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

ErbB2 (HER2, Neu), a member of the epidermal growth factor (EGF) receptor tyrosine kinase family, is often overexpressed in breast cancer and other malignancies. ErbB2 homodimerizes but also presents as a common auxiliary subunit of the EGF and heregulin receptors (erbB1 or EGFR; and erbB3-4, respectively), with which it heteroassociates. ErbB2 is generally regarded as an orphan (ligand-less) receptor with a very potent kinase domain activated either via its associated partners or constitutively as a consequence of discrete mutations. It follows that the extent and regulation of its cell surface interactions are of central importance. We have studied the large-scale association pattern of erbB2 in quiescent and activated cells labeled with fluorescent anti-erbB2 monoclonal antibodies using scanning near-field optical microscopy (SNOM). ErbB2 was found to be concentrated in irregular membrane patches with a mean diameter of approx. 0.5 microm in nonactivated SKBR3 and MDA453 human breast tumor cells. The average number of erbB2 proteins in a single cluster on nonactivated SKBR3 cells was about 10(3). Activation of SKBR3 cells with EGF, heregulin as well as a partially agonistic anti-erbB2 monoclonal antibody led to an increase in the mean cluster diameter to 0.6-0.9 microm, irrespective of the ligand. The EGF-induced increase in the erbB2 cluster size was inhibited by the EGFR-specific tyrosine kinase inhibitor PD153035. The average size of erbB2 clusters on the erbB2-transfected line of CHO cells (CB2) was similar to that of activated SKBR3 cells, a finding correlated with the increased base-line tyrosine phosphorylation of erbB2 in cells expressing only erbB2. We conclude that an increase in cluster size may constitute a general phenomenon in the activation of erbB2.
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PMID:Activation-dependent clustering of the erbB2 receptor tyrosine kinase detected by scanning near-field optical microscopy. 1031 65

SKOV-3, NIH:OVCAR-3, NIH:OVCAR-8, Ovca 429 and Ovca 433 ovarian carcinoma cell lines were examined to correlate biological behavior (growth in monolayer and soft agar) with erbB family receptor expression levels and response to recombinant Heregulin beta1 (Hrg). While all lines expressed variable amounts of each receptor, erbB-3 and to a lesser extent erbB-2 were constitutively tyrosine phosphorylated in all lines. Hrg beta1 treatment enhanced only erbB-3 tyrosine phosphorylation; however, the addition of Hrg in low serum did not stimulate ovarian cell growth, unlike all three breast cancer cell lines examined. In addition, all five of the ovarian carcinoma cell lines expressed Hrg mRNA by RT-PCR, unlike two of the three breast cancer cell lines. These results suggest the apparent importance of erbB-3 and endogenous Hrg in ovarian carcinoma cell growth in vitro.
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PMID:ErbB receptor expression and growth response to heregulin beta 1 in five ovarian carcinoma lines. 1033 75

Activation of heregulin (HRG) signaling has been implicated in the development of aggressive phenotype in breast cancer cells. The mechanisms through which HRG regulates the progression of breast cancer cells to a more invasive or motile phenotype are currently unknown. Because the process of cell migration must involve dynamic changes in the formation of new focal adhesions at the leading edge and dissolution of preexisting focal points, we explored the potential HRG regulation of paxillin, a major component of focal adhesion. Here, we report that HRG stimulation of noninvasive breast cancer MCF-7 cells resulted in the up-regulation of paxillin mRNA and protein. The observed HRG stimulation of paxillin mRNA expression was completely blocked by actinomycin D (a transcriptional inhibitor) as well as by cycloheximide (a protein synthesis inhibitor), suggesting the involvement of an inducible protein factor(s) and transcriptional regulation of paxillin mRNA by HRG. Extension of these observations to other HRG-responsive human cell lines also demonstrated that HRG has a significant capacity to up-regulate the paxillin expression. Furthermore, the levels of paxillin expression were closely linked with the coexpression of human epidermal growth factor receptor 2 (HER2)/HER3 receptors in breast cancer cell lines and in grade III human breast tumors. This study is the first demonstration of regulation of paxillin expression by a polypeptide growth factor, and it suggests a potential role for paxillin in the HER2 pathway in breast cancer.
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PMID:Transcriptional up-regulation of paxillin expression by heregulin in human breast cancer cells. 1038 44

In the present studies, we demonstrate that heregulin is a potent and rapid activator of the serine/threonine kinase called Akt in the MCF-7 breast cancer cell line but not in 3 other breast cancer cell lines (T47D, HBL-100, and MDA-231). The extent of activation of Akt in the 4 cell lines correlated with the ability of heregulin to activate phosphatidylinositol 3-kinase and inhibition of the kinase blocked Akt activation. A monoclonal antibody to HER2 inhibited the ability of heregulin to activate Akt in the MCF-7 cells. BT474, a breast cancer cell line which overexpresses HER2, had high basal Akt enzymatic activity. This high basal activity was lowered when cells were pre-incubated with an anti-HER2 monoclonal antibody which is used to treat breast cancer patients. Our results indicate that heregulin is a potent activator of Akt and that overexpression of HER2 in breast cancers could also lead to activation of Akt.
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PMID:Heregulin regulation of Akt/protein kinase B in breast cancer cells. 1044 22

We have previously reported that Heregulin (HRG)/neu differentiation factor (NDF) induced growth arrest and cellular differentiation in breast cancer cells overexpressing erbB-2 receptor. To elucidate the cellular mechanisms underlying the growth inhibition by HRG, we developed an in vitro model by transfection of HRG cDNA into the erbB-2 overexpressing breast cancer cell line, SKBr-3. We showed that the enforced expression of HRG in SKBr-3 cells induces dramatic morphological changes and pronounced inhibition of anchorage-dependent and -independent growth. Most SKBr-3/HRG-transfected (SK/HRG) cells exhibited about 15-fold increase in size and persisted as multinucleated cells with extended flattened vacuole-filled cytoplasm with reduced cell attachment. The growth suppression of SK/HRG cells was accompanied by a reduction in S phase, the presence of a G2-M cell cycle delay, and an increase in DNA aneuploid components. In addition, DNA fragmentation assays showed that HRG induced apoptosis of SKBr-3 cells. In contrast, while HRG treatment of other erbB-2 overexpressing breast cancer cell lines led to growth arrest and cell detachment, it did not induce apoptotic features. Thus, this study demonstrates that while growth arrest and cell detachment are general effects of HRG towards erbB-2 overexpressing cells, the ability of HRG to induce apoptosis is a phenomenon confined to selective cells including SKBr-3 cells.
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PMID:Constitutive expression of Heregulin induces apoptosis in an erbB-2 overexpressing breast cancer cell line SKBr-3. 1053 69

The breast cancer susceptibility gene BRCA1 encodes a nuclear phosphoprotein that acts as a tumor suppressor. Phosphorylation of BRCA1 has been implicated in altering its function, however, the pathway(s) that leads to the phosphorylation of BRCA1 has not been described. Here, a signaling pathway by which heregulin induces cell cycle-independent phosphorylation of BRCA1 was delineated. We showed that heregulin stimulation induced the phosphorylation of BRCA1 and concomitant activation of the serine/threonine kinase AKT in T47D human breast cancer cells. Heregulin-induced phosphorylation of BRCA1 was abrogated by phosphatidylinositol 3-kinase (PI3K) inhibitors and by a dominant-negative AKT. In the absence of heregulin, the ectopic expression of the constitutively active p110 subunit of PI3K was sufficient to induce BRCA1 phosphorylation. Furthermore, the purified glutathione S-transferase/AKT kinase phosphorylated BRCA1 in vitro. We have also shown that the phosphorylation of BRCA1 by AKT occurs on the residue Thr-509, which is located in the nuclear localization signal. These results reveal a novel signaling pathway that links extracellular signals to the phosphorylation of BRCA1 in breast cancer cells.
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PMID:Heregulin induces phosphorylation of BRCA1 through phosphatidylinositol 3-Kinase/AKT in breast cancer cells. 1054 66

Alterations that affect the ectodomain of receptor tyrosine kinases are often associated with constitutive activation of the enzymic activity of the mutant cell-associated receptor. Since the ectodomain of the ErbB2 receptor tyrosine kinase has been detected as a soluble fragment in the culture supernatant of cells and serum from patients with advanced breast cancer, the possible presence of cell-associated truncated forms of ErbB2 in cancer cells was investigated. Several cell-bound N-terminal truncated forms of ErbB2 were identified in breast cancer cells overexpressing this receptor. The presence of the truncated fragments was independent of lysosomal/proteasomal activity, indicating that classical receptor tyrosine kinase degradation systems were not involved in the N-terminal cleavages. The presence of these truncated forms of ErbB2 was up-regulated by protein kinase C and neuregulin; and down-regulated by phosphatidylinositol 3-kinase, and monoclonal antibodies that target the ectodomain of ErbB2, indicating that N-terminal cleavages of ErbB2 were regulated by multiple mechanisms. The truncated fragments were tyrosine-phosphorylated under resting conditions, and associated with the signalling intermediates Shc and Grb2. It is therefore likely that these truncated forms may be endowed with constitutive activity that allows them to permanently signal.
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PMID:Signalling-competent truncated forms of ErbB2 in breast cancer cells: differential regulation by protein kinase C and phosphatidylinositol 3-kinase. 1056 14

Base-unpairing regions (BURs) contain a specialized DNA context with an exceptionally high unwinding propensity, and are typically identified within various matrix attachment regions. A BUR affinity column was used to purify a doublet of Mr 20,000 proteins from human breast carcinoma cells. These proteins were identified as the high-mobility group (HMG) protein, HMG-I, and its splicing variant, HMG-Y. We show that HMG-I(Y) specifically binds BURs. Mutating BURs so as to abrogate their unwinding property greatly reduced their binding affinity to HMG-I(Y). Numerous studies have indicated that elevated HMG-I(Y) expression is correlated with more advanced cancers and with increased metastatic potential. We studied whether the expression of HMG-I(Y) responds to signaling through the heregulin (HRG)-erbB pathway and the extracellular matrix. HMG-I(Y) expression was increased in MCF-7 cells after stable transfection with an HRG expression construct that led cells to acquire estrogen independence and metastasizing ability. A high level of HMG-I(Y) expression was detected in metastatic MDA-MB-231 cells, but the expression was virtually diminished, and the metastasizing ability was lost after cells were stably transfected with an antisense HRG cDNA construct. HMG-I(Y) was also decreased in MDA-MB-231 cells when treated with a chemical inhibitor for matrix metalloproteinase-9 that led to a reduction of invasive capability in vitro. The level of HMG-I(Y) expression, therefore, is dynamically regulated in human breast cancer cells in response to varying types of signaling that affect metastatic ability, including the HRG-erbB pathway and those from the extracellular matrix.
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PMID:HMG-I(Y) recognizes base-unpairing regions of matrix attachment sequences and its increased expression is directly linked to metastatic breast cancer phenotype. 1058 87

Members of the epidermal growth factor receptor family of tyrosine kinases, including epidermal growth factor receptor, c-erbB-2 (HER-2), c-erbB-3 (HER-3), and c-erbB-4 (HER-4), can be coexpressed at different levels in nonhematopoietic tissues. Amplification and overexpression of HER-2 is found in approximately one-third of cancers that arise in the breast and ovary. In our previous studies, heregulin (HRG) and anti-HER-2 antibodies inhibited proliferation, increased invasiveness, and enhanced tyrosine autophosphorylation of SKBr3 breast cancer cells that overexpressed HER-2. In the present report, the effects of HRG and anti-HER-2 antibody have been compared in six ovarian cancer cell lines. HRG inhibited anchorage-independent growth of SKOv3 cells that overexpressed HER-2 (10(5) receptors/cell) but stimulated the growth of OVCA420, OVCA429, OVCA432, OVCA433, and OVCAR-3 cells that expressed lower levels of the receptor (10(4) receptors/cell). Thus, cell lines with a high level of HER-2 relative to HER-3 or HER-4 were growth inhibited, whereas cell lines with lower levels of HER-2 were growth stimulated by HRG. Stimulation or inhibition of clonogenic growth did not correlate with endogenous expression of HRG or with the impact of exogenous HRG on phosphorylation of HER-2, HER-3, or HER-4. Anti-HER-2 antibodies inhibited the growth of SKOv3 cells but failed to affect the growth of the other cell lines. In OVCAR-3 cells that had been transfected with HER-2 cDNA to increase expression to 10(5) receptors/cell, HRG inhibited rather than stimulated growth. Conversely, when HER-2 expression by SKOv3 cells was downregulated by transfection of the viral E1A gene, HRG stimulated rather than inhibited growth. To evaluate the relative importance of HER-3 and HER-4, NIH 3T3 cells were cotransfected with HER-2 and HER-3 or with HER-2 and HER-4. HRG inhibited the growth of cells with a high ratio of HER-2:HER-3, whereas HRG stimulated the growth of cells with low levels of the two receptors. In cells that express only HER-2 and HER-4, HRG stimulated the growth of cells that expressed HER-4 independent of HER-2 levels. Anti-HER-2 antibodies inhibited the growth of transfectants with high levels of HER-2 expression independent of HER-3 or HER-4 expression. In ovarian cancer cells that express all three receptors, the relative levels of HER-2 and HER-3 appear to determine the response to HRG. Taken together, these studies support the concept that the level of HER-2 expression can modulate response to HRG, determining whether the response is stimulatory or inhibitory. In contrast, agonistic antibodies that bind to HER-2 alone inhibit anchorage-independent growth but fail to mimic HRG's ability to stimulate growth of cells with low HER-2: HER-3 ratios.
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PMID:The outcome of heregulin-induced activation of ovarian cancer cells depends on the relative levels of HER-2 and HER-3 expression. 1058 83

gamma-Heregulin was identified as an isoform resulting from alternate splicing of the neuregulin-1 gene, after cloning of its cDNA from the MDA-MB-175 breast cancer cell line. gamma-Heregulin was shown to promote growth of cultured MDA-MB-175 cells resulting from activation of its cognate ErbB tyrosine kinase reporters. We show here that gamma-heregulin is transcribed from a fusion gene resulting from a chromosome translocation in MDA-MB-175 cells. The fusion chromosome is described as dic(8:11)(8qter-->8p12::11q13-->11pter). As a result, the 5' end of the gamma-heregulin gene is derived from the stress-induced gene, DOC-4 (11q13), while the 3' end is from the neuregulin-1 gene (8p12). Thus, expression of gamma-heregulin is under the control of the DOC-4 promoter. By contrast with MDA-MB-175 cells, RT-PCR failed to detect a gamma-heregulin transcript in either E9.5 to E13.5 embryonic mouse tissues, adult mouse tissues or other human tumour cell lines. We conclude, therefore, that gamma-heregulin is not a native isoform of the neuregulin-1 gene, but a novel growth factor that may contribute to tumour cell proliferation.
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PMID:Gamma-heregulin: a fusion gene of DOC-4 and neuregulin-1 derived from a chromosome translocation. 1059 12


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