Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P04626 (erbB-2)
 5,251 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Given the plethora of well-documented breast carcinoma-associated antigens in humans including MAGE-1, -2 and -3, mutated p53, p21ras, HER-2/neu and DF3/MUC-1, coupled with evidence that humoral and cytotoxic T-cell responses against these antigens exist, the central dilemma facing tumor immunologists is why the host immune response is so inefficient. One possibility is that tumor cells themselves are either inefficient or ineffective antigen-presenting cells (APCs). The failure of tumor cells to function as APCs may be due to their inability to process and present the antigen, the absence or insufficient numbers of adhesion and costimulatory molecules or, potentially, the secretion of inhibitory cytokines. Therefore, we sought to determine whether human breast cancer cell lines could function as APCs and, if not, to identify mechanism(s) responsible for this defect. Here, we show that human breast cancer cell lines fail to present alloantigen. This defect does not reside in their inherent capacity to present antigen but rather is due to apoptosis of activated T cells induced by exposure to the breast carcinoma-associated mucin antigen, DF3/MUC1. These results support the hypothesis that DF3/MUC1 may contribute to the paucity of clinically significant anticarcinoma-specific immune responses.
 ...
PMID:Breast cancer-associated antigen, DF3/MUC1, induces apoptosis of activated human T cells. 894 37

IIB-BR-G is an undifferentiated, highly heterogeneous, hormone receptor negative human breast cancer cell line previously established in our laboratory from a patient's primary tumor. An in vitro growing cell line (IIB-BR-G) and a xenotransplanted tumor growing in nude mice (IIB-BR-G(NUDE)) were derived. To further characterize these systems, immunocytochemical analysis was performed for differentiation antigens (PEM 200 kDa, CEA, NCA 90 kDa), blood-group related antigens (Le(x), sTn), oncogenes and tumor suppressor gene products (Her-2/neu protein, p53), metastasis-related cathepsin D and CD63/5.01 Ag, and the chemokine monocyte chemotactic protein 1 (MCP-1). Expression of markers was heterogeneous in these different systems. Previously reported karyotypic analysis has shown extensive chromosomal alterations including double min. Searching for oncogene amplification, we detected augmented copy number of c-myc and c-fos, the last one with two rearranged fragments. No amplification was found for c-erbB-2 in the cell line or in IIB-BR-G(NUDE), although this oncogene was amplified in the patient's primary tumor DNA. The differences observed between the patient's tumor, the cell line and the IIB-BR-G(NUDE) tumors are probably due to clonal expansion of cell variants not present in the original tumor. Electron microscopy of IIB-BR-G growing cells revealed epithelial characteristics with abundant dense granules, presumably secretory, distributed all over the cytoplasm and great nuclear pleomorphism. In vitro, IIB-BR-G cells showed a significant number of invading cells by Matrigel assay. After nearly 40 sequential subcutaneous passages of the original xenograft through nude mice, 80% of recipients developed spontaneous metastases, primarily to the lung and lymph nodes. Since this experimental model allowed to analyze changes produced in cancer cells from the primary tumor during adaptation to in vitro and in vivo growth, our results provide novel insights on the behaviour of hormone independent metastatic breast cancer.
 ...
PMID:The human breast cancer cell line IIB-BR-G has amplified c-myc and c-fos oncogenes in vitro and is spontaneously metastatic in vivo. 962 Apr 46

Molecular changes associated with breast cancer progression were characterized using the MCF-10F cell series. MCF-10F was established from fibrous mastectomy tissue of a patient without detectable cancer. In vitro treatment of MCF-10F cells with benzo(a)pyrene resulted in a transformed subclone MCF-10F-BP1 (BP1). Transfection of clone BP1 with T24-Hras resulted in the tumorigenic line MCF-10F-BP1-Tras (BP1-Tras). Using flow cytometry, the expression of HLA I, ERBB-2 and MUC-1 was found to be comparable in 'normal' MCF-10F, transformed BP1 and tumorigenic BP1-Tras cells. Glycosylated mucin is elevated in BP1 but reduced in BP1-Tras cells. Using mRNA differential display analysis, cDNA profiles of the 'normal', transformed and tumorigenic cell lines were strikingly similar, yet distinct and elevated expression of several common cDNA fragments was detected in BP1 and BP1-Tras when compared with MCF-10F cells. These fragments were cloned and sequenced. The sequences of clones T1-360 and C4-310 are homologous to two reported EST cDNA clones from human fetal tissue and were further characterized. Elevated expression of the genes corresponding to clones T1-360 and C4-310 was verified using Northern blotting. High-level expression of these genes was also detected in the breast cancer cell line MCF-7 that was derived from the pleural effusion of a patient with advanced breast cancer. Therefore, specific molecular changes associated with breast cancer development were identified and may be indicators of neoplastic progression.
 ...
PMID:Neoplastic progression of breast epithelial cells--a molecular analysis. 968 93

Single micrometastatic tumor cells encased in mesenchymal tissues, such as bone marrow (BM), are regarded as suitable targets for adjuvant immunotherapy since they are easily accessible for both immunoglobulins and immune effector cells. However, the antigen profile of such cells, to which antibody therapy might be targeted, cannot be deduced from the antigen pattern of the primary tumor. To evaluate the antigen profile of disseminated cells found in BM aspirates from 20 breast cancer patients, we applied a quantitative immuno-cytochemical double-marker assay and typed for 4 common tumor-associated cell-surface antigens (c-erbB-2, CO17-1A, MUC-1, LewisY). Individual breast cancer cells were identified by F(ab) fragments of the pan-cytokeratin (CK) monoclonal antibody (MAb) A45-B/B3, directly conjugated with alkaline phosphatase, which identified cancer cells as sensitively as the standard APAAP procedure (r = 0.998; p < 0.0001). CK+ cells co-expressed c-erbB-2, CO17-1A, MUC-1 and LewisY in 87%, 78%, 79% and 79% of patients, respectively; however, the frequency of double-positive cells per sample varied considerably. The mean percentage of double-positive cells per total number of CK+ cells was 41% for c-erbB-2 (range 0-92%), 47% for CO17-1A (range 0-75%), 49% for MUC-1 (range 0-67%) and 32% for LewisY (range 0-59%). In 14 of these patients, we used an antibody cocktail to type CK+ cells for the combined expression of all 4 antigens. The antibody cocktail labeled significantly more CK+ cells than each of the single MAbs alone, resulting in a mean of 71% double-positive tumor cells (34-100%). We conclude that expression of tumor-associated cell-surface antigens on micrometastatic cancer cells in BM is heterogeneous, which may limit the efficacy of monovalent immunotherapeutic strategies directed against only one particular antigen. Thus, defining target antigens expressed by the actual target cells emerges as a crucial first step in selecting appropriate therapeutic targets.
 ...
PMID:Tumor-antigen heterogeneity of disseminated breast cancer cells: implications for immunotherapy of minimal residual disease. 998 23

Over the past 2 decades, numerous anticancer antibodies against different molecular targets and labeled with different gamma-emitting radionuclides have been studied in human tumor xenografts and in clinical trials. In breast cancer, these molecular targets have included principally tumor-associated antigens, such as carcinoembryonic antigen (CEA) and the polymorphic epithelial mucin antigen, MUC1, and more recently the growth factor receptors, EGF-R and HER-2/neu. No antibody-based agent has yet been approved for clinical use in the diagnosis of mammary carcinoma, because few trials have addressed the issue of clinical use of these imaging agents in the management of breast cancer patients. Recently, the CEA antibody Fab' fragment approved for colorectal cancer detection, Arcitumomab (CEA-Scan, [Immunomedics, Morris Plains, NJ]), has been found to image both palpable and nonpalpable breast lesions that were suspicious on screening mammograms. Results to date indicate that Arcitumomab can complement mammography by providing a high specificity and positive predictive value, thus indicating when a patient with an abnormal mammogram may proceed directly to definitive surgery without an intermediate diagnostic biopsy. Breast cancer immunoscintigraphy holds promise for advancing toward immunoPET, which should combine the specificity of antibodies with the high sensitivity and resolution of PET. It is also the foundation of breast cancer radioimmunotherapy with humanized antibodies against CEA and MUC1, as well as other immunotherapy strategies.
 ...
PMID:Breast cancer imaging with radiolabeled antibodies. 999 Jun 82

Adenocarcinomas of the breast behave clinically and epidemiologically in ways that show host resistance factors are important for outcome in addition to grade and stage of malignancy. Immune reactivity to autologous tumors is indicated by the general presence of lymphoid infiltration (LI) and regional lymph node changes; however, these changes predict favorable outcome only in non-metastatic disease. LI is characterized by CD4+ and CD8+ tumor infiltrating lymphocytes reflecting latent cell-mediated immunity (CMI). CMI and humoral immune reactivity have been demonstrated to autologous tumor and a variety of tumor-associated antigens (TAA) have been implicated including CEA, HER-2/neu, MAGE-1, p53, T/Tn and MUC-1. Immune incompetence involving CMI is progressive with the stage of breast cancer and is prognostically significant. Immunotherapy of several types has been designed to address this immunodeficiency and the TAAs involved. Animal models have employed drug therapy, cytokine transfection, vaccines with autologous tumor, cytokines like interferon alpha (IFN-alpha) and interleukin-2 (IL-2), TAA tumor vaccines, and immunotoxins with evidence of tumor regression by immunologic means. Immunotherapy of human breast cancer is a rapidly growing experimental area. Positive results have been obtained with natural IFN and interleukins, particularly in combination strategies (but not with high dose recombinant IFN or IL-2), with autologous tumor vaccine (but not yet with transfected autologous tumor); with a mucin carbohydrate vaccine (Theratope) in a combination strategy (but not with mucin core antigen) and with several immunotoxins. Combination strategies involving immunorestoration, contrasuppression, adjuvant, and immunotoxins are suggested for the future.
 ...
PMID:The immunology and immunotherapy of breast cancer: an update. 1023 Aug 72

Several methods have been used recently to determine gene expression profiles of cell populations. Here we demonstrate the strength of combining two approaches, serial analysis of gene expression (SAGE) and DNA arrays, to help elucidate pathways in breast cancer progression by finding genes consistently expressed at different levels in primary breast cancers, metastatic breast cancers, and normal mammary epithelial cells. SAGE profiles of 21PT and 21MT, two well-characterized breast tumor cell lines, were compared with SAGE profiles of normal breast epithelial cells to identify differentially expressed genes. A subset of these candidates was then placed on an array and screened with clinical breast tumor samples to find genes and expressed sequence tags that are consistently expressed at different levels in diseased and normal tissues. In addition to finding the predicted overexpression of known breast cancer markers HER-2/neu and MUC-1, the powerful coupling of SAGE and DNA arrays resulted in the identification of genes and potential pathways not implicated previously in breast cancer. Moreover, these techniques also generated information about the differences and similarities of expression profiles in primary and metastatic breast tumors. Thus, combining SAGE and custom array technology allowed for the rapid identification and validation of the clinical relevance of many genes potentially involved in breast cancer progression. These differentially expressed genes may be useful as tumor markers and prognostic indicators and may be suitable targets for various forms of therapeutic intervention.
 ...
PMID:Combining serial analysis of gene expression and array technologies to identify genes differentially expressed in breast cancer. 1055 19

The role of major histocompatibility complex expression in cancer prognosis and pathogenesis is contradictory. The aim of the current study was to compare the expression of HLA class I molecules and of oncoproteins that may be sources of peptides presented by HLA class I antigens in non-small-cell lung cancer. For this purpose, the expression of HLA class I antigen and TAP-1 molecule (a transporter in the antigen-processing 1 transport protein) were studied with epidermal growth factor, receptor; c-erbB-2; episialin; wild-type and mutant p53; bcl-2 oncoprotein expression; and angiogenic factor expression (vascular endothelial growth factor and thymidine phosphorylase). The degree of lymphocytic stromal infiltration and of platelet-endothelial cell adhesion molecule-expressing lymphocytes was also studied. A strong association of c-erbB-2 and MUC1 (episialin) expression with HLA class I expression was observed (p = 0.005 and 0.009, respectively). Intense CD31-positive lymphocytic infiltration was also more frequent in HLA class I-positive cases (p = 0.05). Although there was no association of HLA class I expression with survival, loss of the HLA class I expression in MUC1 or c-erbB-2 overexpressing cases conferred a poorer clinical outcome (p = 0.04). Both c-erbB-2 and MUC1 are well-known targets of T-cell-mediated cytotoxicity and cell-cell or cell-matrix adhesion-regulating proteins. The authors provide evidence that the sequence of cell adhesion-disrupting oncoprotein expression, HLA class I induction, and enhanced epitope presentation followed by lymphocytic response is an important pathogenetic three-step sequence of events that define, in part, the clinical outcome in non-small-cell lung cancer.
 ...
PMID:c-erbB-2 and episialin challenge host immune response by HLA class I expression in human non-small-cell lung cancer. 1068 43

Human epithelial mucin, MUC-1, is commonly expressed in adenocarcinoma including 80% of breast cancers. erbB-2 is overexpressed in approximately 30% of breast cancers. Expression of MUC-1 and erbB-2 may be partially overlapping but discoordinate. Therefore, combined use of antibodies directed against these two antigens might increase the number of patients who benefit from immunotherapy. Monoclonal antibody (MAb) DF3 recognizes the MUC-1 tandem repeat. We investigated phagocytosis and cytolysis of cultured human breast cancer cells by monocyte-derived macrophages mediated by MAb DF3 and its bispecific antibody (BsAb) DF3xH22 with the second epitope directed against the Fc component of phagocytic cells. Purified monocytes from healthy donors were cultured with granulocyte macrophage colony-stimulating factor with or without IFN-gamma. antibody-dependent cellular phagocytosis (ADCP) and antibody-dependent cellular cytotoxicity (ADCC) assays were performed with these macrophages and MUC-1-expressing target cells (ZR75-1) in the presence of MAb DF3 and BsAb DF3xH22. ADCP was measured by two-color fluorescence flow cytometry using PKH2 (green fluorescent dye) and R-phytoerythrin (RPE) (red)-conjugated MAb against human CD14 and CD11b and was confirmed by confocal microscopy. ADCC was measured by (51)Cr release assay. Immunohistochemical staining studies of MUC-1 and erbB-2 were performed on 67 primary breast cancer tissues. Expression of MUC-1 and erbB-2 was partially overlapping but discoordinate in 67 consecutive breast cancers. Both MAb DF3 and BsAb DF3xH22 mediated ADCP. However, ADCP mediated by MAb DF3 was greater than that mediated by BsAb DF3xH22. ADCC as detected by (51)Cr release was not seen with either antibody. The addition of IFN-gamma to monocyte-derived macrophage cultures inhibited ADCP compared to granulocyte macrophage colony-stimulating factor alone. Given the partially overlapping but discoordinate expression of MUC-1 and erbB-2 in breast cancer, therapy directed toward both antigens should be considered. MAb DF3 and the BsAb DF3xH22, can effectively mediate phagocytosis of MUC-1-expressing target cells. Further investigations are needed to determine whether this antibody-induced phagocytosis results in long-term specific T-cell activation against MUC-1.
 ...
PMID:Phagocytosis of breast cancer cells mediated by anti-MUC-1 monoclonal antibody, DF3, and its bispecific antibody. 1135 26

Many serological markers have been utilized to indicate the status, risk, or presence of breast cancer. In May 1996, the American Society of Clinical Oncology (ASCO) convened a Tumor Marker Panel and determined clinical practice guidelines for the use of tumor markers in breast cancer. Eight markers containing carcinoembryonic antigen (CEA) and CA15-3 were evaluated and assigned by expert reviewers to be valuable markers of breast cancer. CA15-3 recognizes a mucin-like glycoprotein, MUC-1, which is frequently expressed in breast cancer tissues. BCA225, which may recognize antigens similar to MUC-1 glycoprotein, are sensitive and specific markers for breast cancer. However, it is not recommended to measure the 2 markers in combination. The measurement of carboxy-terminal telopeptide of type I collagen (I CTP) is worthwhile as a serological diagnostic method of bone metastasis from breast cancer. Other markers such as erbB-2, CYFRA 21-1 and PTHrP are candidates for clinical utilization as tumor markers in breast cancer.
 ...
PMID:[Tumor markers in breast cancer]. 1147 35


1 2 Next >>