Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:O76050 (neu)
 3,969 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Breast cancers often contain different clones of tumor cells. Attention to the cellular properties of breast cancer metastases may identify characteristics in primary tumors that are associated with metastasis. Such characteristics could include DNA content, cell proliferation, abnormal oncogene expression, or relative cell population (clonal dominance). We examined DNA ploidy (image analysis), proliferation index (proliferating cell nuclear antigen-1 immunostaining), and expression of Her-2/neu oncoprotein in 17 invasive breast cancer samples (36 primary tumor samples) and 82 corresponding regional metastases. In all samples the primary tumor was multiclonal (usually biclonal) by DNA ploidy analysis. In approximately 90% of metastatic DNA clones (30 of 34) the corresponding clone was identified in a primary tumor sample representing 25% or more of the tumor cell population (significant clone). A majority DNA clone (> or = of tumor cell population) existed in 60% (21 of 36) of primary tumor samples and in 70% (60 of 82) of metastases (30% diploid v 70% nondiploid in both groups). In approximately 50% of metastases (37 of 82) an unexpected majority clone was identified (not a majority in any primary tumor sample) and the ratio of diploid to nondiploid clones also was 30% to 70%. However, in 80% of majority metastatic clones (46 of 60) that clone was a significant primary tumor clone. Proliferation index was quite variable in primary tumor samples and in corresponding metastases. Overexpression of Her-2/neu oncoprotein in the primary tumor of seven of 10 patients also was identified in all corresponding metastases in five of seven patients and in some metastases in two of seven patients. The metastases in three Her-2/neu-negative patients were all negative. We conclude that (1) DNA clones are stable after metastasis, (2) clonal majorities in metastases reflect clones identified in primary tumors, (3) different metastatic clones from an individual tumor can establish clonal majorities, (4) neither diploid nor aneuploid cells have a metastatic advantage in breast cancer, (5) proliferation indices are heterogeneous, and (6) overexpression of Her-2/neu is usually consistent between primary tumors and corresponding metastases.
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PMID:Breast cancer heterogeneity: evaluation of clonality in primary and metastatic lesions. 786 51

Choosing the surgical technique for the cervix carcinoma--vaginal or abdominal--it is particularly necessary to take into account the lymphatic spread of the cervix. As it is not possible to realize a lymphadenectomy in a vaginal procedure, it has to be found a preoperative diagnostic method which enables very surely the exclusion of lymph node involvement. In summary of the facts stated up to now, one can conclude as follows: 1. The FIGO-classification is too subjective. 2. There is a significant correlation between tumor volume and lymph node involvement. 3. The tumor markers--as e.g. PCNA, p53, c-neu, EGF, beta 1 Integrin etc.--show no correlation with the lymph node involvement. 4. Only MRI allows an exact preoperative measurement of the tumor volume. 5. On account of the above mentioned results, it seems to be possible to extend the indication for the vaginal radical surgery on cases with a small tumor volume.
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PMID:The vaginal radical operation of cervical cancer. 855 79

Immunohistochemical studies have suggested that the tyrosine kinase growth factor receptor p185neu is overexpressed in a high percentage of human cholangiocarcinomas. To establish the specificity and temporal relationship between the expression of this receptor in cholangiocarcinogenesis, we investigated c-neu expression in precancerous cholangiofibrotic tissue and subsequently derived primary and transplantable cholangiocarcinomas originated in the livers of furan-treated rats. Proliferated bile ductules formed in rat models of bile ductular hyperplasia and the cell types of normal adult rat liver were also analyzed for c-neu expression. c-neu expression was not detected in normal adult rat liver by either Western blotting, immunohistochemistry, or in situ hybridization. In comparison, all of the cholangiocarcinomas analyzed, which were characterized by intestinal-type mucin-producing neoplastic glands, exhibited a prominent band with a molecular weight 185 kd, corresponding to p185neu. Only the neoplastic glandular epithelia of the cholangiocarcinomas showed a strong immunoreactivity for p185neu, which was predominantly localized to their cell surface but also observed cytoplasmically. In situ hybridization further revealed the cytoplasm of the tumor glandular epithelial cells to be strongly positive for c-neu mRNA transcripts. Of particular interest was our finding that c-neu is expressed early in furan cholangiocarcinogenesis, being more pronounced in the metaplastic intestinal glands of cholangiofibrotic tissue than in hyperplastic biliary epithelial cells in either the same tissue or in hyperplastic bile ductule tissue. Our results demonstrate that c-neu overexpression is a prominent feature of intestinal-type cholangiocarcinomas as well as of metaplastic intestinal glands that precede their development and is detected at lower levels in hyperplastic biliary epithelia. The overexpression of c-neu in the metaplastic and malignant neoplastic glands also correlated with their increased proliferating cell nuclear antigen (PCNA) labeling indices relative to those of hyperplastic biliary ducts and ductules and also appeared to correlate with their intestinal glandular pattern of differentiation.
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PMID:NEU overexpression in the furan rat model of cholangiocarcinogenesis compared with biliary ductal cell hyperplasia. 940 19

Incidence rates have risen rapidly for esophageal and gastric cardia adenocarcinomas. These cancers, arising at and around the gastroesophageal junction (GEJ), share a poor prognosis. In contrast, there is no consensus with respect to clinical staging resulting in possible adverse effects on treatment and survival. The goal of this study was to provide more insight into the genetic changes underlying esophageal and gastric cardia adenocarcinomas. We have used comparative genomic hybridization for a genetic analysis of 28 adenocarcinomas of the GEJ. Eleven tumors were localized in the distal esophagus and related to Barrett's esophagus, and 10 tumors were situated in the gastric cardia. The remaining seven tumors were located at the junction and could not be classified as either Barrett-related, or gastric cardia. We found alterations in all 28 neoplasms. Gains and losses were distinguished in comparable numbers. Frequent loss (> or = 25% of all tumors) was detected, in decreasing order of frequency, on 4pq (54%), 14q (46%), 18q (43%), 5q (36%), 16q (36%), 9p (29%), 17p (29%), and 21q (29%). Frequent gain (> or = 25% of all tumors) was observed, in decreasing order of frequency, on 20pq (86%), 8q (79%), 7p (61%), 13q (46%), 12q (39%), 15q (39%), 1q (36%), 3q (32%), 5p (32%), 6p (32%), 19q (32%), Xpq (32%), 17q (29%), and 18p (25%). Nearly all patients were male, and loss of chromosome Y was frequently noted (64%). Recurrent high-level amplifications (> 10% of all tumors) were seen at 8q23-24.1, 15q25, 17q12-21, and 19q13.1. Minimal overlapping regions could be determined at multiple locations (candidate genes are in parentheses): minimal regions of overlap for deletions were assigned to 3p14 (FHIT, RCA1), 5q14-21 (APC, MCC), 9p21 (MTS1/CDKN2), 14q31-32.1 (TSHR), 16q23, 18q21 (DCC, P15) and 21q21. Minimal overlapping amplified sites could be seen at 5p14 (MLVI2), 6p12-21.1 (NRASL3), 7p12 (EGFR), 8q23-24.1 (MYC), 12q21.1, 15q25 (IGF1R), 17q12-21 (ERBB2/HER2-neu), 19q13.1 (TGFB1, BCL3, AKT2), 20p12 (PCNA), 20q12-13 (MYBL2, PTPN1), and Xq25. The distribution of the imbalances revealed similar genetic patterns in the three GEJ tumor groups. However, loss of 14q31-32.1 occurred significantly more frequent in Barrett-related adenocarcinomas of the distal esophagus, than in gastric cardia cancers (P = 0.02). The unclassified, "pure junction" group displayed an intermediate position, suggesting that these may be in part gastric cardia tumors, whereas the others may be related to (short-segment) Barrett's esophagus. In conclusion, this study has, fist, provided a detailed comparative genomic hybridization-map of GEJ adenocarcinomas documenting new genetic changes, as well as candidate genes involved. Second, genetic divergence was revealed in this poorly understood group of cancers.
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PMID:Comparative genomic hybridization of cancer of the gastroesophageal junction: deletion of 14Q31-32.1 discriminates between esophageal (Barrett's) and gastric cardia adenocarcinomas. 997 27

Based on limited but compelling immunohistochemical data demonstrating individual overexpression of the tyrosine kinase growth factor receptors, c-erbB-2 and c-met, in significant percentages of human cholangiocarcinoma (ChC), we investigated if combined overexpression of both c-neu, the rat homologue of c-erbB-2, and c-met, the receptor for hepatocyte growth factor/scatter factor (HGF/SF), might represent a characteristic, early event associated with furan-induced cholangiocarcinogenesis in rat liver. Specifically, through the use of immunohistochemistry, in situ hybridization (ISH), and Western and Northern blotting, we found that both c-neu and c-met are prominently overexpressed in intestinal metaplastic lesions in early putative precancerous cholangiofibrotic tissue formed in the livers of rats after 6 weeks of furan treatment when compared with normal and hyperplastic intrahepatic biliary epithelia. We further demonstrated that c-neu and c-met are concordantly overexpressed in neoplastic glandular epithelia in later-developed primary "intestinal-type" of ChC formed in the livers of furan-treated rats, as well as in subsequently derived transplantable mucin-producing tumors. Overexpression of c-neu and c-met correlated with increased proliferating cell nuclear antigen (PCNA)-labeling indices, which were determined to be three to four times higher in intestinal metaplastic glands in precancerous cholangiofibrotic tissue and in neoplastic glands in the primary "intestinal type" of ChC than in hyperplastic bile ductular structures within either cholangiofibrotic or bile duct-ligated (BDL) livers. The c-neu and c-met receptor proteins overexpressed in different in vivo passages of a transplantable ChC each contained immunoreactive phosphotyrosines, indicating an activated state. However, we did not detect evidence of either gene amplification of c-neu or c-met or of a common transmembrane-activating mutation in c-neu expressed in transplantable ChC. Our findings indicate that altered expression of c-neu and c-met occurs relatively early in the process of furan-induced cholangiocarcinogenesis in rat liver and may play a potentially important role in its pathogenesis. They further indicate a common alteration in tyrosine kinase growth factor receptor expression linking early putative precancerous intestinal metaplastic lesions in liver to later-developed mucin-producing biliary cancer.
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PMID:Overexpression of C-NEU and C-MET during rat liver cholangiocarcinogenesis: A link between biliary intestinal metaplasia and mucin-producing cholangiocarcinoma. 1021 29

Using immunohistochemistry, expression of p53, transforming growth factor-alpha (TGF-alpha), epidermal growth factor receptor (EGFR), c-erbB-2/neu and proliferating cell nuclear antigen (PCNA) was examined in 26 fresh frozen tissue specimens of oropharyngeal squamous cell carcinomas (SCCs). p53 gene mutations were examined by polymerase chain reaction (PCR)/DNA sequencing methods in 22 carcinomas. The findings were examined for correlations with patients' clinicopathological parameters. Expressions of p53 and PCNA were also examined in 21 formalin-fixed corresponding tissues. Of the fresh frozen tissue specimens, 77% (20/26) showed expression and 68% (15/22) showed mutations (substitutions) of the p53, with significant clustering of the mutations in exons 5 (8/22; 36%), 7 (4/22; 18%) and 8 (5/22; 23%). No mutations were found in exon 6. There was a discordance between expression of p53 protein and mutations of the gene. Parallel to expression and mutations of the p53 found in most of the specimens, expression of TGF-alpha, EGFR, c-erbB-2/neu and PCNA was found in 88% (22/25), 92% (23/25), 58% (14/24) and 91% (21/23) of the specimens, respectively. For the formalin-fixed tissue specimens, 62% (13/21) and 90% (19/21) expressed p53 and PCNA, respectively. Examining for correlations with patients' clinicopathological parameters, expression of p53, TGF-alpha, EGFR and c-erB-2/neu seemed to negatively correlate with the increase of the tumour grade. The present work suggests that: (1) lack of negative growth regulation due to inactivation of the p53 gene together with activation of other proto-oncogenes are necessary genetic events in the carcinogenesis of oropharyngeal SCCs; (2) in oropharyngeal SCCs, p53 gene mutations were clustered in exons 5 (codons 130-186), 7 (codons 230-248) and 8 (codons 271-282) which perhaps suggests that tobacco carcinogens probably affect the mutational hot spots of the p53 gene at codons 157, 175, 186, 248, 273 and 282; and (3) fresh frozen and formalin-fixed tissue specimens give similar results when an immunohistochemical method is applied. The importance of p53, TGF-alpha, EGFR, c-erbB-2/neu and PCNA as biomarkers in oropharyngeal SCCs deserves particular attention because it might offer further understanding of the development of these carcinomas.
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PMID:Expression of biomarkers (p53, transforming growth factor alpha, epidermal growth factor receptor, c-erbB-2/neu and the proliferative cell nuclear antigen) in oropharyngeal squamous cell carcinomas. 1062 52

Breast cancer is one of the common cancers and is a leading cause of cancer mortality in women. The TG.NK transgenic mouse line on FVB strain background expresses the c-neu oncogene under the control of a MMTV promoter in mammary tissue and appears to be a useful animal model for evaluation of strategies to delay or prevent mammary cancer. Fiber-rich nonpurified diet (NTP-2000) and some retinoid analogues have delayed mammary cancer in the TG.NK model. Four week old hemizygous TG.NK female mice with MMTV/c-neu (erbB2) activated oncogene were fed NTP-2000 diet containing the retinoid analogue 4-hydroxyphenylretinamide (4-HPR) at 7 mmol/kg or the arotinoid Ro 40-8757 at 1.5 and 2.5 mmol/kg for 26 weeks. The 4-HPR at 7 mmol/kg diet delayed the development of palpable tumors up to 24 weeks, but by 26 weeks, the incidence markedly increased and was closer to the NTP-2000 diet control group. However, the 4-HPR diet markedly decreased the average weight of the tumors at 26 weeks with no decrease in multiplicity. The 4-HPR also caused significant increase in liver weights without an effect on body weight. Arotinoid Ro 40-8757 caused marked decrease in the number and branching of mammary ducts, and inhibited mammary tumor development with significant decrease in the incidence, multiplicity, and tumor weights compared to the NTP-2000 diet control. Arotinoid also caused a significant dose-related increase in liver weights without a significant effect on body weights. At the doses tested, the arotinoid but not 4-HPR decreased the circulating levels of IGF-1. However, there was no association between the IGF-1 levels and the size, incidence, or absence of tumors when evaluated for any treatment group or for all mice in the study irrespective of treatment. The oncogene erbB2 (c-neu) and the growth factor EGF expression were more prominent in the small tumors of the mice treated with arotinoid than in the larger tumors of the control group. PCNA staining was observed in areas where there was high erbB2 and EGF staining. The delay in onset of mammary tumors by the above retinoid analogues may be related to the delay in development of mammary glands.
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PMID:Changes associated with delay of mammary cancer by retinoid analogues in transgenic mice bearing c-neu oncogene. 1071 86

The aim of this study was to extend our previous observations on the soy modulation of biochemical parameters in 7,12-dimethylbenz[a]anthracene (DMBA)-induced rat mammary tumors, by simultaneously investigating the expression of estrogen receptor-alpha (ERalpha), estrogen receptor-beta (ERbeta), progesterone receptor (PR), apoptosis, neu, and markers of cell proliferation, such as proliferating cell nuclear antigen (PCNA) by immunohistochemistry. The percentage of ERalpha positive tumors was 65.8% in masses from control animals, and significantly dropped to 36.8% in tumors from soy treated rats (P=0.010). The percentage of ERbeta positive tumors was 70.3% in masses from control animals vs. 50.0% in tumors from soy exposed animals (P=0.066). Moreover, the percentage of cases which were both ERalpha and ERbeta positive was significantly lower (17.6%) in soy treated than in control animals (51.3%) (P=0.006). The percentage of PR positive tumors was 34.2% in control animals vs. 2.6% in tumors from soy treated rats (P=0.0006). There were no statistically significant differences in the percentage of tumors positively stained for neu, apoptosis, or PCNA, in control vs. soy treated rats. However, when analyzing the reciprocal correlation among the different biochemical parameters we showed that, in treated animals, the majority of ERalpha positive tumors (91.7%) were also PCNA positive (P=0.036). The median percentage of PCNA positivity was significantly higher in ERalpha positive than in ERalpha negative tumors (25 vs. 5%) (P=0.0031). Moreover, an association was found between PCNA and neu status since all neu positive tumors were also PCNA positive (P=0.011).
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PMID:Dietary soy modulation of biochemical parameters in DMBA-induced mammary tumors. 1218 74

Interactions between the CXCR4 chemokine receptor in breast cancer cells and the ligand CXCL12/SDF-1alpha are thought to play an important role in breast cancer metastases. In this pilot study, CXCR4 expression along with other biomarkers including HER2-neu and EGFR, were measured in primary tumor samples of patients with operable breast cancer to test whether any of these biomarkers alone and in combination could indicate breast cancer with high likelihood of metastasizing to bone marrow. Cytokeratin (CK) positive cells in bone marrow were identified by flow-cytometry following enrichment with CK 7/8 antibody-coupled magnetic beads. Primary tumors (n = 18) were stained with specific antibodies for CXCR4, HER2-neu, EGFR, and PCNA using an indirect avidin-biotin horseradish peroxidase method. The majority of the patients had T2/T3 tumors (72%), or lymph node involvement (67%) as pathologic characteristics that were more indicative of high-risk breast cancer. High CXCR4 cytoplasmic expression was found in 7 of 18 patients (39%), whereas 6 of 18 patients (33%) were found to have CK positivity in bone marrow. The median number of CK(+) cells was 236 (range, 20-847) per 5 x 10(4) enriched BM cells. The presence of CK(+) cells in bone marrow was found to be associated with increased expression of CXCR4 alone or in addition to EGFR and/or HER2-neu expression (P = 0.013, P = 0.005, and P = 0.025, respectively) in primary tumors. Furthermore, three patients with high CK positivity (>236 CK(+) per 5 x 10(4) enriched bone marrow cells) in bone marrow exclusively expressed high levels of CXCR4 with EGFR/HER2-neu (P = 0.001). Our data suggest that high CXCR4 expression in breast cancer may be a potential marker in predicting isolated tumor cells in bone marrow. CXCR4 coexpression with EGFR/HER2-neu might further predict a particular subset of patients with high CK positivity in bone marrow.
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PMID:Chemokine receptor CXCR4 expression in breast cancer as a potential predictive marker of isolated tumor cells in bone marrow. 1613 77

Prognosticators evaluating survival in breast cancer vary in significance in respect to lymph node status. Studies have shown e.g. that HER2/neu immunohistochemistry or HER2/neu gene amplification analysis do perform well as prognosticators in lymph node positive (LN +) patients but are less valuable in lymph node negative (LN -) patients. We collected data from different studies and tried to evaluate the relative significance of different prognosticators in LN+/LN- patient groups. In LN+ patients HER2/neu and E-cadherin immunohistochemistry were the statistically most significant prognosticators followed by proliferation associated features (mitotic counts by SMI (standardised mitotic index) or MAI (mitotic activity index), or S-phase fraction). Bcl-2 immunohistochemistry was also significant but p53 and cystatin A had no significance as prognosticators. In LN- patients proliferation associated prognosticators (SMI, MAI, Ki-67 index, PCNA immunohistochemistry, S-phase fraction) are especially valuable and also Cathepsin D, cystatin A, and p53 are significant, but HER2/neu or bcl-2, or E-cadherin less significant or without significance. We find that in studies evaluating single prognosticators one should distinguish between prognosticators suitable for LN+ and LN- patients. This will allow the choice of best prognosticators in evaluating the prospects of the patient. The distinction between LN+ and LN- patients in this respect may also be of special value in therapeutic decisions.
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PMID:Lymph node status as a guide to selection of available prognostic markers in breast cancer: the clinical practice of the future? 1709 54


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