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 expression of platelet-derived endothelial cell growth factor (PD-ECGF) was determined immunohistochemically in 143 non-small cell lung carcinomas. Staining was observed in 48% of the cases. A relationship between histology, stage, erbB-1, erbB-2, ras and PD-ECGF expression was not found. A relationship of borderline significance was observed between PD-ECGF and p53 expression. There was also no relationship between PD-ECGF expression and proliferative activity (G1 phases, S phases, cyclin A). In contrast, a correlation between PD-ECGF- and VEGF-expression was detectable (p=0.009). Furthermore, PD-ECGF expression was related to the response of lung carcinomas to doxorubicin (p=0.0004). Of 35 sensitive tumors, 26 carcinomas were PD-ECGF-positive (74%) while of 108 resistant carcinomas only 43 tumors (40%) exhibited PD-ECGF expression.
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PMID:Expression of platelet-derived endothelial cell growth factor in non-small cell lung carcinomas: relationship to various biological factors. 977 89

Lymphatic metastases are an important indicator of the malignancy of epithelial cancers. Empirical clinical observations associating specific genetic abnormalities with tumour progression, allied with basic laboratory investigations, are providing not only improved prognostic and diagnostic opportunities, but also a detailed understanding of the molecular machinery of metastasis. One such association--between the c-erbB oncogene family and metastasis--has proved particularly instructive. Functional links between over-expression (and occasionally mutational activation) of c-erbB-1 (EGFR) and c-erbB-2 and specific phenotypes of metastatic cells have been elucidated. Activated c-erbB oncogenes potentiate tumour cell adhesion to endothelial cells and upregulate VEGF, potentially facilitating angiogenesis and vascular invasion. In addition, cells over-expressing these oncogenes frequently show aberrant cell-cell and cell-matrix interactions, mediated by changes in integrin and cadherin function. Thirdly, both EGFR and c-erbB-2 signalling can significantly upregulate specific matrix metalloproteinases, key enzymes involved in angiogenesis and invasion. Finally, c-erbB receptors linked to the actin cytoskeleton and highly expressed on invadopodia, are thought to assist cell migration. Taken together, these observations suggest that such receptors can act as "master switches" in metastasis, whose activation co-ordinately controls events normally utilised in development, now subverted by the metastatic cell. As such, they represent ideal targets for therapeutic intervention.
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PMID:Cell biology of lymphatic metastasis. The potential role of c-erbB oncogene signalling. 1085 61

Axillary dissection is presently a routine staging procedure in the management of breast cancer. The use of adjuvant systemic treatment is largely based on the diagnosis of axillary metastases. Routine axillary dissection leads to acute and chronic side-effects in a large proportion of patients. The sentinel node technique is presently explored with the aim of decreasing the need for standard axillary dissection. A complementary way forward is to analyse the primary breast cancer for molecular markers with prognostic significance with reference to the risk for metastatic capacity and thereby obtain a 'biological staging' and identify those patients in need of systemic adjuvant therapy. A large number of molecular biological factors have been shown to have prognostic significance in breast cancer e.g. c-erbB-2, p53, uPA, PAI-I and VEGF. This article reviews the expression of these and other factors in the primary breast cancers in relation to the risk for axillary and systemic metastatic disease, with the long-term aim of excluding routine axillary dissection.
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PMID:Can axillary dissection be avoided by improved molecular biological diagnosis? 1098 28

Morphologic examinations of salivary gland neoplasias arising in male BALB/c (H-2d) mice carrying the activated HER-2/neu (BALB-NeuT) indicate that expression of the oncogene product in the ductal-acinar structures results in a very human-like acinic cell adenocarcinoma with a smoldering course and infrequent metastatization. Typical and then atypical hyperplasia of ducts and acini preceded the rise of salivary tumors that originated from the confluence of multiple ductal hyperplastic foci, while hyperplastic acini behaved as an abortive preneoplastic lesion. The vascular network in normal, hyperplastic and neoplastic salivary tissue was analysed to see whether activation of the angiogenic process is essential in salivary gland carcinogenesis. Immunostaining with anti-endothelial cells (anti-CD31), anti-beta3 integrin and anti-laminin antibodies revealed that microvessel density was significantly higher in normal and hyperplastic than in neoplastic tissue, in which no signs of new vessel sprouting were found. Assessment of angiogenic factor expression indicates a low presence of VEGF in normal, hyperplastic and neoplastic epithelium, while bFGF was preferentially produced but not exported by neoplastic cells and remained in a cell-associated form. Our data suggest that normal salivary gland vascularization is able to support tumor onset and development with no need for an angiogenic switch.
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PMID:Salivary carcinoma in HER-2/neu transgenic male mice: an angiogenic switch is not required for tumor onset and progression. 1105 59

Even in localized stages of non-small cell lung cancer, which are amenable to curative surgery, prognosis has remained disappointing over the last decades. Thus, in these tumor stages, adjuvant therapy strategies are discussed. In the last decade, numerous prognostic factors have been investigated, which might select patients for additional treatment. In this review, the prognostic impact of individual tumor cell dissemination, tumor cell proliferation, apoptosis, several parameters of angiogenesis (microvessel density, VEGF, bFGF, VEGF receptors), p53, bcl-2, ras, p27(Kip1), erbB-2, telomerase as well as the retinoblastoma tumor suppressor gene is analysed. Up to now, none of these factors has gained a sufficient selectivity to serve as an exclusive discriminator for adjuvant therapy. Nevertheless, a combination of several parameters might contribute to characterize patient subgroups with localized non-small cell lung cancer at high risk for distant relapse.
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PMID:Prognostic factors in stage I/II non-small cell lung cancer. 1157 3

The aim of this study was to evaluate the expression profile of proteins involved in growing of human non-small cell lung cancer (NSCLC) in athymic nude mice. The expressions of 20 gene products in primary NSCLC of 170 patients were analyzed and the proteins were correlated with the transplantability of the carcinomas in nude mice. There was no relationship between xenotransplantability of human non-small cell lung cancer in nude mice and histology, stage or lymph node involvement. Of the analyzed proliferative factors PCNA, cyclin A, cyclin D, cdk2, cdk4 and cell cycle phases only cyclin D, cdk4 and the cell cycle phases were up-regulated in growing carcinomas. There was also a correlation between the apoptotic indices and the take rate in nude mice. Concerning microvessel density and angiogenic factors only VEGF showed a relation to xenotransplantability. Of the proto-oncogenes and suppressor gene products N-RAS, P53, FOS and JUN revealed a relationship to the take rate of NSCLC, while such a relationship was not found with MYC, ERBB-1 and ERBB-2. In a second step, a hierarchical cluster analysis was carried out. The resulting clusters were correlated with the take rate of the carcinomas in nude mice. The expression of JUN, N-RAS, FOS, cyclin D, and cdk4 were significantly different in both groups with non- overlapping confidence intervals. Thus, the up-regulation of the proteins JUN, N-RAS, FOS, cyclin D and cdk4 predicts the growth of NSCLC in nude mice.
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PMID:Expression profile of proteins involved in the xenotransplantability of non-small cell lung cancers into athymic nude mice. 1178 7

Molecular biomarkers for breast cancer are of several types. Risk biomarkers are those associated with increased cancer risk and include mammographic abnormalities, proliferative breast disease with or without atypia, family clustering and inherited germ-line abnormalities. Surrogate endpoint biomarkers are tissue, cellular or molecular alterations that occur between cancer initiation and progression. These biomarkers are utilized as endpoints in short-term chemoprevention trials. Prognostic biomarkers provide information regarding outcome irrespective of therapy, while predictive biomarkers provide information regarding response to therapy. Candidate prognostic biomarkers for breast cancer include elevated proliferation indices such as Ki-67 and proliferating cell nuclear antigen (PCNA); ER and PR overexpression; markers of oncogene overexpression such as c-erbB-2, TGF-a and EGFr; indicators of apoptotic imbalance including overexpression of bcl-2 and an increased bax/bcl-2 ratio; markers of disordered cell signaling such as p53 nuclear protein accumulation; alteration of differentiation signals such as overexpression of c-myc and related proteins; loss of differentiation markers such as TGF-b II receptor and retinoic acid receptor; and alteration of angiogenesis proteins such as VEGF overexpression. As our knowledge regarding molecular biomarkers for breast cancer increases, prognostic indices will be developed that combine the predictive power of individual molecular biomarkers with specific clinical and pathologic factors.
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PMID:Biomarkers for breast cancer. 1214 73

The paucity of tools that control expression of specific genes in vivo represents a major limitation of functional genomics in mammals; most available small-molecule regulators of transcription-e.g. histone deacetylase inhibitors-exert pan-genomic effects. Recent developments in understanding the role of chromatin in regulating the genome, and of protein-DNA interactions have allowed the development of designed transcription factors that regulate specific genes in vivo (Reik et al., Curr Opin Genet Dev 2002;12:233). These proteins contain two modules: (i) a zinc finger protein (ZFP)-based DNA-binding domain (DBD) designed to recognize a specific sequence (for example, a motif in the promoter of a certain gene); (ii) a functional module (for example, a transcriptional activation or repression domain). Recent data describe the use of such designed transcription factors to regulate a variety of clinically relevant gene targets in human cells: these include MDR1, erythropoietin, erbB-2 and erbB-3, VEGF, and PPARgamma. In the case of VEGF (Liu et al., J Biol Chem 2001;276:11323), proportional upregulation by the designed transcription factor of all three distinct splice isoforms generated by this locus was observed, illuminating the utility of endogenous gene control in therapeutic settings (proper isoform ratio is essential for the proangiogenic function of VEGF). In the case of PPARgamma, use of a transcriptional repressor designed to downregulate the expression of two PPARgamma isoforms allowed "mutation-free reverse genetics" analysis that illuminated a unique role for the PPARgamma2 isoform in adipogenesis (Ren et al., Genes Dev 2002;16:27). The ability to selectively activate or repress specific mammalian genes in vivo using designed transcription factors thus has considerable promise in clinical and in basic science settings.
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PMID:Designed transcription factors as tools for therapeutics and functional genomics. 1221 87

Advances in molecular and cell biology have led to further understanding of the mechanisms of malignant growth and metastasis in human breast cancer cells. Initiation and progression of breast cancer results from mutations and the abnormal expression of many genes that control cellular proliferation, differentiation, invasion, metastasis and sensitivity to therapy (chemotherapy and radiation therapy). Inhibition of host immunity also plays a role in breast cancer progression. Many genes have been selected as targets for antisense therapy, including HER-2/neu, PKA, TGF-alpha, EGFR, TGF-beta, IGFIR, P12, MDM2, BRCA, Bcl-2, ER, VEGF, MDR, ferritin, transferrin receptor, IRE, C-fos, HSP27, C-myc, C-raf and metallothionein genes. The strategy behind antisense therapy is the development of specific therapeutic agents that aim to correct the mutations and abnormal expression of cellular genes in breast tumour cells by decreasing gene expression, inducing degradation of target mRNA and causing premature termination of transcription. Many in vitro and in vivo studies have investigated the therapeutic efficacy of oligonucleotides and antisense RNAs. These studies have demonstrated specific inhibition of tumour cell growth by antisense therapy and have shown synergistic inhibitory effects between antisense oligonucleotides or antisense RNA and conventional chemotherapeutic drugs used in the treatment of breast cancer. Antisense oligonucleotides have been modified to improve their ability to penetrate cells, bind to gene sequences and downregulate target gene function. Many delivery systems for antisense RNA and antisense oligonucleotides have been developed, including virus vectors (retrovirus, adenovirus and adeno-associate virus) and liposomes, to carry the antisense RNA or oligonucleotides through the cell membrane into the cytoplasm and nucleus of the tumour cells. However, in order to determine their feasibility antisense therapies need to be further investigated to determine their antitumour activity, pharmacokinetics and toxicity in breast cancer patients.
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PMID:Gene targets of antisense therapies in breast cancer. 1222 74

In this study we describe and discuss the dichotomous effects of docetaxel trastuzumab (Herceptin)/docetaxel therapy on the angiogenic molecular profile in two patients with her-2 + chemo-resistant recurrent breast carcinoma. In the first case, an intensification of angiogenesis occurred following therapy, accompanied by an impressive increase of the cancer cell proliferation index. This tumor did not express HIF1 alpha and shared a HIF-independent VEGF overexpression, which remained unaffected by therapy. An intensified formation of thymidine phosphorylase (TP)-rich stroma, presumably a response to docetaxel, shows a TP-dependent angiogenic response. In the second patient, VEGF and HIF1 alpha were down-regulated in post-treatment biopsies and this was accompanied by a sharp reduction of the vascular density and of the cancer cell proliferation rate. In both cases, c-erbB-2 expression was abrogated by Herceptin. Taking into account that Herceptin down-regulates VEGF through reduction of HIF1 alpha synthesis, this clinical study provides evidence that an anti-angiogenic effect from Herceptin/Docetaxel therapy is expected only in tumors with HIF1 alpha-dependent VEGF overexpression. In contrast, HIF1 alpha-independent VEGF angiogenic activity cannot be abrogated by Herceptin. Docetaxel mediated up-regulation of TP in the tumoral stroma may, on the contrary, result in angiogenesis intersification and rapid tumor relapse. Such an effect should be of clinical importance since Herceptin/Docetaxel-based regimens are currently evaluated for the adjuvant therapy of her-2 + breast cancer patients. Studying the Herceptin-induced phenotypic changes of tumors could lead to the identification of specific molecular profiles that bring about diverging angiogenic responses. Adjustment of the chemotherapy regimen accordingly would prove of clinical importance.
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PMID:The effect of trastuzumab/docatexel combination on breast cancer angiogenesis: dichotomus effect predictable by the HIFI alpha/VEGF pre-treatment status? 1282 Apr 39


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