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)

The class I IgG receptor (Fc gamma RI or CD64 receptor), which is present on key cytotoxic effector cells, has been shown to initiate the destruction of tumor cells in vitro and has been hypothesized to play a role in the destruction of antibody-coated cells such as platelets in idiopathic thrombocytopenia purpura (ITP). This overview summarizes the clinical experience with CD64-directed immunotherapy in cancer patients with the bispecific antibodies MDX-447 [humanized Fab anti-CD64 x humanized Fab anti-(epidermal growth factor receptor, EGFR)] and MDX-H210 (humanized Fab anti-DC64 x Fab anti-HER2/neu), and with the anti-CD64 monoclonal antibody (mAB) MDX-33 (H22) in the modulation of monocyte CD64 in vivo. In an ongoing phase I/II open-label trial with progressive dose escalation (1-15 mg/m2), patients with treatment refractory EGFR-positive cancers (renal cell carcinoma (RCC), head and neck, bladder, ovarian, prostate cancer and skin cancer) are treated weekly with intravenous MDX-447, with and without granulocyte-colony-stimulating factor (G-CSF). MDX-447 has been found to be immunologically active at all doses, binding to circulating monocytes and neutrophils (when given with G-CSF), causing monocytopenia and stimulating increases in circulating plasma cytokines. MDX-447 is well tolerated, the primary toxicities being fever, chills, blood pressure lability, and pain/ myalgias. Of 36 patients evaluable for response, 9 have experienced stable disease of 3-6 month's duration. The optimal dose and the maximal tolerated dose (MTD) have yet to be defined; dose escalation continues to define better the dose, toxicity, and the potential therapeutic role of this bispecific antibody. Three MDX-H210 phase II trials are currently in progress, all using the intravenous dose of 15 mg/m2 given with granulocyte/macrophage (GM-CSF). These consist of one trial each in the treatment of RCC patients, patients with prostate cancer, and colorectal cancer patients, all of whom have failed standard therapy. At the time of writing, 11 patients have been treated in these phase II trials. Four patients have demonstrated antitumor effects. Patients demonstrating responses include 2 with RCC and 2 with prostate cancer. One RCC patient has had a 54% reduction in size of a hepatic metastatic lesion and the other has had a 49% decrease in the size of a lung metastasis with simultaneous clearing of other non-measurable lung lesions. Regarding the two patients with prostate cancer, one has had a 90% reduction in serum prostate-specific antigen (PSA; 118-11 ng/ml), which has persisted for several months; the other patient with prostate has had a 70% reduction of serum PSA (872 ng/ml to 208 ng/ml) within the first month of treatment. Both patients have also demonstrated symptomatic improvement. In a completed phase I and in ongoing phase I/II clinical trials, patients with treatment-refractory HER2/neu positive cancers (breast, ovarian, colorectal, prostate) have been treated with MDX-H210, which has been given alone and in conjunction with G-CSF, GM-CSF, and interferon gamma (IFN gamma). These trials have been open-label, progressive dose-escalation (0.35-135 mg/m2) studies in which single, and more often, multiple weekly doses have been administered. MDX-H210 has been well tolerated, with untoward effects being primarily mild-to-moderate flu-like symptoms. The MTD has not yet been defined. MDX-H210 is immunologically active, binding to circulating monocytes, causing monocytopenia, as well as stimulating increases in plasma cytokine levels. Furthermore, some patients have evidence of active antitumor immunity following treatment with MDX-210. Antitumor effects have been seen in response to MDX-H210 administration; these include 1 partial, 2 minor, and 1 mixed tumor response; 15 protocol-defined stable disease responses have occurred. (ABSTRACT TRUNCATED)
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PMID:Clinical experience with CD64-directed immunotherapy. An overview. 943 76

HLA-transgenic mice have been developed to facilitate studies of HLA-restricted cytotoxic responses, e.g., for the identification of immunodominant HLA-restricted CTL epitopes and the optimization of peptide or DNA vaccine constructs for human use. We have developed HLA-A2402/K(b)-transgenic mice expressing chimeric human (alpha1 and alpha2 domains of HLA-A2402) and mouse (alpha3, transmembrane and cytoplasmic domains of H-2K(b)) class I molecules. Immunization of these HLA-A2402/K(b)-transgenic mice with various known HLA-A24-restricted immunodominant cancer CTL epitope peptides derived from gp100, MAGE-1, MAGE-3, Her2/neu, CEA and TERT induced HLA-A24-restricted, peptide-specific CTLs. Using these transgenic mice, we identified a novel HLA-A24-restricted CTL epitope, PSA(152-160), encoded by human prostate-specific antigen. Staining with HLA tetramers showed that the cytotoxic activity induced by immunizing with PSA(152-160) in HLA-A2402/K(b) transgenic mice was HLA-A2402-restricted and CD8-dependent. Therefore, PSA(152-160) might be a candidate peptide for vaccination of HLA-A24(+) patients with prostate cancer. Our results suggest that HLA-A2402/K(b) transgenic mice might be useful in the search for HLA-A24-restricted CTL epitopes functioning as human cancer antigens and for the development of peptide-based cancer immunotherapy.
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PMID:Development of HLA-A2402/K(b) transgenic mice. 1212 6

We report the case of an 82-year-old male patient with a > 8-year history of prostate cancer (PrCa), who developed breast adenocarcinoma (BrCa) (Ki-67+ and negative for ER, PR, PSA and HER2/neu) after prolonged (approximately 7-year) anti-androgen (flutamide) monotherapy for locally advanced PrCa. Biochemical and molecular analyses showed hyperestrogenemia (serum estradiol = 266 pg/ml, with normal range < 74 pg/ml), germline BRCA-1 mutation (T to C at nucleotide 3232, in exon 11, causing Glu to Gly change at codon 1038) and chromosome 9 inversion (karyotype of 46,XY with inv(9) (p11q21)). Following bilateral mastectomy without adjuvant systemic therapy, the patient has been disease-free (from both BrCa and PrCa) for > 3 years. In contrast to LHRH-based hormonal therapies for PrCa, anti-androgen monotherapy causes hyper-estrogenemia due to the suppressed negative feedback loop of androgens on LHRH and LH production, stimulation of testicular androgen production and their intracrine transformation to estrogens in peripheral target tissues. In this case report, the hyperestrogenemia may have further increased the BrCa risk in a patient with other risk factors (BRCA-1 mutation and chromosome 9 inversion, which has been previously shown to impinge upon testicular function and intracrine balance of androgens vs. estrogens). This case report illustrates that PrCa patients receiving anti-androgen monotherapy may be at risk of BrCa, in the event of the concomitant presence of other genetically-determined predisposing factors, and indicates the importance of exercising caution against indiscriminate and prolonged use of anti-androgen monotherapy in patients with risk factors for male BrCa.
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PMID:Male breast adenocarcinoma in a prostate cancer patient following prolonged anti-androgen monotherapy. 1515 26

Publicly available human genomic sequence data provide an unprecedented opportunity for researchers to decode the functionality of human genome. Such information is extremely valuable in cancer prevention diagnosis and treatment. Cancer Genome Anatomy Project (CGAP) and Gene Expression Omnibus (GEO) are two bioinformatic infrastructures for studying functional genomics. The goal of this study is to explore the feasibility of incorporating the Internet-available bioinformatic databases to discover human breast cancer-related genes. Several tools including the Gene Finder, Virtual Northern (vNorthern) and SAGE digital gene expression displayer (DGED) were used to analyze differential gene expression between benign and malignant breast tissues. A pilot study was performed using both EST and SAGE vNorthern to analyze the expression of a panel of known genes, including high abundance genes beta-actin and G3PDH, low abundance genes BRCA1 and p53, tissue-specific genes CEA and PSA and two breast cancer-related genes Her2/neu and MUC1. We found a high expression of beta-actin and G3PDH and a low expression of BRCA1 and p53 across different types of tissues as well as a tissue-specific expression of CEA in colon and PSA in prostate. A further analysis of 30 known breast cancer-related genes in breast cancer tissues by vNorthern demonstrated a high expression of oncogenes and low expression of tumor suppressor genes. An open-end analysis of two pools of breast cancer and benign breast tissue libraries by SAGE DGED produced 53 differentially expressed genes according to the screening criteria of a >five-fold difference and p<0.01. Further analysis by EST vNorthern and virtual microarray analysis reduced the candidate genes to six, with four down-regulated genes, ANXA1, CAV1, KRT5 and MMP7, and two up-regulated genes, ERBB2 and G1P3 in breast cancer. These findings were validated by a real-time RT-PCR analysis in eight paired human breast cancer tissue samples. We conclude that the combined multiple high throughput analyses is an effective data mining strategy in cancer gene identification. This approach may improve the usage of public available genomic data through strategic data mining of high throughput analysis.
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PMID:In silico identification of breast cancer genes by combined multiple high throughput analyses. 1564 32

The immunoexpression of prostate-specific antigen in breast cancers has been well established, but the role of this extra-prostate PSA appears to be a complex, poorly understood and of doubtful prognostic value. In this context, our aim was to evaluate PSA in breast carcinomas and to compare the results with several established prognostic markers of breast cancer: estrogen and progesterone receptors status, HER2/neu status, histological type of tumor, grade of differentiation, stage, tumor size, nodal and menopausal status. We have immunohistochemically assessed 53 breast carcinomas for PSA, ER, PR and oncoprotein HER2/neu status. The relationship between the clinical and histopathological markers was analyzed by chi-square test. In the present study PSA was expressed in 60.3% of cases, and we have found a significant correlation with the histological type and HER2/neu negative status in premenopausal women. No statistically significant difference was found between PSA positivity and menopausal status of the patients, nodal status, estrogen and progesterone receptors, HER2/neu status in postmenopausal patients, tumor size or histological grade. We conclude that in our study PSA can not be considered as a valuable independent prognostic factor in breast carcinoma. As long as the majorities of PSA positive carcinomas were small in size, early stage, better and moderately differentiated, HER2/neu negative and 70% of ER/PR positive carcinomas expressed PSA, it might be useful as a marker for a subset of breast cancers with better prognosis, which could respond to endocrine therapy, in correlation with other prognostic markers.
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PMID:Prostate-specific antigen value as a marker in breast cancer. 1657 73

AR (androgen receptor) and PSA (prostate-specific antigen) are involved in the pathogenesis of breast cancer, but their role is not clearly defined. The purpose of this study was to analyze by immunohistochemistry the AR and PSA (prostate-specific antigen) expression in 156 female breast carcinomas and to correlate the results with some histopathological parameters, like ER (estrogen receptor), PR (progesterone receptor), HER2/neu, nodal and metastasis status, histological type and grade. ARs and PSA were expressed in 112/156 (72%) and respectively in 61/156 (39%) of cases and we found a positive correlation between AR and PSA expression in breast carcinomas (p<0.0002). We also found an association between the histological type of the tumor and AR (p<0.001), respectively PSA (p=0.01) and between AR and the grade of differentiation (p=0.007) and the nodal status (p=0.02). No correlations were found between the metastasis status and AR or PSA. 47.3% (53/112) of AR-positive cases and 46% (28/61) of PSA-positive cases were ER-negative. High frequency of AR (87.5%) and PSA (75%) expression was found in medullary carcinomas and 53% of lobular invasive carcinomas co-expressed AR and PSA. We found an inverse correlation between HER2/neu and PSA (p=0.05). Although most of the PSA-positive carcinomas were lymph node-negative, well and moderately differentiated, we did not find any statistically significant correlations between these parameters and PSA expression. Our study confirms that ARs are commonly expressed in breast cancer and the expression of PSA and AR are highly correlated. Moreover, all the lobular carcinomas and the majority of medullary carcinomas co-expressed AR and PSA, the majority of AR-positive carcinomas were lymph node-negative, well and moderately differentiated, and large number of ER-negative carcinomas expressed AR and PSA.
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PMID:Immunohistochemical expression of androgen receptor and prostate-specific antigen in breast cancer. 1697 95

PSA (prostate-specific antigen), a serine protease with chymotrypsin-like activity is the most useful tumor marker for prostate cancer screening, diagnosis, prognosis and monitoring. The identification of PSA in normal and tumoral mammary gland was regarded as a curiosity, but the confirmation of PSA expression in the mammary gland by others teams of researchers and the identification of specific mRNA in tumors with PSA immunoexpression initiated new perspectives for studies. The aim of this study was to examine the prevalence of PSA in breast cancers and to evaluate the correlations between PSA expression and some clinicopathological markers. We analyzed the expression of PSA in series of consecutive breast carcinomas by immunohistochemistry and correlated the PSA expression with the histological type and grade, nodal and metastasis status, estrogen receptor (ER), progesterone receptor (PR), androgen receptor (AR) and HER2/neu expression. PSA expression was observed in 44.5% of breast cancers, particularly in lobular types of carcinoma (p<0.0001). In univariate analysis, the expression of PSA was statistically correlated with AR (p<0.0001), PR (p=0.01) and inversely correlated with HER2/neu overexpression (p=0.008) and G3 (p=0.02). PSA did not significantly correlate with ER expression, lymph node and metastasis status. In multivariate analysis, PR was a moderate predictor (p=0.024) but the lobular type (p=0.000), AR (p=0.000), HER2/neu (p=0.002) and G3 (p=0.008) were strong predictors for PSA immunoexpression.
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PMID:Prostate-specific antigen may serve as a pathological predictor in breast cancer. 1851 23

The role of estrogen and androgen receptors signaling in breast cancer is widely accepted, but the interrelations between them are not well understood. It was suggested that PSA could be a marker of endogenous balance between androgens and estrogens. In this context, we intended to investigate the potential of relationship between polymorphic tandem repeats (CAG, TA and CA) in AR (androgen receptor), ERalpha (estrogen receptor alpha) and ERbeta (estrogen receptor beta) genes and the immunoexpression of PSA and AR proteins. We assessed also the possible influences of CAG, TA, and CA variables and other available prognostic factors (ER, PR, AR, HER2/neu, PSA expression, and nodal status) on disease-free survival. We assessed the polymorphic tandem repeats lengths by genotyping, followed by high-resolution denaturing polyacrylamide gel electrophoresis in 163 breast cancers. Immunohistochemistry was performed to assess the expressions of AR, PSA, ER, PR and HER2/neu proteins. Our results showed that PSA was correlated with the length of CA repeats in the 3'-untranslated region of ERbeta, shorter CA repeats being correlated with PSA expression (p=0.03). AR immunoexpression was correlated with CAG repeats on AR gene, higher number of repeats being linked to a higher AR immunoexpression (p=0.04). Performing logistic regression to investigate relationships with prognosis, we observed that PSA immunoexpression (p=0.004), the nodal status (p-<0.001) and marginally, longer TA repeats (p=0.05) were correlated with increased disease-free survival. AR expression presented a low statistical value (p=0.054) in predicting evolution and was not entered into the multivariate regression analysis. Altogether, our findings supports the hypothesis that estrogens, through both alpha and beta-receptors variants are mediating the AR signaling pathway.
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PMID:Interaction between estrogens and androgen receptor genes microsatellites, prostate-specific antigen and androgen receptor expressions in breast cancer. 2035 69

TAAs (tumor-associated antigens) microarrays were designed to detect auto-antibodies directly in patient sera. Twelve different probes were chosen according to their described occurrence in cancer pathologies (Cyclin B1, Cyclin D1, Complement factor H, c-myc, IMP1, p53, p62, survivin, Her2/neu, Koc, NY-ESO-1 and PSA). Microarrays of these 12 proteins were immobilized within the nitrocellulose/cellulose acetate membrane of a 96-well filtering microtiter plate bottom. The captured auto-antibodies were detected using a staining approach based on alkaline phosphatase labeling. Thus, the presence of specific auto-antibodies in samples was visualized through the positive staining of the corresponding TAA spots. The TAA HiFi microarrays were shown to be able to capture specific purified anti-TAA antibodies. In real samples, 9 proteins from the 12 TAAs panel were shown to generate specific signal and 5 antigens (p53, NY-ESO-1, IMP1, cyclin B1 and c-myc) were shown to have interaction with more than 10% of the positive sera from cancer patients. This protein subpanel was proven to be able to detect 72.2% of the cancer patients tested (within a 34 panel of 18 patients and 16 healthy donors).
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PMID:Multiplexed immunoassay for the rapid detection of anti-tumor-associated antigens antibodies. 2166 12

While androgen deprivation therapy (ADT) reduces tumor burden, autocrine growth factor loops such as human epidermal growth factor receptor 2 (HER2/ErbB-2/neu) have been proposed to contribute to prostate cancer (PCa) survival and relapse. However, the role of ErbB-2 in regulating androgen-sensitive (AS) and castration-resistant (CR) cell proliferation remains unclear. Here, we determined the role of ErbB-2 in PCa progression and survival under steroid-reduced conditions using two independent PCa cell progression models. In AR-positive androgen-independent (AI) PCa cells that exhibit the CR phenotype, ErbB-2 was constitutively activated, compared to corresponding AS PCa cells. In AS LNCaP C-33 cells, androgen-induced ErbB-2 activation through ERK1/2 mediates PCa cell proliferation. Further, the ErbB-2-specific but not EGFR-specific inhibitor suppresses basal and androgen-stimulated cell proliferation and also blocks ERK1/2 activation. ErbB-2 ectopic expression and cPAcP siRNA transfection of LNCaP C-33 cells each increases ErbB-2 tyrosine phosphorylation, correlating with increased AI PSA secretion and cell proliferation. Conversely, trapping ErbB-2 by transfected endoplasmic reticulum-targeting ScFv5R expression vector abolished DHT-induced LNCaP C-33 cell growth. Moreover, inhibition of ErbB-2 but not EGFR in AI LNCaP C-81 and MDA PCa2b-AI PCa cells significantly abolished AI cell growth. In contrast to androgens via ErbB-2/ERK1/2 signaling in AS PCa cells, the inhibition of ErbB-2 abrogated AI cell proliferation by inhibiting the cell survival protein Akt in those AI cells. These results suggest that ErbB-2 is a prominent player in mediating the ligand-dependent and -independent activation of AR in AS and AI/CR PCa cells respectively for PCa progression and survival.
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PMID:ErbB-2 signaling plays a critical role in regulating androgen-sensitive and castration-resistant androgen receptor-positive prostate cancer cells. 2625 1


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