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)

The calcium-binding protein S100A4 is capable of inducing metastasis in rodent models for breast cancer. We now show that rabbit antibodies to recombinant rat S100A4 recognize specifically human S100A4 using Western blotting techniques and use them to assess the prognostic significance of S100A4 in primary tumors from a group of 349 patients treated between 1976 and 1982 for stage I and stage II breast cancer. The antibody stains normal breast tissue heterogeneously, but stains positively 41% of the carcinomas, leaving the remaining 59% as negatively stained. In addition to the carcinoma cells, some host stromal cells and lymphocytes are also stained, but these have been discounted in subsequent analyses. There is an association of staining of carcinomas for S100A4 with some tumor variables considered to be associated with poor prognosis for patients: tumor present in axillary lymph nodes (borderline P = 0.058), staining for c-erbB-3 (P = 0.002), cathepsin D (P = 0.024), and c-erbB-2 (P = 0.048). The association of staining for S100A4 with patient survival has been evaluated using life tables and analyzed using generalized Wilcoxon statistics. Eighty percent of the S100A4-negative patients but only 11% of the S100A4-positive patients are alive after 19 years of follow-up, and this association is highly significant (P < 0.0001); the former have a median survival of >228 months and the latter 47 months. The other tumor variables that show significant association with survival time are nodal status (P < 0.0001), tumor size (P = 0.0035), histological grade (P = 0.013), staining for c-erbB-2 (P = 0.0015), estrogen receptor (P = 0.028), and p53 (P = 0.032). Analysis of the association of patients with carcinomas staining for S100A4 and their survival in subgroups defined by these other tumor variables shows that in each subgroup, staining for S100A4 is associated with poorer survival. Patients whose tumors stain for S100A4 and possess involved lymph nodes (P < 0.0001), which are fixed to the chest wall (P = 0.015) or which stain for c-erbB-2 (P = 0.050), show a significant reduction in survival times over those with only S100A4-staining tumors. Patients with involved lymph nodes, or staining for c-erbB-2 in the S100A4-negative group fail to show any significant reduction in survival times. Multivariate regression analysis for 137 patients shows that staining for S100A4 is most highly correlated with patient deaths (P < 0.0001), but involved lymph nodes (P = 0.001), fixed tumors (P = 0.0002), and high histological grade (P = 0.022) are also significant independent prognostic variables. These results suggest that in this group of patients, the metastasis-inducing protein S100A4 is most tightly correlated with patient demise.
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PMID:Prognostic significance of the metastasis-inducing protein S100A4 (p9Ka) in human breast cancer. 1074 28

Our aim was to compare the occurrence and prognostic significance over 14-20 years of immunocytochemically detected S100A4 and other tumour variables in primary tumours from 349 patients with operable breast cancer. For a cut-off of 1% staining of the malignant cells, the antibody to S100A4 stains positively 56% of the carcinomas. There was a significant association of staining for S100A4 with tumours fixed to the chest wall, staining for c-erbB-2, c-erbB-3, pS2, cathepsin D and, inversely, at borderline levels with staining for estrogen receptor. Using Wilcoxon statistics in univariate analyses, staining for S100A4, nodal status, tumour class, histological grade and staining for c-erbB-2, p53 were associated negatively and staining for estrogen receptor, progesterone receptor were associated positively with patient survival times. The survival times of patients with S100A4-negative carcinomas with or without one of the other tumour variables showed no significant differences, whilst those of patients with S100A4-positive carcinomas showed significant differences in a negative or a positive way. Multivariate regression analysis for 137 patients showed that staining for S100A4 is most highly correlated with patient deaths, but involved lymph nodes, fixed tumours, high histological grade and staining for progesterone receptor were also significant independent prognostic variables. Our results suggest that in this set of patients, the tumour variable most tightly correlated with patient death is S100A4.
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PMID:Comparison of the metastasis-inducing protein S100A4 (p9ka) with other prognostic markers in human breast cancer. 1075

The neu differentiation factors/heregulins (HRGs) comprise a family of polypeptide growth factors that activate p185(erbB-2) through direct binding to either erbB-3 or erbB-4 receptor tyrosine kinases. We have previously shown that HRG-beta is mitogenic for various human mammary epithelial cell lines that coexpress c-erbB-2 and c-erbB-3. Phosphatidylinositol 3-kinase (PI3K) is activated by p185(erbB-2) /erbB-3 heterodimers in cells stimulated by HRG, and PI3K is constitutively activated by p185(erbB-2) /erbB-3 in breast carcinoma cells that overexpress c-erbB-2. To better understand the relative abilities of HRGs, epidermal growth factor (EGF), or insulin to activate PI3K under normal physiological conditions, we compared the levels of recruitment of the 85-kDa regulatory subunit of PI3K when activated by the type I (erbB) or type II [insulin-like growth factor (IGF)] receptor tyrosine kinases in two different nontransformed human mammary epithelial cell lines. The nontransformed H16N-2 cells isolated from normal tissue express EGFR, p185(erbB-2), and erbB-3, and are highly responsive to the mitogenic effects of HRG-beta as well as to the combination of EGF and insulin in serum-free culture. We measured the stoichiometry of p85 recruited by tyrosine-phosphorylated proteins induced in H16N-2 cells by either the alpha or the beta isoform of HRG. HRG-beta was greater than 10-fold more potent in inducing p85 recruitment than was the less biologically active HRG-alpha isoform. HRG-beta was also a more potent inducer of p85 recruited by tyrosine-phosphorylated proteins than was either EGF, insulin, or EGF and insulin combined. Furthermore, erbB-3 principally mediated the direct recruitment of p85 in cells stimulated by HRG or EGF, indicating that, in addition to the high-level activation of PI3K by p185(erbB-2) / erbB-3, EGFR/erbB-3 heterodimer interaction is essential for the weak but significant level of PI3K activated by EGF in cells that express normal EGFR levels. Studies using the PI3K inhibitor wortmannin also indicated that PI3K activation was required for the proliferation of H16N-2 cells induced by either HRG-beta or EGF and insulin in serum-free culture. Finally, HRG-beta was also an especially potent inducer of PI3K in the nontransformed MCF-10A cells, which were derived spontaneously from normal reduction mammoplasty tissue. These data show, for the first time, a side-by-side quantitative comparison of the relative degree of PI3K activated by different growth factors in nontransformed growth factor-dependent cells under precisely defined conditions in culture.
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PMID:Heregulin-beta is especially potent in activating phosphatidylinositol 3-kinase in nontransformed human mammary epithelial cells. 1079 4

Members of the c-erbB family have been implicated in poor prognosis in breast cancer. Given the propensity for heterodimerisation within the erbB family, the pattern of co-expression of these receptors is likely to be as functionally important as aberrant expression of any given receptor alone. Therefore, the patterns of expression of the receptors, epidermal growth factor receptor (EGF-R), c-erbB-2, c-erbB-3, c-erbB-4, and one of the erbB ligands, heregulin (HRG), were examined in normal and malignant breast cell lines and compared with expression of oestrogen receptor (ER), a classical indicator of good prognosis. There was an inverse correlation between ER and EGF-R mRNA levels, as previously described, but no correlation between either of these receptors and c-erbB-2. c-erbB-3 expression was positively correlated with ER. In contrast, HRG expression was inversely related to ER. Expression of antisense-ER resulted in increased EGF-R mRNA, demonstrating a functional link between the expression of these 2 genes, however, there was no significant change in c-erbB-2 or c-erbB-3 mRNA, suggesting that ER is not directly involved in control of expression of these genes. A comparison of individual erbB receptors and HRG revealed that the majority of lines expressing increased levels of c-erbB-2 also expressed elevated levels of c-erbB-3 mRNA, and none of the cell lines that expressed both c-erbB-2 and either c-erbB-3 or c-erbB-4 expressed the ligand HRG. In summary, the levels of expression of c-erbB-1, -2, -3, and -4 varied in this series of breast cell lines, and the pattern of expression and the relationship of each growth factor receptor to the expression of ER was quite distinct. The lack of expression of HRG in cell lines that express receptors may be indicative of paracrine interactions between erbB ligands and their cognate receptors and may suggest that the ligand and receptors are expressed in different subtypes of breast epithelial cells from which the cell lines are derived.
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PMID:Expression of c-erbB receptors, heregulin and oestrogen receptor in human breast cell lines. 1091 87

We measured the expression of the type I growth factor receptor gene family [epidermal growth factor receptor (EGFR), c-erbB-2, c-erbB-3 and c-erbB-4] in a series of 365 unselected primary breast cancers. The expression was quantified with a real-time one-step reverse transcriptase-PCR (RT-PCR) assay, based upon the 5' nuclease activity of the Taq polymerase and using an Abi Prism 7700 Sequence Detector System (Perkin-Elmer, Courtaboeuf, France). c-erbB-3 and c-erbB-4 were positively correlated to each other (Spearman test) and negatively correlated to EGFR. EGFR and c-erbB-2 were inversely correlated to the presence of estradiol receptors (ER) and progesterone receptors (PgR), and positively correlated to the histoprognostic grading (HPG). Conversely, c-erbB-3 and c-erbB-4 were positively correlated to the presence of ER and PgR, and inversely correlated to the grading HPG. EGFR was inversely related (chi2 test) to the presence of ER and PgR, and positively associated with HPG. In contrast, both c-erbB-3 and c-erbB-4 were inversely related to HPG, and positively associated with the presence of ER and PgR. The expression level of EGFR and c-erbB-2 was significantly higher in ER- and PgR-negative tumors compared with ER- and PgR-positive tumors (Student's t test), and in tumors with higher grade compared with tumors with lower grade. The expression level of c-erbB-3 and c-erbB-4 was significantly higher in ER- and PgR-positive tumors compared with ER- and PgR-negative tumors and in tumors with lower grade compared with tumors with higher grade. In overall survival studies, Cox univariate analyses showed prognostic values of EGFR [> or = median; P = 0.026; risk ratio (RR), 1.6], c-erbB-3 (> or = median; P = 0.0093; RR, 0.58), c-erbB-4 (> or = median; P = 0.0024; RR, 0.52), HPG, node involvement, tumor diameter, ER, and PgR. In Cox multivariate analyses, tumor diameter, ER, and PgR had a prognostic value. In relapse-free survival studies, univariate analyses demonstrated prognostic values of tumor diameter, node involvement, and c-erbB-4 (P = 0.015; RR, 0.65). These three parameters maintained their prognostic value in multivariate analyses (c-erbB-4, P = 0.035; RR, 0.67). This study confirms that EGFR expression and c-erbB-2 expression are markers of tumor aggressiveness in breast cancer. Conversely, we demonstrate that c-erbB-3 and c-erbB-4 elevated expressions are associated with a better prognosis.
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PMID:Prognostic value of the type I growth factor receptors in a large series of human primary breast cancers quantified with a real-time reverse transcription-polymerase chain reaction assay. 1110 35

The type I family of growth factor receptors is known to play a role in the development of several carcinomas, but its role in hepatic malignancies is not clearly understood. In this study we investigated the expression of this family of EGF-R, c-erbB-2, c-erbB-3 and c-erbB-4 in 38 intrahepatic cholangiocellular carcinomas (CCC) by means of immunohistochemistry. EGF-R expression was related to lymph node metastasis, aberrant p53 expression, proliferating activity, and carcinoma differentiation. c-erbB-2 expression was observed in more than 50% of the cases, but was not related to any clinicopathological features, c-erbB-3 expression was linked to lymph node metastasis, and c-erbB-4 expression was directly related to proliferating activity and lymph node metastasis. These results indicate that: 1) EGF-R contributes greatly to CCC progression, and c-erbB-3 and c-erbB-4 have roles similar to but less than that of EGFR, and 2) c-erbB-2 is expressed in CCC in high incidence, but its clinical role in CCC remains unclear.
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PMID:Expression and clinical significance of the erbB family in intrahepatic cholangiocellular carcinoma. 1126 24

In order to elucidate the clinical significance of the erbB family, epidermal growth factor receptor (EGF-R), c-erbB-2, c-erbB-3 and c-erbB-4 in hepatocellular carcinoma (HCC), we investigated the expression of these proteins by means of immunohistochemistry for HCC as well as adjacent noncancerous lesions. EGF-R was expressed in 68% of the HCC examined and showed correlation with the proliferating activity, stage, intrahepatic metastasis and carcinoma differentiation. c-erbB-2 was expressed in only 21% of the cases and showed no relationships with the clinicopathological parameters. c-erbB-3 protein was observed in 84% of the HCC and 38.1% of the noncancerous lesions. Its expression in HCC was equal to or greater than noncancerous lesions in 90.5% of the cases, and was related to the stage, portal invasion, cell proliferating activity, tumour size, intrahepatic metastasis and carcinoma differentiation. c-erbB-4 protein was expressed in 61.0% of HCC and in as much as 86.1% of the noncancerous lesions. Unlike the expression of c-erbB-3, that of c-erbB-4 in HCC was less than that of the adjacent noncancerous lesions in 51.2% of the cases. No statistical significance could be established between this protein expression in HCC and clinicopathological features. EGF-R and c-erbB-3 affected disease-free survival, but were not recognized as independent prognostic factors by multivariate analysis. The present study suggests that, of the four receptors, EGF-R and c-erbB-3 play important roles in the progression of HCC.
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PMID:Expression and clinical significance of erb-B receptor family in hepatocellular carcinoma. 1135 50

In this study the expression of epidermal growth factor receptor (EGFR) and c-erbB-2, c-erbB-3 and c-erbB-4 oncogenes were investigated in gestational trophoblastic diseases and normal first trimester placenta. Furthermore, the possibility that macrophage (IL-1 alpha, IL-1 beta, TNF) and lymphocyte (IL-2, gamma-IFN, GM-CSF) cytokines effects are mediated by changes in EGFR expression were studied. Paraffin sections of 16 cases of partial mole, 25 cases of complete mole, 10 cases of gestational choriocarcinoma and 11 cases of therapeutic abortion were studied immunohistochemically for EGFR, c-erbB-2, c-erbB-3 and c-erbB-4 proteins. The presence of EGFR mRNA was studied using in situ hybridization. JEG-3 human choriocarcinoma cells were incubated with varying concentrations of interleukin 1-alpha, interleukin 1-beta, interleukin 2, gamma-interferon, granulocyte-macrophage colony stimulating factor and tumor necrosis factor-alpha, and the expression of EGFR was measured by radioimmunoassay using a murine monoclonal antibody with specificity for EGFR. Staining for EGFR was detected immunohistochemically in all cell type in gestational trophoblastic diseases and normal placenta. The levels of expression of EGFR in choriocarcinoma and syncytiotrophoblasts and cytotrophoblasts in complete mole were significantly greater than those in syncytiotrophoblasts and cytotrophoblasts in both normal placenta and partial mole (p < 0.01, p < 0.01). The immunoreactivity of c-erbB-2 was significantly stronger in choriocarcinoma and extravillous trophoblast in complete mole than that in extravillous trophoblast in partial mole and normal placenta (p < 0.02, p < 0.01, respectively). Strong immunostaining for EGFR (p = 0.02) and c-erbB-3 (p < 0.01) in extravillous trophoblasts of complete mole was found to be significantly correlated with the development of persistent postmolar gestational trophoblastic tumor. Macrophage-derived cytokines IL-1 alpha, IL-1 beta and TNF significantly suppressed cell growth; this was associated with a significant increase in EGFR expression. The lymphocyte (IL-2, gamma-IFN, GM-CSF) cytokines had no significant effect on either EGFR expression or cell growth. These findings support the concept that cytokines may act as paracrine mediators of autocrine processes involved in choriocarcinoma cell growth regulation by modulating growth factor receptor expression. The EGFR-related family of oncogenes may be important in the pathogenesis and prognosis of gestational trophoblastic diseases.
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PMID:[The c-erbB-related oncoproteins in normal placenta and in gestational trophoblastic diseases (in vitro study)]. 1142 88

Ten human head and neck squamous carcinoma (HNSCC) cell lines were established in order to study the role of c-erbB signaling pathways in HNSCC progression. Five cell lines were derived from primary tumors at four different sites, and five were from lymph node metastases in the neck. Two pairs of lines were derived from the primary tumor and metastatic lymph node in the same patient. Basic characteristics including morphology, doubling time, phenotypes, cytogenetic profiles and tumorigenicity in nude mice were described. We examined the expression of c-erbB receptors and ligands in early passage new HNSCC lines and compared with five long-term established lines, normal keratinocytes and fibroblasts. Amplification of c-erbB-1 (EGFR) gene was observed in only one cell line whereas no amplification of other c-erbB genes was found. Overexpression of EGFR, c-erbB-2, c-erbB-3 and c-erbB-4 mRNAs was observed in 10, 14, 10 and 8 out of 15 head and neck cell lines respectively. Overexpression of c-erbB-3 and c-erbB-4 was more frequently observed in newly derived HNSCC lines than in long-established cell lines. The majority of tumor cells also expressed multiple c-erbB ligands. One selected cell line, SIHN-006, was shown to exhibit tyrosine phosphorylation via all four receptors. These new cell lines could provide a useful experimental model to study the co-operative signaling of type I tyrosine kinase receptors in HNSCC progression.
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PMID:Characterization of ten newly-derived human head and neck squamous carcinoma cell lines with special reference to c-erbB proto-oncogene expression. 1149 83

Over-expression of epidermal growth factor receptor (EGFR) and c-erbB-2, in uterine cervical carcinomas, is associated with a worsened prognosis. A third member of this proto-oncogene family, c-erbB-3, has now been identified and its over-expression has been described in a variety of carcinomas. In this immunohistochemical study we have shown that c-erbB-3 is widely expressed in cervical carcinomas, but we have found no association between its over-expression and lymph node status or clinical outcome. In a similar study examining the expression of EGFR and c-erbB-2 it was possible to demonstrate an association between over-expression and a worse prognosis. We conclude, therefore, that it is unlikely that demonstration of c-erbB-3 over-expression will be of any value as a prognostic indicator in carcinoma of the uterine cervix.
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PMID:c-erbB-3 proto-oncogene expression in uterine cervical carcinoma. 1157 90


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