Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The erbB-2 (or HER-2 or neu) gene is amplified and overexpressed in approximately one-third of cancers of the breast, stomach, and ovary. Evidence is accumulating that erbB-2 overexpression is associated with decreased survival of breast cancer patients. In an effort to understand how erbB-2 overexpression might impart a more malignant potential to breast cancer cells, we have searched for evidence of changes in gene expression associated with erbB-2 overexpression. Using differential screening of a complementary DNA library we identified several complementary DNAs that represent mRNAs the expression of which may vary according to erbB-2 level. One complementary DNA was studied in detail. The mRNA encoding the ribosomal protein L19 (1.9 kilobases) was more abundant in breast cancer samples that express high levels of erbB-2 (P < 6 x 10(-7)). The level of L19 mRNA expression varied over a 1- to 64-fold range among the tumor samples. No evidence of gene amplification for L19 was identified. The L19 overexpression in these breast tumor samples was not associated with the increased expression of the mRNAs for other ribosomal proteins (S16 and L26).
 ...
PMID:High-level expression of the ribosomal protein L19 in human breast tumors that overexpress erbB-2. 809 82

Cloned sequences encoding a truncated form of the HER2 receptor were obtained from cDNA libraries derived from two HER2-overexpressing human breast cancer cell lines, BT-474 and SK-BR-3. The 5' 2.1 kb of the encoded transcript is identical to that of full-length 4.6-kb HER2 transcript and would be expected to produce a secreted form of HER2 receptor containing only the extracellular ligand binding domain (ECD). The 3' end of the truncated transcript diverges 61 nucleotides before the receptor's transmembrane region, reads through a consensus splice donor site containing an in-frame stop codon, and contains a poly(A) addition site, suggesting that the truncated transcript arises by alternative RNA processing. S1 nuclease protection assays show a 40-fold variation in the abundance of the truncated 2.3-kb transcript relative to full-length 4.6-kb transcript in a panel of eight HER2-expressing tumor cell lines of gastric, ovarian, and breast cancer origin. Expression of this truncated transcript in COS-1 cells produces both secreted and intracellular forms of HER2 ECD; however, immunofluorescent labeling of HER2 ECD protein in MKN7 tumor cells that natively overexpress the 2.3-kb transcript suggests that transcriptionally generated HER2 ECD is concentrated within the perinuclear cytoplasm. Metabolic labeling and endoglycosidase studies suggest that this HER2 ECD (100 kDa) undergoes differential trafficking between the endoplasmic reticulum and Golgi compartments compared with full-length (185-kDa) HER2 receptor. Transfection studies indicate that excess production of HER2 ECD in human tumor cells overexpressing full-length HER2 receptor can result in resistance to the growth-inhibiting effects of anti-HER2 monoclonal antibodies such as muMAb4D5. These findings demonstrate alternative processing of the HER2 transcript and implicate a potentially important growth regulatory role for intracellularly sequestered HER2 ECD in HER2-amplified human tumors.
 ...
PMID:A truncated intracellular HER2/neu receptor produced by alternative RNA processing affects growth of human carcinoma cells. 809 58

The Neu/HER-2 receptor tyrosine kinase is overexpressed in some types of human adenocarcinomas, including tumors of the breast and the ovary. A 44 kDa glycoprotein that elevates tyrosine phosphorylation of Neu has been isolated and named Neu differentiation factor (NDF), or heregulin. Here we show that NDF affects tyrosine phosphorylation of Neu in human tumor cells of breast, colon and neuronal origin, but not in ovarian cells that overexpress the receptor. By using monoclonal antibodies (mAbs) to Neu, we found that the ovarian receptor is immunologically and biochemically similar to the mammary p185neu. Nevertheless, unlike breast-derived Neu, the ovarian protein did not display covalent cross-linking to radiolabeled NDF, and was devoid of ligand-induced association with phosphatidylinositol 3'-kinase. Direct binding analysis showed that NDF binds with high affinity (Kd approximately 10(-9) M) to mammary cells, but its weak association with ovarian cells is probably mediated by heparin-like molecules. Similar to the endogenous receptor, the ectopically overexpressed Neu of mammary cells, but not of ovarian and fibroblastic cells, exhibited elevated levels of NDF-induced phosphorylation and covalent cross-linking of the radiolabeled factor. Taken together, our results imply that NDF binding to cells requires both Neu and an additional cellular component, whose identity is still unknown, but its tissue distribution is more restricted than the expression of the neu gene.
 ...
PMID:Cell-type specific interaction of Neu differentiation factor (NDF/heregulin) with Neu/HER-2 suggests complex ligand-receptor relationships. 809 77

HER2/neu-overexpressing tumor cell lines are relatively resistant to lymphokine-activated killer (LAK) cell cytotoxicity when compared to HER2/neu-nonexpressing lines. HER2/neu+ targets were also resistant to binding by LAK large granular lymphocytes (LGL) as shown by visualization at the single-cell level, a target monolayer binding assay and in "cold" target inhibition experiments. HER2/neu+ LAK-resistant ovarian cell lines demonstrated an absence of ICAM-1 expression while expression of LFA-3, N-CAM, laminin and beta 1 integrins was comparable to that of HER2/neu- targets. In contrast, the HER2/neu+ breast cell line, SKBR-3, which was also resistant to lysis and binding by LAK LGL, demonstrated normal expression of ICAM-1. Anti-ICAM-1 antibodies blocked binding and lysis of HER2/neu- carcinoma targets by LAK cells, further supporting the notion that lack of ICAM-1 expression on HER2/neu+ cells contributes to their resistance. The modest binding and lysis of HER2/neu+ targets by LAK cells was significantly inhibited by anti-LFA-1 antibodies, suggesting the existence of another counter-receptor for LFA-1 on HER2/neu+ targets. The following also supported deficiencies in post-binding events when HER2/neu+ cells resisted the lytic activity of LAK cells: (a) when the relative resistance to effector cell binding was overcome by exogenous lectin. HER2/neu+ cell lines were still resistant to LAK cytolysis, and (b) HER2/neu+ targets were resistant to perforin-containing granule extracts obtained from the CTLL-R8 cytotoxic lymphocyte cell line. These results indicate that deficiency in effector binding as well as post-binding events contributes to the resistance of HER2/neu-overexpressing tumor targets to LAK-cell-mediated lysis.
 ...
PMID:Resistance of HER2/neu-overexpressing tumor targets to lymphokine-activated-killer-cell-mediated lysis: evidence for deficiency of binding and post-binding events. 809 27

The HER2 protooncogene encodes a receptor tyrosine kinase, p185HER2. The overexpression of p185HER2 has been associated with a worsened prognosis in certain human cancers. In the present work we have screened a variety of different tumor cell lines for p185HER2 expression using both enzyme-linked immunosorbent and fluorescence-activated cell sorting assays employing murine monoclonal antibodies directed against the extracellular domain of the receptor. Increased levels of p185HER2 were found in breast (5/9), ovarian (1/6), stomach (2/3) and colorectal (5/16) carcinomas, whereas all kidney and submaxillary adenocarcinoma cell lines tested were negative. Some monoclonal antibodies directed against the extracellular domain of p185HER2 inhibited growth in monolayer culture of breast and ovarian tumor cell lines overexpressing p185HER2, but had no effect on the growth of colon or gastric adenocarcinomas expressing increased levels of this receptor. The most potent growth-inhibitory anti-p185HER2 monoclonal antibody in monolayer culture, designated mumAb 4D5 (a murine IgG1 kappa antibody), was also tested in soft-agar growth assays for activity against p185HER2-overexpressing tumor cell lines of each type, with similar results. In order to increase the spectrum of tumor types potentially susceptible to monoclonal antibody-mediated anti-p185HER2 therapies, to decrease potential immunogenicity issues with the use of murine monoclonal antibodies for human therapy, and to provide the potential for antibody-mediated cytotoxic activity, a mouse/human chimeric 4D5 (chmAb 4D5) and a "humanized" 4D5 (rhu)mAb 4D5 HER2 antibody were constructed. Both engineered antibodies, in combination with human peripheral blood mononuclear cells, elicited antibody-dependent cytotoxic responses in accordance with the level of p185HER2 expression. Since this cytotoxic activity is independent of sensitivity to mumAb 4D5, the engineered monoclonal antibodies expand the potential target population for antibody-mediated therapy of human cancers characterized by the overexpression of p185HER2.
 ...
PMID:Differential responses of human tumor cell lines to anti-p185HER2 monoclonal antibodies. 810 22

Bispecific monoclonal antibodies (BsmAb) with specificity for tumor Ag and effector cell trigger molecules have been shown to redirect the cytotoxicity of several peripheral blood mononuclear cell populations against relevant tumor. The BsmAb, 2B1, binds to the extracellular domain of the c-erbB-2 gene product of the HER2/neu proto-oncogene and to CD16. In this report, the binding and cytotoxic characteristics of 2B1 are presented. Maximal saturation binding of 2B1 to PBL and c-erbB-2 expressing SK-OV-3 cells occurred in the 1 microgram/ml concentration range. However, substantial lysis potentiation was observed at 1000-fold lower BsmAb concentrations. Optimal tumor lysis was obtained when the BsmAb, PBL, and target cells were continuously coincubated. When PBL were franked with 2B1, washed, and added to labeled targets, substantially less lysis was observed. These results suggest that the best way to therapeutically exploit the cytotoxic attributes of 2B1 may be to obtain continuous BsmAb exposure to tumor. Approaches based on franking of this BsmAb to PBL may not be warranted.
 ...
PMID:Binding and cytotoxicity characteristics of the bispecific murine monoclonal antibody 2B1. 810 70

Neu differentiation factor (NDF, also called heregulin) is a 44-kilodalton glycoprotein that stimulates tyrosine phosphorylation of the Neu/HER-2 receptor and induces phenotypic differentiation of certain mammary cancer cell lines to growth-arrested and milk-producing cells. To determine which molecules participate in the concomitant morphological alterations, we analyzed the expression of several cytoskeletal and surface molecules and found that NDF elevated the expression of the intercellular adhesion molecule 1 (ICAM-1) in cultured AU-565 human adenocarcinoma cells. The levels of both the protein and the mRNA of ICAM-1 were elevated after 3-5 days of treatment with NDF. Elevated expression of ICAM-1 was induced also by gamma-interferon and by the tumor-promoting phorbol ester (PMA), albeit with different kinetics. Down-regulation of protein kinase C or its inhibition by calphostin C partially inhibited the effect of NDF, implying that the induction of ICAM-1 may be mediated by protein kinase C. NDF transcripts were detectable in 3 of 9 human mammary tumors, suggesting that the in vitro effect of the factor may be relevant to breast cancer. By selecting Neu-positive human mammary tumors (n = 39), we found a significant correlation (P < 0.001) between the expression of ICAM-1 and histological features of invasive ductal carcinoma with a prominent carcinoma in situ component. When cultured in vitro the cells of these tumors grew in clusters and formed domelike structures reminiscent of comedo-type carcinoma in situ. In addition, the majority of patients with tumors that coexpressed ICAM-1 and Neu had no lymph node involvement, unlike most Neu-positive but ICAM-1-negative tumors, which metastasized to the lymphatic system. Taken together, our observations suggest that the induction of ICAM-1 by NDF may affect the morphology, differentiation state, and metastasis of Neu-expressing mammary tumor cells.
 ...
PMID:Neu differentiation factor (heregulin) induces expression of intercellular adhesion molecule 1: implications for mammary tumors. 810 45

To study potential sources of tumor-associated Ags in human ovarian cancer, we have established two ovarian tumor cell lines (OvS1 and OvA2) from two ovarian cancer patients, which express the cellular oncogene HER2/neu. Corresponding tumor infiltrating lymphocyte cultures have also been established and display an autologous tumor-specific pattern of cytotoxicity that is HLA-A2 restricted. To determine the potential relationship between HER2/neu expression and CTL-mediated cytolysis, we first established tumor cell clones from OvS1. These were categorized as high or low expressors of HER2/neu (cOvS1+ or cOvS1-, respectively), and cOvS1+ clones displayed a significantly higher sensitivity to CTL killing as compared with cOvS1- clones. To modulate the expression of HER2/neu, ovarian cancer cells were treated with IFN-gamma. After this exposure, HER2/neu expression was significantly decreased, whereas the expression of HLA Class I was significantly increased. Despite the increase in HLA Class I molecules on the cell surface, CTL-mediated cytolysis of both OvS1 and OvA2 was significantly decreased. IFN-gamma treated cOvS1+ clones displayed a similar decrease in sensitivity to CTL killing, whereas IFN-gamma treated cOvS1- clones displayed an increase or no change in sensitivity to CTL. To confirm this apparent association between HER2/neu expression and CTL recognition, melanoma tumor cell lines that were insensitive to ovarian tumor-specific CTL were transfected with the HER2/neu gene. An HLA-A2+ HER2/neu-transfected melanoma cell line was made sensitive to HLA-A2 restricted ovarian tumor-specific CTL but not to HLA-A2 unrestricted CTL, whereas an HLA-A2- HER2/neu-transfected melanoma remained insensitive to HLA-A2 restricted CTL. These results demonstrate that the sensitivity of ovarian epithelial tumor cells to CTL-mediated lysis is associated with the level of expression of HER2/neu, suggesting that this oncogene product may serve as a source of tumor-associated Ags or as an inducer of such peptides. This is the first time in a human tumor system that oncogene expression has been related to the induction of antigenicity. These results prompt us to approach new strategies for immunotherapy of cancer.
 ...
PMID:Association of HER2/neu expression with sensitivity to tumor-specific CTL in human ovarian cancer. 813 50

Recent studies have begun to elucidate the molecular events involved in the development of ovarian cancer. First, it has been shown that epithelial ovarian cells both produce and have receptors for many peptide growth factors. It is possible that these growth factors may participate in autocrine and paracrine growth-regulatory pathways in these cells. Increased activity of stimulatory factors, eg, transforming growth factor-alpha, or decreased activity of inhibitor factors, eg, transforming growth factor-beta, may facilitate malignant transformation. In addition, it has been shown that ovarian cancer cells often have acquired the ability to degrade extracellular matrix and invade the underlying tissues. Finally, alterations in several oncogenes and tumor-suppressor genes, including HER2/neu, c-myc, and p53, have been found in ovarian cancers. Although exciting insights into the molecular pathology of ovarian cancer have been gained, we remain far from a comprehensive understanding of the biology of this highly lethal disease.
 ...
PMID:The biology of ovarian cancer. 821 3

In an attempt to define the type and temporal sequences of somatic genetic changes that precede the onset of invasive lung cancer, and to search for biological markers useful in screening multiple primary tumors of the upper aerodigestive tract, we have performed a cytogenetic and genetic study using normal bronchial epithelium and primary tumor specimens of 68 patients undergoing pulmonary resection for early stage lung cancer, and normal bronchial epithelium of 5 controls with metastatic sarcomas. Of the 68 lung cancer cases, 31 had a single tumor and 37 displayed multiple synchronous or metachronous tumors. Cytogenetic alterations were observed in 59% (23/39) of the evaluable tumor specimens with complex rearranged karyotypes, particularly involving chromosomes 3 (70%), 17 (39%), 11 (26%), 8, 9, 12 (22%), and 7 (17%). Gene alterations were also detected including overexpression of epidermal growth factor receptor (EGFR) in 63% (36/57), HER2/NEU in 21% (12/56), and p53 mutations in 50% (12/24). The overall frequency of genetic changes (any type) in the tumors was 76% (52/68). In the normal bronchial mucosa, we identified a rearranged karyotype in 20% of the evaluable cases (13/63); particularly simple rearrangements involving chromosomes 3p (6 cases), 7 (6 cases), 17 (3 cases), 9, 11 (2 cases), 8 (1 case); as well as overexpression of EGFR in 39% (20/51) and of HER2/NEU in 14% (7/51). The overall frequency of genetic changes (any type) in the normal epithelium was 46% (30/65). The presence of a rearranged karyotype in the bronchial mucosa was associated with a rearranged karyotype in the tumor sample. Other statistically significant correlations were found between histopathologic and clinical features and the occurrence of the different cytogenetic and genetic changes both in tumors and in the normal bronchial mucosa. No genetic abnormalities were found in the bronchial epithelium of the 5 controls.
 ...
PMID:Genetic changes in lung cancer. 841


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>