Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0006142 (breast cancer)
160,383 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The proliferating cell nuclear antigen (PCNA) is an essential protein for DNA replication and damage repair. How its function is controlled remains an important question. Here, we show that the chromatin-bound PCNA protein is phosphorylated on Tyr 211, which is required for maintaining its function on chromatin and is dependent on the tyrosine kinase activity of EGF receptor (EGFR) in the nucleus. Phosphorylation on Tyr 211 by EGFR stabilizes chromatin-bound PCNA protein and associated functions. Consistently, increased PCNA Tyr 211 phosphorylation coincides with pronounced cell proliferation, and is better correlated with poor survival of breast cancer patients, as well as nuclear EGFR in tumours, than is the total PCNA level. These results identify a novel nuclear mechanism linking tyrosine kinase receptor function with the regulation of the PCNA sliding clamp.
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PMID:Tyrosine phosphorylation controls PCNA function through protein stability. 1711 32

Advancements in medical genetics are resulting in the identification of key molecules in the pathways that lead to carcinogenesis. With these discoveries, drugs are developed that target a protein or block a particular molecular pathway with the potential to bring about disease regression. The HER2/neu tyrosine kinase receptor is one such target. Therapy based on the humanised monoclonal antibody, trastuzumab, targets HER-2/neu and inhibits the growth of HER2/neu-overexpressing breast cancer cells. Assays for markers to HER2/neu are forerunners of many more predictive assays that are likely to enter the clinical arena in the near future, many of which will require quantitative analysis. In the field of tissue based assay systems controversies are well documented on the lack of reproducibility in the immunohistochemical analysis HER2/neu. The problems encountered to date lye with the difficulty in reliably standardising the immunohistochemical assay. One of the first steps in addressing this issue is to develop a standard reference material against which the 'variable' of assay sensitivity for HER2/neu can be accurately gauged. Work in the United States and Europe aimed at providing a standard reference material for HER2/neu has already commenced. Preliminary work conducted in Europe shows that development of a standard comprised of cell lines is feasible and when employed as part of an external quality assurance programme, results in significant improvement in the numbers of clinical laboratories achieving appropriate results. In the United States it has been proposed that two standards consisting of well characterized cell lines will be produced, one a National Institute of Standards and Technology (NIST)--certifiable standard, and the other a commercially developed standard for use in all HER2/neu testing. The aim is that this approach will act as a template for other important predictive markers of the future.
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PMID:Developing a cell line standard for HER2/neu. 1719 46

Pertuzumab (Omnitarg) is a novel antibody against HER-2, domain II. HER-2 is a tyrosine kinase receptor that is overexpressed in several carcinomas, especially breast cancer. Pertuzumab, labeled with the low-energy beta emitter (177)Lu, might be a candidate for targeted radiotherapy of disseminated HER-2-positive micrometastases. The radiolabeled antibody [(177)Lu]pertuzumab showed favorable targeting properties in BALB/c (nu/nu) mice with HER-2-overexpressing xenografts. The absorbed dose in tumors was more than five times higher than the absorbed dose in blood and more than seven times the absorbed dose in any other normal organ. Experimental therapy showed that [(177)Lu]pertuzumab delayed tumor progression compared with controls (no treatment, P < 0.0001; nonlabeled pertuzumab antibody, P < 0.0001; and (177)Lu-labeled irrelevant antibody, P < 0.01). No adverse side effects of the treatment could be detected. Thus, the experimental results support the planning of clinical studies applying [(177)Lu]pertuzumab for therapy.
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PMID:[177Lu]pertuzumab: experimental therapy of HER-2-expressing xenografts. 1721 Jul 14

hMena (ENAH), an actin regulatory protein involved in the control of cell motility and adhesion, is modulated during human breast carcinogenesis. In fact, whereas undetectable in normal mammary epithelium, hMena becomes overexpressed in high-risk benign lesions and primary and metastatic tumors. In vivo, hMena overexpression correlates with the HER-2(+)/ER(-)/Ki67(+) unfavorable prognostic phenotype. In vitro, neuregulin-1 up-regulates whereas Herceptin treatment down-modulates hMena expression, suggesting that it may couple tyrosine kinase receptor signaling to the actin cytoskeleton. Herein, we report the cloning of hMena and of a splice variant, hMena(+11a), which contains an additional exon corresponding to 21 amino acids located in the EVH2 domain, from a breast carcinoma cell line of epithelial phenotype. Whereas hMena overexpression consistently characterizes the transformed phenotype of tumor cells of different lineages, hMena(+11a) isoform is concomitantly present only in epithelial tumor cell lines. In breast cancer cell lines, epidermal growth factor (EGF) treatment promotes concomitant up-regulation of hMena and hMena(+11a), resulting in an increase of the fraction of phosphorylated hMena(+11a) isoform only. hMena(+11a) overexpression and phosphorylation leads to increased p42/44 mitogen-activated protein kinase (MAPK) activation and cell proliferation as evidenced in hMena(+11a)-transfected breast cancer cell lines. On the contrary, hMena knockdown induces reduction of p42/44 MAPK phosphorylation and of the proliferative response to EGF. The present data provide new insight into the relevance of actin cytoskeleton regulatory proteins and, in particular, of hMena isoforms in coupling multiple signaling pathways involved in breast cancer.
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PMID:Molecular cloning of hMena (ENAH) and its splice variant hMena+11a: epidermal growth factor increases their expression and stimulates hMena+11a phosphorylation in breast cancer cell lines. 1736 86

The human epidermal growth factor receptor 2 (HER2) tyrosine kinase receptor is overexpressed in approximately 20-30% of human breast cancers, and is associated with reduced survival. Hence, numerous therapeutic strategies have been tested for their ability to target the HER2 protein. The humanized monoclonal antibody trastuzumab (Herceptin) was the first HER2-targeted agent approved for clinical use in breast cancer patients. Response rates to single-agent trastuzumab range from 12 to 34% for metastatic breast cancer (MBC), and significant improvements in survival rates are achieved in patients with early-stage HER2-overexpressing breast cancer in the adjuvant setting. Despite its initial efficacy, acquired resistance to trastuzumab develops in a majority of patients with MBC, and a large subset never responds, demonstrating primary resistance. Molecular mechanisms of trastuzumab antineoplastic activity and potential mechanisms contributing to its resistance will be discussed in this review. Novel agents that may enhance trastuzumab efficacy will also be discussed.
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PMID:Trastuzumab: triumphs and tribulations. 1753 17

As several aromatase inhibitors are now available for treating breast cancer, we developed a model system to compare their antitumor efficacy and to explore strategies for their optimal use. Tumors are grown in ovariectomized, immunodeficient mice from MCF-7 human breast cancer cells transfected with the aromatase gene (MCF-7Ca) and can therefore synthesize as well as respond to estrogen. Results from this model have been predictive of clinical outcome. Thus, inhibiting estrogen action and estrogen synthesis by treating mice with the aromatase inhibitor letrozole and the antiestrogen tamoxifen in combination did not result in synergy. Moreover, when tamoxifen treatment was no longer effective, tumor growth was significantly reduced in response to sequential letrozole treatment. However, our findings indicate that letrozole alone was better than all other treatments. Although letrozole resulted in long sustained growth inhibition, tumors eventually grew despite continued treatment. Mechanisms of resistance to letrozole were investigated during the course of treatment. ER was initially upregulated in responding tumors, but subsequently decreased below control levels in tumors no longer responsive to letrozole. Her-2 as well as adapter proteins (p-Shc and Grb-2) and signaling proteins in the MAPK cascade (p-Raf, p-Mekl/2, and p-MAPK), were all increased in letrozole resistant tumors. In LTLT cells, isolated from the letrozole resistant tumors and treated with inhibitors of the MAPKinase pathway, MAPK activity was decreased and ER expression restored to control levels. Inhibitors of EGFR/Her-2 also restored the sensitivity of LTLT cells to letrozole. These results suggest that crosstalk occurs between ER and tyrosine kinase receptor signaling. Therefore, to investigate whether down-regulating ER would prevent activation of MAPK and resistance to letrozole, xenografts were treated with letrozole and faslodex in combination. Her-2 and MAPK were not increased and tumor growth was inhibited throughout 29 weeks of treatment. These results suggest that blocking both ER and growth factor mediated transcription may delay development of resistance to letrozole and maintain its growth inhibition of breast cancer.
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PMID:Xenograft models for aromatase inhibitor studies. 1761 Nov 1

The nerve growth factor (NGF)-tyrosine kinase receptor TrkA plays a critical role in various neuronal and non-neuronal cell types by regulating cell survival, differentiation, and proliferation. In breast cancer cells, TrkA stimulation results in the activation of cellular growth, but downstream signaling largely remains to be described. Here we used a proteomics-based approach to identify partners involved in TrkA signaling in breast cancer cells. Wild type and modified TrkA chimeric constructs with green fluorescent protein were transfected in MCF-7 cells, and co-immunoprecipitated proteins were separated by SDS-PAGE before nano-LC-MS/MS analysis. Several TrkA putative signaling partners were identified among which was the DNA repair protein Ku70, which is increasingly reported for its role in cell survival and carcinogenesis. Physiological interaction of Ku70 with endogenous TrkA was induced upon NGF stimulation in non-transfected cells, and co-localization was observed with confocal microscopy. Mass spectrometry analysis and Western blotting of phosphotyrosine immunoprecipitates demonstrated the induction of Ku70 tyrosine phosphorylation upon NGF stimulation. Interestingly no interaction between TrkA and Ku70 was detected in PC12 cells in the absence or presence of NGF, suggesting that it is not involved in the initiation of neuronal differentiation. In breast cancer cells, RNA interference indicated that whereas Ku70 depletion had no direct effect on cell survival, it induced a strong potentiation of apoptosis in TrkA-overexpressing cells. In conclusion, TrkA signaling appears to be proapoptotic in the absence of Ku70, and this protein might therefore play a role in the long time reported ambivalence of tyrosine kinase receptors that can exhibit both anti- and eventually proapoptotic activities.
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PMID:Nerve growth factor receptor TrkA signaling in breast cancer cells involves Ku70 to prevent apoptosis. 1761 66

The colony-stimulating-factor 1 receptor (CSF-1 R) is a tyrosine kinase receptor that is absolutely required for macrophage differentiation and thus occupies a central role in hematopoiesis. Mice deficient for the csf1r gene show multiple defects in macrophage development, reproduction and tissue remodeling. Moreover, deregulation of this gene is a hallmark of many tumors. This includes repression of expression in acute myeloid leukemia and aberrant activation in certain solid tumors, such as breast cancer. Expression of this gene therefore needs to be tightly controlled. This review summarizes experiments providing a detailed picture of how transcription of csf1r gene expression is regulated. Aside from the direct relevance to hematopoiesis, studies of csf1r transcriptional regulation provide a model for understanding the molecular mechanisms that control mammalian cell fate.
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PMID:The transcriptional regulation of the Colony-Stimulating Factor 1 Receptor (csf1r) gene during hematopoiesis. 1798 68

Receptor mediated internalization is a crucial step for targeted intracellular delivery of therapeutic and imaging agents. It was recently demonstrated that trastuzumab, an FDA approved humanized monoclonal antibody against Her-2/ neu tyrosine kinase receptor, did not induce endocytosis of the internalization resistant Her-2/ neu receptor. Here we report that accelerated internalization of trastuzumab can be induced by cross-linking the cell membrane bound antibody-receptor complex with an avidin/streptavidin-biotin system. We demonstrated that internalization was achieved both in vitro and in vivo in Her-2/ neu expressing human breast cancer cell lines (BT-474, SK-BR-3 and AU-565) and that repetitive labeling cycles further amplified the loading of cargo molecules within the targeted cells. No trastuzumab binding and internalization was observed in Her-2/ neu negative MDA-MB-231 cells, whereas weak membrane binding and negligible internalization were detected in MCF-7 cells with low expression level of Her-2/ neu receptor. The method was used to noninvasively image Her-2/ neu receptors in isolated cells and in a preclinical breast cancer model with MRI. The controlled internalization of Her-2/ neu receptors can potentially enhance intracellular delivery of drugs and imaging probes, and improve imaging sensitivity and selectivity as well as therapeutic efficacy, through antibody-directed binding and internalization using a pretargeting approach.
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PMID:Controlled internalization of Her-2/ neu receptors by cross-linking for targeted delivery. 1807 96

RON (recepteur d'origine nantais), a tyrosine kinase receptor for macrophage-stimulating protein (MSP) was implicated in tumor progression. However, it was not investigated how this important oncogene is regulated. We show that MSP promotes invasion of MDA MB 231 and MDA MB 468 but not MCF-7 breast cancer cells. Reverse transcription-PCR and Western analysis indicated the expression of RON message and protein, respectively, in MDA MB 231 and MDA MB 468 cells but not in MCF-7 cells. RON expression correlated with Sp1 expression. Initial analysis of a 1.2-kb and 400-bp RON promoter in MDA MB 231 and MDA MB 468 cells suggested the presence of all the necessary regulatory elements within 400 bp from the transcription start site. Site-directed mutagenesis of the 400-bp RON promoter revealed that the overlapping Sp1 sites at-94 (Sp1-3/4) and Sp1 site at -113 (Sp1-5) are essential for RON gene transcription. Electrophoretic mobility shift assays and chromatin immunoprecipitation analysis indicated that Sp1 binding to these sites is required for RON promoter activity. Ectopic Sp1 expression in Sp1 null SL2 cells confirmed the involvement of these Sp1 sites in the regulation of oncogenic RON tyrosine kinase. Treatment of MDA MB 231 cells with mithramycin A, an inhibitor of Sp1 binding, or siRNA knock-down of Sp1 blocked RON gene expression and MSP-mediated invasion of MDA MB 231 cells. This is the first report demonstrating a clear link between Sp1-dependent RON tyrosine kinase expression and invasion of breast carcinoma cells.
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PMID:Regulation of RON tyrosine kinase-mediated invasion of breast cancer cells. 1816 35


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