UNIPROT:P04626 - FACTA Search

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Query: UNIPROT:P04626 (erbB-2)
5,251 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Previously we reported that neu differentiation factor (NDF)/heregulin (HRG) elevates tyrosine phosphorylation of its receptors erbB-3, erbB-4, and erbB-2 (through heterodimer formation). We also showed that both NDF/HRG and antibodies to erbB-2 can arrest growth and induce differentiation in breast cancer cells. In this study, we report on the mechanism of NDF/HRG-induced cellular effects. We show that NDF/HRG and antibodies to erbB-2 receptors up-regulate expression of p53 by stabilizing the protein. This is accompanied by up-regulation of the p53 inducible gene, p21CIP1/WAF1, in a variety of cell lines: MCF7 and their derivatives (MCF7/HER2, MN1 and MCF-7-puro), ZR75T and LnCap cells. The induction of p21 is further enhanced when cells are treated with both NDF/HRG and DNA-damaging chemotherapeutic agents (i.e. doxorubicin). The NDF/HRG mediated induction of p21 is dependent on wildtype p53, as it fails to occur in cells expressing dominant negative p53 (MDD2). Furthermore, p21 induction is capable of inactivating cdk2 complexes as measured by Histone H1 phosphorylation assays. Finally, we show that in primary cultures of breast and other cancers, p21 is significantly induced in response to NDF/HRG treatment. Collectively, these observations suggest that the mechanism of breast cancer cell growth inhibition and differentiation via erbB receptors activation is through a p53-mediated pathway.
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PMID:Neu differentiation factor (Heregulin) activates a p53-dependent pathway in cancer cells. 870 May 12

New retroviral constructs with a grafted specificity of infection could become useful gene delivery vehicles with applications in systemic gene therapy. We have constructed retroviral vectors to target gene transfer to human tumor cells. Chimeric envelope proteins have been expressed to obtain viral particles with a defined specificity of infection. Two tumor cell-specific recognition domains were cloned and fused with the viral envelope gene. A recognition domain specific for ErbB-2 expressing tumor cells was derived from a monoclonal antibody directed against the ErbB-2 receptor in the form of a single chain antibody domain (scFv-erbB-2). The receptor binding domain was derived from the heregulin gene (HRG70). This domain provides recognition specificity for ErbB-3 and ErbB-4 receptor expressing tumor cells. The recognition domains were inserted at the amino terminal end into the MoMLV envelope gene. Helper cell lines were established which express the recombinant envelope protein genes, the gag and pol genes and packageable retroviral RNA. The analysis of the helper cell line revealed that the recombinant ErbB-2 scFv-envelope protein was expressed, but not incorporated into viral particles. The scFv-erbB-2 envelope protein was not inserted into the cell membrane and the assembly of retroviral particles was not completed. In contrast, the HRG70-envelope protein was expressed on the surface of the helper cells and incorporated into retroviral particles. The HRG70-envelope protein, however, did not alter the host range of infection. Only cells expressing the ecotropic viral receptor could be infected.
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PMID:Expression of chimeric envelope proteins in helper cell lines and integration into Moloney murine leukemia virus particles. 873 65

Amplification and overexpression of the c-erbB-2 gene in 21MT-2 and 21MT-1 human breast carcinoma cells results in progressively elevated levels of constitutively tyrosine-phosphorylated p185erbB-2 and is associated with progressive insulin-like growth factor (IGF) and combined IGF/epidermal growth factor (EGF) independence in culture. In addition, the neu differentiation factor/heregulins (HRGs), a family of ligands that activate p185erbB-2 through direct binding to erbB-3 or erbB-4, are potent mitogens for various nonneoplastic mammary epithelial cells and carcinoma cell lines in the absence of both IGF and EGF in culture. We have investigated the ability of ligand induction with HRGs or the constitutive activation of p185erbB-2 in the 21MT breast carcinoma cells to induced the recruitment of phosphatidylinositol 3-kinase (PI3K) by p185erbB-2 and erbB-3. HRG was found to potently induce the recruitment of the M(r) 85,000 regulatory subunit of PI3K by phosphotyrosine proteins in both nonneoplastic H16N-2 mammary epithelial cells (which express normal c-erbB-2 levels) and in the 21MT-2 and 21MT-1 cell lines, which were all isolated from a single patient with intraductal and invasive ductal carcinoma of the breast and express c-erbB-3 but not c-erbB-4 in culture. The activation of PI3K in these cells was also associated with high-level mitogenic responsiveness to HRG, as well as the IGF/EGF-independent proliferation of the 21MT cell lines in culture. The recruitment of PI3K by phosphotyrosine protein during ligand-induced activation, or that seen constitutively in the 21MT tumor cells, did not involve detectable tyrosine phosphorylation of p85. The HRG-induced recruitment of p85 and the constitutive recruitment of p85 in the 21MT cell lines involved direct association with both p185erbB-2 and erbB-3, although greater levels were recruited directly by erbB-3. Wortmannin, a potent inhibitor of PI3K enzymatic activity, also blocked the autonomous proliferation of the 21MT cells, and this effect was reversible in long-term cultures. These data indicate that PI3K may be an especially important mediator of HRG-induced proliferation in mammary epithelial cells and is involved in the autonomous proliferation of growth factor-independent breast carcinoma cells with c-erbB-2 gene amplification.
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PMID:Phosphatidylinositol 3-kinase recruitment by p185erbB-2 and erbB-3 is potently induced by neu differentiation factor/heregulin during mitogenesis and is constitutively elevated in growth factor-independent breast carcinoma cells with c-erbB-2 gene amplification. 873 65

The erbB-2 receptor plays an important role in the prognosis of breast cancer. Amplification or overexpression of the erbB-2 proto-oncogene has been detected in 30% of breast cancers and is associated with poor patient prognosis. The significance of erbB-3 and erbB-4 in breast cancer is not yet known. The discovery of the growth factor heregulin (HRG) has allowed us to investigate a number of biological events that are regulated by erbB-2, -3, and -4 signal transduction. To determine the role of HRG in breast cancer tumor progression, we have developed an in vitro/in vivo model. We transfected HRG cDNA into the estrogen receptor (ER)-positive breast cancer cell line, MCF-7, and studied these cells as they progressed from a hormone-dependent to -independent phenotype. The biochemical and biological characteristics presented here demonstrate that overexpression of HRG induces morphological changes in MCF-7 cells as well as erbB-2, erbB-3, and erbB-4 autophosphorylation. MCF-7/ heregulin-transfected cells, which express relatively high levels of HRG, developed estrogen independence and resistance to antiestrogens in vitro and in vivo. This is consistent with a more aggressive hormone-independent phenotype. In contrast with control parental/wild-type cells, estradiol-mediated down-regulation of erbB-2 expression is blocked completely in this particular model system. These results indicate that HRG plays a role in the disruption of ER function. When a transient transfection with an ERE-CAT construct was introduced into these HRG-transfected MCF-7 cells, we observed that the ER was transcriptionally inactive. This suggests that ER signaling is altered in HRG-transfected cells. We observed that overexpression of HRG induces a more aggressive, hormone-independent phenotype that is most likely directly related to the constitutive activation of the erbB-2, erbB-3, and erbB-4 receptor signaling cascade. The data presented here suggest a close cross-regulation between the erbB-2/4 receptors and ER and provide new insights into the mechanism by which breast cancer cells acquire a hormone-independent phenotype.
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PMID:Involvement of heregulin-beta2 in the acquisition of the hormone-independent phenotype of breast cancer cells. 876 33

The erbB-2 receptor plays an important role in the prognosis of breast cancer and is expressed at high levels in nearly 30% of tumors in breast cancer patients. While evidence accumulates to support the relationship between erbB-2 overexpression and poor overall survival in human breast cancer, understanding of the biological consequence(s) of erbB-2 overexpression remains elusive. The discovery of heregulin has allowed us to identify a number of related but distinct biological endpoints which appear responsive to signal transduction through the erbB-2/4 receptor. These endpoints of growth, invasiveness, and differentiation have clear implications for the emergence, maintenance, and/or control of malignancy, and represent established endpoints in the assessment of malignant progression in human breast cancer. Preliminary studies in vitro have shown that heregulin induces a biphasic growth effect on cells with erbB-2 overexpression. Interestingly, we observed that expression of heregulin correlates with a more aggressive/invasive, vimentin-positive phenotype in breast cancer cells lines. Therefore, we have postulated that heregulin is involved in breast cancer tumor progression. We have shown that heregulin induces in vitro chemoinvasion and chemotaxis of breast cancer cells as well as growth in an anchorage dependent and independent manner. Interestingly, a heregulin neutralizing antibody inhibits chemotaxis and results in cell growth inhibition and blockade of the invasive phenotype. Strikingly, genetically engineered cells which constitutively express heregulin demonstrate critical phenotypic changes that are associated with a more aggressive phenotype. Specifically, these cells are no longer dependent on estrogen for growth and are resistant to tamoxifen in vitro and in vivo, and moreover these cells metastasize to lymph nodes in athymic nude mice. These tumors appear to have lost bcl-2 expression as compared with the control tumors. In addition, presumably by activation/regulation of topoisomerase II, the heregulin-transfected cells become exquisitely sensitive to doxorubicin and VP-16. Clearly, mechanistic aspects of the erbB-2/4 and heregulin interaction need to be understood from a therapeutic standpoint which could provide additional insights into synergistic treatments for certain patients, or improve treatment regimens for a large number of women. The study of heregulin and its co-expression with erbB-2/4 receptor and the assessment of its involvement in the progression from the in situ stage of breast tumors to the invasive one will additionally increase the relevance of heregulin as a prognostic/diagnostic factor. We believe that our studies provide new insights into breast cancer diagnosis, prognosis, and treatment.
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PMID:The significance of heregulin in breast cancer tumor progression and drug resistance. 882 23

The erbB-2 oncoprotein is overexpressed in 30% of tumors from breast and ovarian cancer patients and it is related to poor overall and disease-free survival. In vitro studies on erbB-2-overexpressing cells have found a strong correlation between this oncogene overexpression and relative resistance to lymphokine-activated killer (LAK) cell lysis. gp30/heregulin/NDF (neu differentiation factor), indirect activators of erbB-2, are able to induce a more differentiated phenotype on erbB-2-overexpressing, erbB-3- and/or erbB-4-positive breast cancer cells. We tested the ability of these highly homologous growth factors to stimulate LAK cell lysis of breast cancer cells. Our experiments demonstrated a marked increase in LAK cell cytotoxicity towards an erbB-2-overexpressing, erbB-3-positive cell line by treatment of these cells with heregulin for 72 h. In contrast we did not observe any enhancement of lysis of MCF-7, a cell line that does not overexpress erbB-2 and is positive for the erbB-3 and erbB-4 receptors, after treatment with heregulin. The increased lysis was associated with upregulation of intercellular adhesion molecule 1 (ICAM-1), down-regulation of erbB-2 and increased binding between breast cancer cells and LAK cells. Pre incubation of target (SKBR3) cells with blocking anti-ICAM-1 antibody completely abrogated the enhanced cytotoxicity. A similar effect was observed by pretreatment of the effector (LAK) cells with antibodies directed against LFA-1, the receptor for ICAM-1. These results suggest the possible utilization of gp30/heregulin in the treatment of breast cancer patients by its ability to stimulate patient immune responses.
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PMID:Heregulin induces increase in sensitivity of an erbB-2-overexpressing breast cancer cell type to lysis by lymphokine-activated killer cells. 891 31

The growth and differentiation of olfactory sensory neurons are regulated tightly. We had shown previously, by immunohistochemistry, that transforming growth factor-alpha (TGF-alpha) and epidermal growth factor (EGF) receptor are present in the olfactory epithelium of untreated adult rats and that TGF-alpha is a potent mitogen of olfactory epithelium in vitro. Expression of EGF receptor and TGF-alpha was detected primarily in horizontal basal cells and supporting cells but rarely in globose basal cells, which suggested that EGF receptor is not a likely candidate for the mitotic regulator of sensory neurons. In order to expand the search for candidate regulators, we have now examined other members of the EGF family of receptors and ligands. By utilizing reverse transcriptase-polymerase chain reaction (RT-PCR) methodology, we have detected the messenger RNA encoding the protein of the neu gene (p185neu) and Neu differentiation factor (NDF) isoforms in the olfactory mucosa. Immunohistochemical localization of p185neu and NDF indicates expression of these proteins in the olfactory epithelium of adult rats in regions where globose basal cells and immature sensory neurons are found, as well as in the ensheathing cells of the olfactory nerve. The presence of neu and NDF transcripts in the olfactory tissue and the localization of their encoded polypeptides to proliferative regions of the epithelium suggest involvement of these gene products in the regulated proliferation/differntiation of the sensory neurons.
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PMID:Expression of neu and Neu differentiation factor in the olfactory mucosa of rat. 901 Jul 26

Breast carcinomas are frequently characterized by hyperactivated c-erbB receptor tyrosine kinase signaling. Combination of anti-proliferative retinoids with growth-inhibitory c-erbB-specific agents might induce therapeutic benefit. We demonstrate close interactions between the c-erbB and the retinoic acid receptor system in SK-BR-3 breast cancer cells. Epidermal growth factor and heregulin-beta1 activate c-erbB receptors and dose- and time-dependently up-regulate retinoic acid receptor-alpha (RAR-alpha) mRNA. Similar effects have been found for the growth-inhibitory c-erbB-2 receptor tyrosine kinase-activating antibody 4D5 and the tyrosine phosphatase inhibitor orthovanadate. In contrast, the tyrosine kinase-inhibitor herbimycin A reduces tyrosine-specific protein phosphorylation and down-regulates RAR-alpha. Our data demonstrate that the expression of RAR-alpha, which represents a key mediator of the anti-proliferative effects of retinoids in breast cancer cells, is regulated by modulators of tyrosine kinase signaling. The levels of RAR-beta and -gamma mRNAs, however, are not affected by such agents.
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PMID:Tyrosine kinase signaling pathways control the expression of retinoic acid receptor-alpha in SK-BR-3 breast cancer cells. 909 80

Growth factor receptors of the epidermal growth factor (EGF) receptor family play pivotal roles in the regulation of cell proliferation and differentiation and are involved in the development of human cancers. It has been well documented that these receptors undergo growth factor-stimulated homo- and heterodimerization as a first step in the initiation of signaling cascades. Here we provide evidence for a new mechanism for growth factor-stimulated receptor dimer formation, designated secondary dimerization. The growth factor-induced dimerization and ensuing receptor trans-autophosphorylation results in the dissociation of the original (primary) receptor dimer. Each phosphorylated receptor monomer then interacts with a new (nonphosphorylated) receptor to form a secondary dimer. Treatment of cells with EGF yields Neu-ErbB3 secondary dimers, and heregulin treatment induces the formation of Neu-EGF receptor (secondary) dimers. The ability of EGF and heregulin to stimulate a cascade of dimerization events points to a novel mechanism by which multiple signaling activities and diverse biological responses are initiated by members of the EGF receptor family.
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PMID:Secondary dimerization between members of the epidermal growth factor receptor family. 911 72

Several growth factors and proto-oncogenes play a leading regulatory role during human carcinogenesis. In this systematic immunocytochemical study we observed the expression (overexpression) of the c-erbB-2 and c-erbB-3 oncoproteins in 30 primary cutaneous malignant melanomas (CMMs), 10 already metastasized malignant melanomas (MMMs) and 15 lymph-node negative breast carcinomas (BCs). Both oncoproteins were expressed as a result of either oncogene amplification or post-translational stabilization c-erbB-2 alone is unable to bind neuregulins, but it is able to act as a pan c-erbB receptor subunit. Heterodimerization between cerbB-2 and c-erbB-3 is required to initiate neuregulin directed signal transduction. We employed an indirect, four step streptavidinbiotin conjugated immunocytochemical technique for antigen detection. The visualization of the primary antigen-antibody reaction was carried out with alkaline phosphatase or immunoperoxidase labeling and the use of the appropriate enzymatic substrates. The presence of c-erbB-2 oncoprotein was detected in 12/30 CMMs, 8/10 MMMs and 6/15 BCs, while c-erbB-3 was identified in 14/30 CMMs, 7/10 MMMs and 6/15 BCs. The intensity of the cell membrane localized immunoreactivity was observed to be greater when the c-erbB-2 oncoprotein was targeted (A, AB and B). The c-erbB-3 oncoprotein was also detected in the cytoplasm with medium intensity (B, BC and C). Unfortunately, little is known concerning the range of oncoprotein overexpression after formalin fixation and paraffin embedding. We demonstrated overexpression localized to several cell clones within the oncoprotein positive population of malignant cells. The immunocytochemically defined extent of expression of both oncoproteins was between 10-40% (+ to +2) of the total cell population in the malignant melanomas and 20-35% (+2) of the total cell population in the BCs. In conclusion a) the results of the present study demonstrate the presence of c-erbB-2 and c-erbB-3 oncoprotein expression (overexpression) in melanoma and breast carcinoma, and b) oncogene receptor directed immunotherapy, as part of a more individualized anti-cancer treatment, represents a potentially valuable targeted treatment for the future.
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PMID:Clinical and prognostic significance of the expression of the c-erbB-2 and c-erbB-3 oncoproteins in primary and metastatic malignant melanomas and breast carcinomas. 913 92

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