transformation of cells could involve quantitative and qualitative alteration of integrin function, the effects of EGF on cell-matrix interactions were studied using HSC-1 cells, a human squamous carcinoma cell line showing EGF receptor overexpression. The EGF-treated HSC-1 cells interacted with matrix proteins differently from the untreated cells, as shown by cell adhesion and phagokinetic track assays. Among fibronectin, laminin, fibrinogen, and type I collagen, fibronectin was the most efficient substratum to promote untreated HSC-1 cell adhesion and migration. Pretreatment of the cells with 50 ng/ml EGF for 18 h selectively increased the number of spread cells and the size of the individual cell migration area on type I collagen by 250 and 400%, respectively. The same pretreatment diminished cell adhesion and migration on other substrata so that the EGF treatment converted type I collagen as the most efficient substratum for cell adhesion and migration of the HSC-1 cells. ELISA and immunoprecipitation studies showed that EGF up-regulated the expression of alpha 2 beta 1 integrin collagen receptor in a time- and dose-dependent manner by stimulating biosynthesis of alpha 2 subunit, but did not up-regulate those of the alpha 3 beta 1, alpha 5 beta 1, or alpha v beta 3 integrins. These results suggest that EGF preferentially enhances HSC-1 cell interaction with type I collagen, leading to the enhanced cellular migratory activity on the substratum, as a result of selective up-regulation of alpha 2 beta 1 integrin expression.
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PMID:Epidermal growth factor enhancement of HSC-1 human cutaneous squamous carcinoma cell adhesion and migration on type I collagen involves selective up-regulation of alpha 2 beta 1 integrin expression. 752 89

Overexpression of the proto-oncogene product, p185neuN, in a non-tumorigenic mammary epithelial line (31E) facilitates aspects of lactogenic differentiation. Formation of branching cords and induction of beta-casein synthesis by 31E cells normally require co-culture of these cells with fibroblasts, or the presence of collagen or fibronectin. In contrast, 31E cells expressing p185neuN spontaneously form branching cords when grown on tissue culture plastic and can synthesize beta-casein in the absence of exogenous substrates or feeder layers. Under these conditions, the cells deposit laminin and fibronectin, indicating a possible role for p185neuN in the deposition of extracellular matrix proteins. Overexpression of the corresponding oncogene product, p185neuT, has markedly different effects. Expression of p185neuT does not facilitate the formation of branching cords or the synthesis of beta-casein when grown on tissue culture plastic, although these cells do deposit laminin and fibronectin. Confocal microscopy indicates a significant difference in the distribution of laminin and fibronectin in 31E cells expressing p185neuT compared to those expressing p185neuN. The effects of p185neuN and p185neuT expression on cell transformation depend on cell type. Expression of both p185neuN and p185neuT increases anchorage-independent growth of 31E cells, but only p185neuT induces anchorage-independent growth of NIH 3T3 fibroblasts. This lineage specificity in the action of p185neuN may be related to observations that overexpression of p185c-erbB-2 (the human homologue of p185neuN) is only associated with the development of human epithelial cancers. The effects of p185neuN on laminin deposition by 31E cells may be relevant to the transforming ability of p185neuN, since laminin can induce anchorage-independent growth of mouse mammary cells. These results suggest that p185neuN and p185neuT could exert their effects on differentiation and transformation of mammary epithelial cells in part by promoting the deposition of extracellular matrix proteins.
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PMID:The effects of the neuN and neuT genes on differentiation and transformation of mammary epithelial cells. 787 57

Eph, Elk, and Eck are prototypes of a large family of transmembrane protein-tyrosine kinases, which are characterized by a highly conserved cysteine-rich domain and two fibronectin type III repeats in their extracellular regions. Despite the extent of the Eph family, no extracellular ligands for any family member have been identified, and hence, little is known about the biological and biochemical properties of these receptor-like tyrosine kinases. In the absence of a physiological ligand for the Elk receptor, we constructed chimeric receptor molecules, in which the extracellular region of the Elk receptor is replaced by the extracellular, ligand-binding domain of the epidermal growth factor (EGF) receptor. These chimeric receptors were expressed in NIH 3T3 cells that lack endogenous EGF receptors to analyze their signaling properties. The chimeric EGF-Elk receptors became glycosylated, were correctly localized to the plasma membrane, and bound EGF with high affinity. The chimeric receptors underwent autophosphorylation and induced the tyrosine phosphorylation of a specific set of cellular proteins in response to EGF. EGF stimulation also induced DNA synthesis in fibroblasts stably expressing the EGF-Elk receptors. In contrast, EGF stimulation of these cells did not lead to visible changes in cellular morphology, nor did it induce loss of contact inhibition in confluent monolayers or growth in semisolid media. The Elk cytoplasmic domain is therefore able to induce tyrosine phosphorylation and DNA synthesis in response to an extracellular ligand, suggesting that Elk and related polypeptides function as ligand-dependent receptor tyrosine kinases.
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PMID:Biological and biochemical activities of a chimeric epidermal growth factor-Elk receptor tyrosine kinase. 841 96

The adhesion of different epidermal growth factor (EGF) receptor (EGFR) expressing cell lines to various extracellular matrix (ECM) proteins is influenced by EGF. To investigate a putative receptor crosstalk between EGFR and integrins we chose two cell lines for a more detailed analysis: the highly metastatic rat mammary carcinoma clone MTLn3 that showed increased adhesion to a panel of ECM proteins in the presence of 10 ng/ml EGF and the nonmetastatic human vulva carcinoma cell line A431 which showed a decreased adhesion under the same conditions. These EGF-mediated stimulatory or inhibitory effects on adhesion were observed within a few minutes. On human A431 cells the inhibitory effect was blocked by an EGFR specific antibody that interferes with ligand binding. In cell adhesion assays performed in the presence of divalent cations MTLn3 and A431 cells exhibited the typical behavior described for integrin-dependent matrix adhesion: Mn2+ enhanced binding to collagen IV and fibronectin whereas Ca2+ inhibited adhesion to collagen IV but not to fibronectin. Adhesion-inhibition assays with anti-human integrin antibodies revealed that A431 cells adhere to collagen via alpha 1 beta 1 and alpha 2 beta 1, and that adhesion to fibronectin is mediated predominantly through alpha 5 beta 1. The interaction of MTLn3 cells with fibronectin was in part RGD dependent, indicating the involvement of either alpha 3 beta 1 or alpha 5 beta 1. Addition of EGF in these assays showed that affecting the integrin extracellular domains by addition of either bivalent cations, RGD peptides, or function-blocking integrin antibodies did not prevent the effects mediated by EGF. We conclude that signals downstream of EGFR can modulate integrin-mediated adhesion to ECM proteins in both an inhibitory and a stimulatory manner.
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PMID:Signaling by epidermal growth factor differentially affects integrin-mediated adhesion of tumor cells to extracellular matrix proteins. 891 81

The interaction between laminin and the oncoprotein encoded by the c-erbB-2 oncogene was studied in vitro and in vivo in human breast carcinomas. In vitro analysis of breast carcinoma cell lines overexpressing p185HER2 revealed that laminin, but not fibronectin, induced tyrosine phosphorylation and down-modulation of oncoprotein membrane expression. Laminin also specifically inhibited growth of p185HER2-positive cell lines. No direct binding between the recombinant extracellular domain of p185HER2 and laminin was found. Induction of oncoprotein down-modulation by anti-integrin antibodies and coprecipitation of the oncoprotein with the beta 4 integrin subunit indicate that the interaction between p185HER2 and laminin occurs through integrin molecules. The relevance of this in vitro observation was verified in vivo by analysing the prognostic value of p185HER2 overexpression as a function of laminin production on archival paraffin-embedded sections of 887 primary breast tumours. The results revealed an association between p185HER2 overexpression and unfavourable prognosis in tumours negative for laminin production, whereas in laminin-producing tumours, the oncoprotein overexpression was not associated with tumour aggressiveness.
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PMID:Laminin activates the p185HER2 oncoprotein and mediates growth inhibition of breast carcinoma cells. 891 40

Matrix metalloproteinases (MMPs) are a group of enzymes thought to be responsible for both normal connective tissue matrix remodelling and accelerated breakdown associated with tumour development. The current study aimed to investigate the immunohistochemical expression of matrix metalloproteinase 3 (MMP-3, stromelysin-1) in correlation with the expression of Basement Membrane (BM) antigen (type IV collagen, laminin), fibronectin, cathepsin D, p53, c-erbB-2, proliferative activity (Ki-67, PCNA), steroid receptor content as well as to the other conventional clinicopathological parameters in breast cancer. This study was performed on a series of frozen and paraffin sections from 84 breast cancer specimens by immunohistochemistry using the monoclonal antibody MMP-3 (Ab-1). Stromelysin-1 (ST1) was observed in about 10% of epithelial cells in the control groups (cases of fibrocystic and benign proliferative breast disease), while expression (> 10% of expression) was detected in 89.7% of tumours. The expression of ST1 in carcinoma cells was strongly associated with its presence in the stroma (p < 0.001). A significantly positive correlation was found between ST1 expression, and p53 tumour suppressor gene product (p = 0.004), and a relationship with c-erbB-2 protein and progesterone receptor status was also indicated. These findings suggest that ST1 expression in breast cancer tissue is irrespective of the expression of the extracellular matrix component, the proteolytic enzyme cathepsin D and the growth fraction of the tumour, and that it could be a potential new prognostic marker in breast cancer.
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PMID:Matrix metalloproteinase expression in human breast cancer: an immunohistochemical study including correlation with cathepsin D, type IV collagen, laminin, fibronectin, EGFR, c-erbB-2 oncoprotein, p53, steroid receptors status and proliferative indices. 967 87

CD44 has diverse functions in cell-cell and cell-matrix interactions and may be a determinant of metastatic and invasive behaviour in carcinomas. The immunohistochemical expression of CD44 in a series of 110 colorectal carcinomas and 25 adenomas was examined using the monoclonal mouse anti-human phagocytic glycoprotein-1, CD44 (clone DF 1485) in correlation with the expression of basement membrane (BM) antigens (type IV collagen, laminin), fibronectin, cathepsin D, p53, Rb, bcl-2, c-erbB-2, EGFR, proliferation indices (Ki-67, PCNA) and with other conventional clinicopathological variables. In adenomas, low CD44 expression (<10% of neoplastic cells) was present in 16%, moderate (10-50% of neoplastic cells) in 52% and extensive (>50% of neoplastic cells) in 32% of cases. In carcinomas, low CD44 expression was found in 14.5%, moderate in 28.2% and extensive in 57.30%. Although the CD44 expression was higher in carcinomas than in adenomas, we found no statistically significant difference between these two groups. CD44 expression in carcinomas was positively correlated with tumour size (P=0.018), tumour cells cathepsin D (P=0.022), stromal cell cathepsin D (P=0.003) and Rb protein (P=0.021). An inverse correlation was observed between CD44 and the anti-apoptotic protein expression bcl-2 in adenocarcinomas (P=0.039) and in adenomas (P=0.021). These data suggest that CD44 may be involved in the process of invasion and metastasis, probably with the cooperation of cathepsin D. Its expression may be an indicator of poor prognosis in colorectal adenocarcinomas.
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PMID:Glycoprotein CD44 expression in colorectal neoplasms. An immuno-histochemical study including correlation with cathepsin D, extracellular matrix components, p53, Rb, bcl-2, c-erbB-2, EGFR and proliferation indices. 1007 Dec 34


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