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BIN1; bridging integrator 1 (2q14)

Gene Summary

Gene:BIN1; bridging integrator 1
Aliases: AMPH2, AMPHL, SH3P9
Location:2q14
Summary:This gene encodes several isoforms of a nucleocytoplasmic adaptor protein, one of which was initially identified as a MYC-interacting protein with features of a tumor suppressor. Isoforms that are expressed in the central nervous system may be involved in synaptic vesicle endocytosis and may interact with dynamin, synaptojanin, endophilin, and clathrin. Isoforms that are expressed in muscle and ubiquitously expressed isoforms localize to the cytoplasm and nucleus and activate a caspase-independent apoptotic process. Studies in mouse suggest that this gene plays an important role in cardiac muscle development. Alternate splicing of the gene results in ten transcript variants encoding different isoforms. Aberrant splice variants expressed in tumor cell lines have also been described. [provided by RefSeq, Sep 2011]
Databases:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:myc box-dependent-interacting protein 1
HPRD
Source:NCBI
Updated:14 December, 2014

Gene
Ontology:

What does this gene/protein do?
Show (17)

Cancer Overview

Research Indicators

Publications Per Year (1989-2014)
Graph generated 14 December 2014 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • DNA Methylation
  • Phosphorylation
  • Biological Models
  • Neoplastic Cell Transformation
  • myc Genes
  • Up-Regulation
  • Sensitivity and Specificity
  • Proto-Oncogene Proteins c-myc
  • Blotting, Southern
  • Infant
  • CpG Islands
  • Polymerase Chain Reaction
  • Cell Division
  • Nuclear Proteins
  • Cancer Gene Expression Regulation
  • Oligonucleotide Array Sequence Analysis
  • Alternative Splicing
  • Liver Cancer
  • Immunohistochemistry
  • Chromosome 2
  • Genes, Neoplasm
  • Tumor Suppressor Proteins
  • BIN1
  • Transcription Factors
  • Breast Cancer
  • Blotting, Northern
  • Tumor Markers
  • Prostate Cancer
  • Tumor Suppressor Gene
  • Signal Transducing Adaptor Proteins
  • Brain Tumours
  • Nerve Tissue Proteins
  • Apoptosis
  • Lymphatic Metastasis
  • Messenger RNA
  • Gene Expression Profiling
  • Melanoma
  • Childhood Cancer
  • Carrier Proteins
  • Neuroblastoma
  • Drug Resistance
  • Poly(ADP-ribose) Polymerases
  • RTPCR
Tag cloud generated 14 December, 2014 using data from PubMed, MeSH and CancerIndex

Notable (4)

Scope includes mutations and abnormal protein expression.

Entity Topic PubMed Papers
Breast CancerBIN1 and Breast Cancer View Publications8
NeuroblastomaReduced BIN1 expression in MYCN amplified Neuroblastoma View Publications6
Prostate CancerBIN1 and Prostate Cancer View Publications3
MelanomaBIN1 and Melanoma View Publications1

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Related Links

Latest Publications: BIN1 (cancer-related)

Barekati Z, Radpour R, Lu Q, et al.
Methylation signature of lymph node metastases in breast cancer patients.
BMC Cancer. 2012; 12:244 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Invasion and metastasis are two important hallmarks of malignant tumors caused by complex genetic and epigenetic alterations. The present study investigated the contribution of aberrant methylation profiles of cancer related genes, APC, BIN1, BMP6, BRCA1, CST6, ESR-b, GSTP1, P14 (ARF), P16 (CDKN2A), P21 (CDKN1A), PTEN, and TIMP3, in the matched axillary lymph node metastasis in comparison to the primary tumor tissue and the adjacent normal tissue from the same breast cancer patients to identify the potential of candidate genes methylation as metastatic markers.
METHODS: The quantitative methylation analysis was performed using the SEQUENOM's EpiTYPER™ assay which relies on matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS).
RESULTS: The quantitative DNA methylation analysis of the candidate genes showed higher methylation proportion in the primary tumor tissue than that of the matched normal tissue and the differences were significant for the APC, BIN1, BMP6, BRCA1, CST6, ESR-b, P16, PTEN and TIMP3 promoter regions (P<0.05). Among those candidate methylated genes, APC, BMP6, BRCA1 and P16 displayed higher methylation proportion in the matched lymph node metastasis than that found in the normal tissue (P<0.05). The pathway analysis revealed that BMP6, BRCA1 and P16 have a role in prevention of neoplasm metastasis.
CONCLUSIONS: The results of the present study showed methylation heterogeneity between primary tumors and metastatic lesion. The contribution of aberrant methylation alterations of BMP6, BRCA1 and P16 genes in lymph node metastasis might provide a further clue to establish useful biomarkers for screening metastasis.

Related: Breast Cancer


McKenna ES, Tamayo P, Cho YJ, et al.
Epigenetic inactivation of the tumor suppressor BIN1 drives proliferation of SNF5-deficient tumors.
Cell Cycle. 2012; 11(10):1956-65 [PubMed] Free Access to Full Article Related Publications
Emerging evidence demonstrates that subunits of the SWI/SNF chromatin remodeling complex are specifically mutated at high frequency in a variety of human cancer types. SNF5 (SMARCB1/INI1/BAF47), a core subunit of the SWI/SNF complex, is inactivated in the vast majority of rhabdoid tumors (RT), an aggressive type of pediatric cancer. SNF5-deficient cancers are diploid and genomically stable, suggesting that epigenetically based changes in transcription are key drivers of tumor formation caused by SNF5 loss. However, there is limited understanding of the target genes that drive cancer formation following SNF5 loss. Here we performed comparative expression analyses upon three independent SNF5-deficient cancer data sets from both human and mouse and identify downregulation of the BIN1 tumor suppressor as a conserved event in primary SNF5-deficient cancers. We show that SNF5 recruits the SWI/SNF complex to the BIN1 promoter, and that the marked reduction of BIN1 expression in RT correlates with decreased SWI/SNF occupancy. Functionally, we demonstrate that re-expression of BIN1 specifically compromises the proliferation of SNF5-deficient RT cell lines. Identification of BIN1 as a SNF5 target gene reveals a novel tumor suppressive regulatory mechanism whose disruption can drive cancer formation.

Related: Malignant Rhabdoid Tumour


Golan-Gerstl R, Cohen M, Shilo A, et al.
Splicing factor hnRNP A2/B1 regulates tumor suppressor gene splicing and is an oncogenic driver in glioblastoma.
Cancer Res. 2011; 71(13):4464-72 [PubMed] Related Publications
The process of alternative splicing is widely misregulated in cancer, but the contribution of splicing regulators to cancer development is largely unknown. In this study, we found that the splicing factor hnRNP A2/B1 is overexpressed in glioblastomas and is correlated with poor prognosis. Conversely, patients who harbor deletions of the HNRNPA2B1 gene show better prognosis than average. Knockdown of hnRNP A2/B1 in glioblastoma cells inhibited tumor formation in mice. In contrast, overexpression of hnRNP A2/B1 in immortal cells led to malignant transformation, suggesting that HNRNPA2B1 is a putative proto-oncogene. We then identified several tumor suppressors and oncogenes that are regulated by HNRNPA2B1, among them are c-FLIP, BIN1, and WWOX, and the proto-oncogene RON. Knockdown of RON inhibited hnRNP A2/B1 mediated transformation, which implied that RON is one of the mediators of HNRNPA2B1 oncogenic activity. Together, our results indicate that HNRNPA2B1 is a novel oncogene in glioblastoma and a potential new target for glioblastoma therapy.


Pyndiah S, Tanida S, Ahmed KM, et al.
c-MYC suppresses BIN1 to release poly(ADP-ribose) polymerase 1: a mechanism by which cancer cells acquire cisplatin resistance.
Sci Signal. 2011; 4(166):ra19 [PubMed] Related Publications
Cancer cells acquire resistance to DNA-damaging therapeutic agents, such as cisplatin, but the genetic mechanisms through which this occurs remain unclear. We show that the c-MYC oncoprotein increases cisplatin resistance by decreasing production of the c-MYC inhibitor BIN1 (bridging integrator 1). The sensitivity of cancer cells to cisplatin depended on BIN1 abundance, regardless of the p53 gene status. BIN1 bound to the automodification domain of and suppressed the catalytic activity of poly(ADP-ribose) polymerase 1 (PARP1, EC 2.4.2.30), an enzyme essential for DNA repair, thereby reducing the stability of the genome. The inhibition of PARP1 activity was sufficient for BIN1 to suppress c-MYC-mediated transactivation, the G(2)-M transition, and cisplatin resistance. Conversely, overexpressed c-MYC repressed BIN1 expression by blocking its activation by the MYC-interacting zinc finger transcription factor 1 (MIZ1) and thereby released PARP1 activity. Thus, a c-MYC-mediated positive feedback loop may contribute to cancer cell resistance to cisplatin.

Related: Cisplatin Cancer Prevention and Risk Reduction PARP1


Ganesan S
MYC, PARP1, and chemoresistance: BIN there, done that?
Sci Signal. 2011; 4(166):pe15 [PubMed] Related Publications
Dysregulation of c-MYC plays a critical role in the development of many human cancers. New evidence has uncovered a previously unknown mechanism whereby increased abundance of c-MYC can promote poly(ADP-ribose) polymerase (PARP)-dependent DNA repair pathways and induce relative chemoresistance. The adaptor protein BIN1, whose expression is regulated by c-MYC, interacts with PARP1 and inhibits its enzymatic activity. A model has been proposed in which increased abundance of c-MYC indirectly leads to decreased BIN1 expression, in turn leading to increased PARP activity and resistance to DNA-damaging agents. The clinical implications of these findings are discussed.

Related: Cancer Prevention and Risk Reduction PARP1


Radpour R, Barekati Z, Kohler C, et al.
Hypermethylation of tumor suppressor genes involved in critical regulatory pathways for developing a blood-based test in breast cancer.
PLoS One. 2011; 6(1):e16080 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Aberrant DNA methylation patterns might be used as a biomarker for diagnosis and management of cancer patients.
METHODS AND FINDINGS: To achieve a gene panel for developing a breast cancer blood-based test we quantitatively assessed the DNA methylation proportion of 248 CpG sites per sample (total of 31,248 sites in all analyzed samples) on 10 candidate genes (APC, BIN1, BMP6, BRCA1, CST6, ESR-b, GSTP1, P16, P21 and TIMP3). The number of 126 samples consisting of two different cohorts was used (first cohort: plasma samples from breast cancer patients and normal controls; second cohort: triple matched samples including cancerous tissue, matched normal tissue and serum samples). In the first cohort, circulating cell free methylated DNA of the 8 tumor suppressor genes (TSGs) was significantly higher in patients with breast cancer compared to normal controls (P<0.01). In the second cohort containing triple matched samples, seven genes showed concordant hypermethylated profile in tumor tissue and serum samples compared to normal tissue (P<0.05). Using eight genes as a panel to develop a blood-based test for breast cancer, a sensitivity and specificity of more than 90% could be achieved in distinguishing between tumor and normal samples.
CONCLUSIONS: Our study suggests that the selected TSG panel combined with the high-throughput technology might be a useful tool to develop epigenetic based predictive and prognostic biomarker for breast cancer relying on pathologic methylation changes in tumor tissue, as well as in circulation.

Related: Breast Cancer


Muller AJ, DuHadaway JB, Chang MY, et al.
Non-hematopoietic expression of IDO is integrally required for inflammatory tumor promotion.
Cancer Immunol Immunother. 2010; 59(11):1655-63 [PubMed] Free Access to Full Article Related Publications
Indoleamine 2,3-dioxygenase (IDO) is generally considered to be immunosuppressive but recent findings suggest this characterization oversimplifies its role in disease pathogenesis. Recently, we showed that IDO is essential for tumor outgrowth in the classical two-stage model of inflammatory skin carcinogenesis. Here, we report that IDO loss did not exacerbate classical inflammatory responses. Rather, IDO induction could be elicited by environmental signals and tumor promoters as an integral component of the inflammatory tissue microenvironment even in the absence of cancer. IDO loss had limited impact on tumor outgrowth in carcinogenesis models that lacked an explicit inflammatory tumor promoter. In the context of inflammatory carcinogenesis where IDO was critical to tumor development, the most important source of IDO was radiation-resistant non-hematopoietic cells, consistent with evidence that loss of the IDO regulatory tumor suppressor gene Bin1 in transformed skin cells facilitates IDO-mediated immune escape by a cell autonomous mechanism. Taken together, our results identify IDO as an integral component of 'cancer-associated' inflammation that tilts the immune system toward tumor support. More generally, they promote the concept that mediators of immune escape and cancer-associated inflammation may be genetically synonymous.

Related: Skin Cancer


Gao YF, Peng RQ, Li J, et al.
The paradoxical patterns of expression of indoleamine 2,3-dioxygenase in colon cancer.
J Transl Med. 2009; 7:71 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: One of the putative mechanisms of tumor immune escape is based on the hypothesis that carcinomas actively create an immunosuppressed state via the expression of indoleamine 2,3-dioxygenase (IDO), both in the cancer cells and in the immune cells among the tumor-draining lymph nodes (TDLN). In an attempt to verify this hypothesis, the patterns of expression of IDO in the cancer cells and the immune cells among colon cancers were examined.
METHODS: Seventy-one cases of pathologically-confirmed colon cancer tissues matched with adjacent non-cancerous tissues, lymph node metastases, and TDLN without metastases were collected at the Sun Yat-sen Cancer Center between January 2000 and December 2000. The expression of IDO and Bin1, an IDO regulator, was determined with an immunohistochemical assay. The association between IDO or Bin1 expression and TNM stages and the 5-year survival rate in colon cancer patients was analyzed.
RESULTS: IDO and Bin1 were detected in the cytoplasm of cancer cells and normal epithelium. In primary colon cancer, the strong expression of IDO existed in 9/71 cases (12.7%), while the strong expression of Bin1 existed in 33/71 cases (46.5%). However, similar staining of IDO and Bin1 existed in the adjacent non-cancerous tissues. Among the 41 cases with primary colon tumor and lymph node metastases, decreased expression of IDO was documented in the lymph node metastases. Furthermore, among the TDLN without metastases, a higher density of IDO+cells was documented in 21/60 cases (35%). Both univariate and multivariate analyses revealed that the density of IDO+cells in TDLN was an independent prognostic factor. The patients with a higher density of IDO+cells in TDLN had a lower 5-year survival rate (37.5%) than the cells with a lower density (73.1%).
CONCLUSION: This study demonstrated paradoxical patterns of expression of IDO in colon cancer. The high density IDO+cells existed in TDLN and IDO was down-regulated in lymph nodes with metastases, implying that IDO in tumor and immune cells functions differently.


Radpour R, Kohler C, Haghighi MM, et al.
Methylation profiles of 22 candidate genes in breast cancer using high-throughput MALDI-TOF mass array.
Oncogene. 2009; 28(33):2969-78 [PubMed] Related Publications
Alterations of DNA methylation patterns have been suggested as biomarkers for diagnostics and therapy of cancers. Every novel discovery in the epigenetic landscape and every development of an improved approach for accurate analysis of the events may offer new opportunity for the management of patients. Using a novel high-throughput mass spectrometry on matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) silico-chips, we determined semiquantitative methylation changes of 22 candidate genes in breast cancer tissues. For the first time we analysed the methylation status of a total of 42 528 CpG dinucleotides on 22 genes in 96 different paraffin-embedded tissues (48 breast cancerous tissues and 48 paired normal tissues). A two-way hierarchical cluster analysis was used to classify methylation profiles. In this study, 10 hypermethylated genes (APC, BIN1, BMP6, BRCA1, CST6, ESRb, GSTP1, P16, P21 and TIMP3) were identified to distinguish between cancerous and normal tissues according to the extent of methylation. Individual assessment of the methylation status for each CpG dinucleotide indicated that cytosine hypermethylation in the cancerous tissue samples was mostly located near the consensus sequences of the transcription factor binding sites. These hypermethylated genes may serve as biomarkers for clinical molecular diagnosis and targeted treatments of patients with breast cancer.

Related: Breast Cancer


Kennah E, Ringrose A, Zhou LL, et al.
Identification of tyrosine kinase, HCK, and tumor suppressor, BIN1, as potential mediators of AHI-1 oncogene in primary and transformed CTCL cells.
Blood. 2009; 113(19):4646-55 [PubMed] Related Publications
AHI-1 is an oncogene often targeted by provirus insertional mutagenesis in murine leukemias and lymphomas. Aberrant expression of human AHI-1 occurs in cutaneous T-cell lymphoma (CTCL) cells and in CD4(+)CD7(-) Sezary cells from patients with Sezary syndrome. Stable knockdown of AHI-1 using retroviral-mediated RNA interference in CTCL cells inhibits their transforming activity in vitro and in vivo. To identify genes involved in AHI-1-mediated transformation, microarray analysis was performed to identify differentially expressed genes in AHI-1-suppressed CTCL cells. Fifteen up-regulated and 6 down-regulated genes were identified and confirmed by quantitative reverse transcription-polymerase chain reaction. Seven were further confirmed in a microarray analysis of CD4(+)CD7(-) Sezary cells from Sezary syndrome patients. HCK and BIN1 emerged as new candidate cooperative genes, with differential protein expression, which correlates with observed transcript changes. Interestingly, changes in HCK phosphorylation and biologic response to its inhibitor, dasatinib, were observed in AHI-1-suppressed or -overexpressed cells. The tumor suppressor BIN1 physically interacts with MYC in CTCL cells, which also exhibit differential MYC protein expression. In addition, aberrant expression of alternative splicing forms of BIN1 was observed in primary and transformed CTCL cells. These findings indicate that HCK and BIN1 may play critical roles in AHI-1-mediated leukemic transformation of human CTCL cells.

Related: Cutaneous T-cell lymphoma


Prendergast GC, Muller AJ, Ramalingam A, Chang MY
BAR the door: cancer suppression by amphiphysin-like genes.
Biochim Biophys Acta. 2009; 1795(1):25-36 [PubMed] Free Access to Full Article Related Publications
The evolutionarily conserved amphiphysin-like genes Bin1 and Bin3 function in membrane and actin dynamics, cell polarity, and stress signaling. Recent genetic studies in mice discriminate non-essential roles in endocytic processes commonly ascribed to amphiphysins from essential roles in cancer suppression. Bin1 acts in default pathways of apoptosis and senescence that are triggered by the Myc and Raf oncogenes in primary cells, and Bin1 gene products display a 'moonlighting function' in the nucleus where a variety of other 'endocytic' proteins are also found. Together, genetic investigations in yeast, flies, and mice suggest that amphiphysin-like adapter proteins may suppress cancer by helping integrate cell polarity signals generated by actin and vesicle dynamics with central regulators of cell cycle arrest, apoptosis, and immune surveillance.

Related: Cancer Prevention and Risk Reduction


Prendergast GC
Immune escape as a fundamental trait of cancer: focus on IDO.
Oncogene. 2008; 27(28):3889-900 [PubMed] Related Publications
Immune escape is a critical gateway to malignancy. The emergence of this fundamental trait of cancer represents the defeat of immune surveillance, a potent, multi-armed and essential mode of cancer suppression that may influence the ultimate clinical impact of an early stage tumor. Indeed, immune escape may be a central modifier of clinical outcomes, by affecting tumor dormancy versus progression, licensing invasion and metastasis and impacting therapeutic response. Although relatively little studied until recently, immune suppression and escape in tumors are now hot areas with clinical translation of several new therapeutic agents already under way. The interconnections between signaling pathways that control immune escape and those that control proliferation, senescence, apoptosis, metabolic alterations, angiogenesis, invasion and metastasis remain virtually unexplored, offering rich new areas for investigation. Here, an overview of this area is provided with a focus on the tryptophan catabolic enzyme indoleamine 2,3-dioxygenase (IDO) and its recently discovered relative IDO2 that are implicated in suppressing T-cell immunity in normal and pathological settings including cancer. Emerging evidence suggests that during cancer progression activation of the IDO pathway might act as a preferred nodal modifier pathway for immune escape, for example analogous to the PI3K pathway for survival or the VEGF pathway for angiogenesis. Small molecule inhibitors of IDO and IDO2 heighten chemotherapeutic efficacy in mouse models of cancer in a nontoxic fashion and an initial lead compound entered phase I clinical trials in late 2007. New modalities in this area offer promising ways to broaden the combinatorial attack on advanced cancers, where immune escape mechanisms likely provide pivotal support.

Related: Cancer Prevention and Risk Reduction Polymorphisms Signal Transduction


Tajiri T, Higashi M, Souzaki R, et al.
Classification of neuroblastomas based on an analysis of the expression of genes related to prognosis.
J Pediatr Surg. 2007; 42(12):2046-9 [PubMed] Related Publications
PURPOSE: To select the optimal treatment according to the grade of malignancy of neuroblastoma (NB), it is essential to accurately and rapidly identify genetic abnormalities associated with the prognosis. We have identified BIN1 and neuronatin beta as the novel prognosis-related genes for NBs. This study aims to assess the correlation between the combination of the expression level of prognosis-related genes and the outcome of NB.
METHODS: In 44 NB samples, the expression levels of TrkA, BIN1, and neuronatin beta were determined using quantitative reverse transcriptase-polymerase chain reaction; furthermore, the correlation between the expression of these genes' expression levels and the clinical progression of NB were assessed.
RESULTS: It was possible to classify 44 NBs into 4 groups regarding the grade of malignancy of NB. These 4 groups were all significantly associated with the clinical stages international NB staging system as well as the outcomes of the patients (P < .001, according to the trend test by Kruskal-Wallis exact test).
CONCLUSION: The combination of the expression levels of these genes using quantitative reverse transcriptase-polymerase chain reaction is indicated as the effective method to quickly and accurately evaluate the grade of malignancy of NBs.

Related: Neuroblastoma NTRK1 gene MYCN (n-myc)


Karni R, de Stanchina E, Lowe SW, et al.
The gene encoding the splicing factor SF2/ASF is a proto-oncogene.
Nat Struct Mol Biol. 2007; 14(3):185-93 [PubMed] Related Publications
Alternative splicing modulates the expression of many oncogene and tumor-suppressor isoforms. We have tested whether some alternative splicing factors are involved in cancer. We found that the splicing factor SF2/ASF is upregulated in various human tumors, in part due to amplification of its gene, SFRS1. Moreover, slight overexpression of SF2/ASF is sufficient to transform immortal rodent fibroblasts, which form sarcomas in nude mice. We further show that SF2/ASF controls alternative splicing of the tumor suppressor BIN1 and the kinases MNK2 and S6K1. The resulting BIN1 isoforms lack tumor-suppressor activity; an isoform of MNK2 promotes MAP kinase-independent eIF4E phosphorylation; and an unusual oncogenic isoform of S6K1 recapitulates the transforming activity of SF2/ASF. Knockdown of either SF2/ASF or isoform-2 of S6K1 is sufficient to reverse transformation caused by the overexpression of SF2/ASF in vitro and in vivo. Thus, SF2/ASF can act as an oncoprotein and is a potential target for cancer therapy.

Related: Apoptosis EIF4E Cancer Prevention and Risk Reduction


Ghaneie A, Zemba-Palko V, Itoh H, et al.
Bin1 attenuation in breast cancer is correlated to nodal metastasis and reduced survival.
Cancer Biol Ther. 2007; 6(2):192-4 [PubMed] Related Publications
Clinical outcomes in breast cancer are likely influenced by modifier genes that affect tumor dormancy versus progression. The Bin1 gene encodes a nucleocytosolic adapter protein that suppresses neoplastic cell transformation and that is often attenuated in human breast carcinoma. Recent mouse genetic studies indicate that Bin1 loss cooperates with ras activation to drive progression of mammary carcinoma, establishing Bin1 as a negative modifier of tumor progression in breast cancer. In this study, we investigated whether immunohistochemical losses of nuclear Bin1 proteins in cases of human breast cancer were correlated to progression status. In American and Japanese groups of low or middle grade breast cancers, losses were associated with reduced survival and increased nodal metastasis, respectively. Taken together with recent findings from mouse genetic studies, these findings encourage further evaluation of the potential utility of Bin1 as a clinical prognostic marker in breast cancer.

Related: Breast Cancer


Korshunov A, Sycheva R, Golanov A
Recurrent cytogenetic aberrations in central neurocytomas and their biological relevance.
Acta Neuropathol. 2007; 113(3):303-12 [PubMed] Related Publications
Central neurocytomas are rare central nervous system neoplasms. Since the first description, approximately 500 cases of these tumors have been published to date. Nevertheless, only a limited number of genetic studies on these tumors have been reported. Here we investigated 20 "typical" central neurocytomas using array-based comparative genomic hybridization (array-CGH) with the GenoSensor Array 300. The functional significance of detected chromosomal aberrations harboring potent candidate genes was also examined at the mRNA expression level. Each tumor examined displayed DNA copy-number aberrations (CNAs), and mean number of CNAs per tumor was 38.1 +/- 7.1 (range 19-53). Frequent gains were mapped at 2p24.1-22.1, 10q23.3-26.3, 11q23-25, and 18q21.3-qter. Frequent losses were identified at 1pter-36.3, 1p34.3, 6q13-21, 12q23-qter, 17p13.3, 17q11-23, and 20pter-12.3. There were 10 gained and 23 lost single DNA clones affecting >or=40% of samples tested. mRNA expression levels of 24 selected candidate genes harbored in these imbalanced clones were analyzed. MYCN, PTEN, and OR5BF1 were strongly overexpressed, whereas BIN1, SNRPN, and HRAS were found to be strongly underrepresented at the transcriptional level. Thus these data support that MYCN oncogene gain/overexpression accompanied by reduced expression of BIN1 tumor suppressor may contribute to central neurocytoma tumorigenesis.

Related: Brain and Spinal Cord Tumours Chromosome 17 FISH


Capurso G, Lattimore S, Crnogorac-Jurcevic T, et al.
Gene expression profiles of progressive pancreatic endocrine tumours and their liver metastases reveal potential novel markers and therapeutic targets.
Endocr Relat Cancer. 2006; 13(2):541-58 [PubMed] Related Publications
The intrinsic nature of tumour behaviour (stable vs progressive) and the presence of liver metastases are key factors in determining the outcome of patients with a pancreatic endocrine tumour (PET). Previous expression profile analyses of PETs were limited to non-homogeneous groups or to primary lesions only. The aim of this study was to investigate the gene expression profiles of a more uniform series of sporadic, non-functioning (NF) PETs with progressive disease and, for the first time, their liver metastases, on the Affymetrix human genome U133A and B GeneChip set. Thirteen NF PET samples (eight primaries and five liver metastases) from ten patients with progressive, metastatic disease, three cell lines (BON, QGP and CM) and four purified islet samples were analysed. The same samples were employed for confirmation of candidate gene expression by means of quantitative RT-PCR, while a further 37 PET and 15 carcinoid samples were analysed by immunohistochemistry. Analysis of genes differentially expressed between islets and primaries and metastases revealed 667 up- and 223 down-regulated genes, most of which have not previously been observed in PETs, and whose gene ontology molecular function has been detailed. Overexpression of bridging integrator 1 (BIN1) and protein Z dependent protease inhibitor (SERPINA10) which may represent useful biomarkers, and of lymphocyte specific protein tyrosine kinase (LCK) and bone marrow stromal cell antigen (BST2) which could be used as therapeutic targets, has been validated. When primary tumours were compared with metastatic lesions, no significantly differentially expressed genes were found, in accord with cluster analysis which revealed a striking similarity between primary and metastatic lesions, with the cell lines clustering separately. We have provided a comprehensive list of differentially expressed genes in a uniform set of aggressive NF PETs. A number of dysregulated genes deserve further in-depth study as potentially promising candidates for new diagnostic and treatment strategies. The analysis of liver metastases revealed a previously unknown high level of similarity with the primary lesions.

Related: Cancer of the Pancreas Pancreatic Cancer


Tajiri T, Tanaka S, Higashi M, et al.
Biological diagnosis for neuroblastoma using the combination of highly sensitive analysis of prognostic factors.
J Pediatr Surg. 2006; 41(3):560-6 [PubMed] Related Publications
BACKGROUND/PURPOSE: To select the optimal treatment according to the degree of malignancy of neuroblastoma, it is essential to accurately and rapidly identify any genetic abnormalities associated with the prognosis. This study aims to assess the correlation between the combination of prognostic factors and the biologic findings of neuroblastoma using a highly sensitive analysis of prognostic factors.
METHODS: In 44 neuroblastoma primary samples, we determined the gene dosages of MYCN and Survivin (as the target of 17q gain) and the expression levels of MYCN, Survivin, and BIN1 using highly sensitive analysis (the quantitative polymerase chain reaction method); furthermore, we assessed the correlation between the combination of their prognostic factors and the biology of neuroblastoma.
RESULTS: The gene dosage of MYCN or Survivin was significantly associated with all known prognostic factors. The expression level of MYCN or Survivin was not significantly associated with any prognostic factors, whereas the expression level of BIN1 was significantly associated with 5 of 6 prognostic factors. Regarding the combination of MYCN amplification and 17q gain (the gene dosage of Survivin), and the low expression of BIN1, the rates of advanced stages (stage III or IV) were 100% for the cases with 3 factors, 63% for the cases with 2 factors, 42% for the cases with 1 factor, and 0% for the cases with null factor. Furthermore, the survival rates were 20% for the cases with 3 factors, 50% for the cases with 2 factors, 100% for the cases with 1 factor, and 100% for the cases with null factor.
CONCLUSION: The combination of gene dosages of MYCN and Survivin and the expression level of BIN1 using the quantitative polymerase chain reaction method was significantly correlated with the clinical stage and the patients' outcome. This combination of biologic factors may enhance the accuracy to the conventional criteria, but this would have to be shown in a much larger study that is adequately powered to detect such an advantage.

Related: Neuroblastoma BIRC5 MYCN (n-myc)


De Pittà C, Tombolan L, Albiero G, et al.
Gene expression profiling identifies potential relevant genes in alveolar rhabdomyosarcoma pathogenesis and discriminates PAX3-FKHR positive and negative tumors.
Int J Cancer. 2006; 118(11):2772-81 [PubMed] Related Publications
We analyzed the expression signatures of 14 tumor biopsies from children affected by alveolar rhabdomyosarcoma (ARMS) to identify genes correlating to biological features of this tumor. Seven of these patients were positive for the PAX3-FKHR fusion gene and 7 were negative. We used a cDNA platform containing a large majority of probes derived from muscle tissues. The comparison of transcription profiles of tumor samples with fetal skeletal muscle identified 171 differentially expressed genes common to all ARMS patients. The functional classification analysis of altered genes led to the identification of a group of transcripts (LGALS1, BIN1) that may be relevant for the tumorigenic processes. The muscle-specific microarray platform was able to distinguish PAX3-FKHR positive and negative ARMS through the expression pattern of a limited number of genes (RAC1, CFL1, CCND1, IGFBP2) that might be biologically relevant for the different clinical behavior and aggressiveness of the 2 ARMS subtypes. Expression levels for selected candidate genes were validated by quantitative real-time reverse-transcription PCR.

Related: FOXO1A gene PAX3 gene


Tajiri T, Liu X, Thompson PM, et al.
Expression of a MYCN-interacting isoform of the tumor suppressor BIN1 is reduced in neuroblastomas with unfavorable biological features.
Clin Cancer Res. 2003; 9(9):3345-55 [PubMed] Related Publications
PURPOSE: Amplification of the MYCN proto-oncogene is strongly correlated with poor outcome in neuroblastoma (NB), although deregulated MYCN is a potent inducer of apoptosis. BIN1 (2q14) encodes multiple isoforms of a Myc-interacting adaptor protein that has features of a tumor suppressor, including the ability to inhibit Myc-mediated cell transformation and to promote apoptosis. We hypothesized that BIN1 may function as a suppressor gene in NB, because Bin1 is highly expressed in neural tissues and binds the Myc Box motifs that are conserved in MycN. EXPERMENTAL DESIGN: Expression of MYCN, total BIN1, and BIN1 isoforms were determined in 56 primary NBs using the real-time PCR. Expression was correlated with biological and genetic features. To determine the functional significance of BIN1 expression we ectopically expressed BIN1 isoforms in NB cell lines with and without MYCN amplification, and assessed clonogenic growth.
RESULTS: Four predominant BIN1 isoforms resulting from alternative splicing of exon 12A (a neural tissue-specific exon) and exon 13 (a Myc-binding domain encoding exon) were variably expressed in the 56 primary NBs. Expression of BIN1 was lower in: NBs with MYCN amplification (n = 10) compared with those without, P < 0.03; in International Neuroblastoma Risk Group high-risk NB (n = 19) compared with low- or intermediate-risk NB, P < 0.01; and in metastatic NB (n = 21) compared with localized NB, P < 0.06. BIN1 inactivation by deletion or genomic rearrangement was identified infrequently. Forced expression of BIN1 isoforms containing the Myc-binding domain (with or without exon 12A) inhibited colony formation in NB cell lines with MYCN amplification (P < 0.01) but not in those without. Forced expression of BIN1 isoforms with a MBD deletion did not inhibit colony formation in any cell line assessed.
CONCLUSIONS: These data support that reduced BIN1 expression contributes to the malignant phenotype of childhood NB. As we reported previously, BIN1 may function to circumvent MycN-mediated apoptosis in NBs with MYCN amplification.

Related: Neuroblastoma MYCN (n-myc)


DuHadaway JB, Lynch FJ, Brisbay S, et al.
Immunohistochemical analysis of Bin1/Amphiphysin II in human tissues: diverse sites of nuclear expression and losses in prostate cancer.
J Cell Biochem. 2003; 88(3):635-42 [PubMed] Related Publications
The Bin1/Amphiphysin II gene encodes at least seven alternately spliced adapter proteins that have been implicated in membrane dynamics and nuclear processes. Nuclear localized Bin1 polypeptides have tumor suppressor and proapoptotic activities, suggesting that Bin1 may suppress cancer in tissues where nuclear expression may occur. One question is the extent to which human tissues express nuclear Bin1 isoforms. A secondary issue has been the need for a specific antibody that can detect all the splice isoforms expressed by the human, mouse, and rat Bin1 genes. Using a novel mouse monoclonal antibody with these characteristics, we performed an immunohistochemical analysis of Bin1 expression in a panel of normal human tissues. We also compared the expression profile of Bin1 in normal or malignant tissues derived from human prostate, where Bin1 is a candidate tumor suppressor gene. In brain, a distinct nuclear staining pattern overlapped with a cytosolic staining pattern present in certain layers of the cerebral cortex and cerebellum. Bone marrow cells displayed mainly nuclear localization whereas peripheral lymphoid cells exhibited mainly cytosolic localization. In several epithelial tissues, nuclear or nucleocytosolic staining patterns were displayed by basal cells in skin, breast, or prostate, whereas cytosolic or plasma membrane-associated staining patterns were noted in gastrointestinal cells. Interestingly, a striking gradient of expression was observed in gastrointestinal epithelia, particularly in the large intestine, with the strongest staining displayed by cells destined to undergo apoptosis at the villus tip. In prostate, Bin1 staining was frequently absent in cases of primary prostate adenocarcinoma. This study used a novel reagent to document the extent of expression of nuclear Bin1 isoforms, which exhibit cancer suppression and proapoptotic activity in human cells.

Related: Monoclonal Antibodies Prostate Cancer


DuHadaway JB, Sakamuro D, Ewert DL, Prendergast GC
Bin1 mediates apoptosis by c-Myc in transformed primary cells.
Cancer Res. 2001; 61(7):3151-6 [PubMed] Related Publications
The Bin1 gene encodes a c-Myc-interacting adapter protein with tumor suppressor and cell death properties. In this study, we offer evidence that Bin1 participates in a mechanism through which c-Myc activates programmed cell death in transformed primary chick or rat cells. Antisense or dominant inhibitory Bin1 genes did not affect the ability of c-Myc to drive proliferation or transformation, but they did reduce the susceptibility of cells to c-Myc-induced apoptosis. Protein-protein interaction was implicated, suggesting that Bin1 mediates a death or death sensitization signal from c-Myc. Our findings offer direct support for the "dual signal" model of Myc apoptotic function, based on interactions with a binding protein. Loss of Bin1 in human tumors may promote malignant progression in part by helping to stanch the death penalty associated with c-Myc activation.

Related: Apoptosis


Huang H, Colella S, Kurrer M, et al.
Gene expression profiling of low-grade diffuse astrocytomas by cDNA arrays.
Cancer Res. 2000; 60(24):6868-74 [PubMed] Related Publications
Diffuse astrocytoma WHO grade II is a well-differentiated, slowly growing tumor that has an inherent tendency to progress to anaplastic astrocytoma (WHO grade III) and, eventually, to glioblastoma (WHO grade IV). Little is known about its molecular basis, except for p53 mutations that are found in >60% of cases. In a search for additional genetic alterations, we carried out gene expression profiling of 11 diffuse astrocytomas using cDNA expression arrays. Expression of six genes (TIMP3, c-myc, EGFR, DR-nm23, nm23-H4, and GDNPF) was detected in 64-100% of diffuse astrocytomas, but not in nontumorous brain tissue. Seven genes (AAD14, SPARC, LRP, PDGFR-alpha, 60S ribosomal protein L5, PTN, and hBAP) were found to be up-regulated more than 2-fold in 20-60% of cases, whereas 11 genes (IFI 9-27, protein kinase CLK, TDGF1, BIN1, GAB1, TYRO3, LDH-A, adducin 3, GUK1, CDC10, and KRT8) were down-regulated to less than 50% of normal levels in 64-100% of cases. Semiquantitative conventional reverse transcription-PCR was performed for 11 genes, 9 of which showed an expression profile similar to that obtained with cDNA expression arrays. Immunohistochemical staining for SPARC showed cytoplasmic immunoreactivity of neoplastic cells in all diffuse astrocytomas analyzed. These results indicate significant changes in gene expression in diffuse astrocytomas, but it remains to be shown which of these are causally related to the transformation of glial cells.


Hogarty MD, Liu X, Thompson PM, et al.
BIN1 inhibits colony formation and induces apoptosis in neuroblastoma cell lines with MYCN amplification.
Med Pediatr Oncol. 2000; 35(6):559-62 [PubMed] Related Publications
BACKGROUND: MYCN amplification and overexpression occurs in 25% of neuroblastomas and independently predicts for poor prognosis disease, an effect thought to be mediated by its role as a transcriptional activator of growth promoting genes. However, in many mammalian cells, deregulated expression of MYC family genes (including MYCN) induces apoptosis. We hypothesized that BIN1, a MYC interacting protein capable of inducing apoptosis, may be an important regulator of MYCN in neuroblastoma.
RESULTS: BIN1 expression was found to be reduced in MYCN-amplified cell lines. Further, forced expression of BIN1 markedly reduced colony formation in MYCN-amplified, but not single-copy, cell lines. This effect appeared to be caused by an increase in apoptosis, and was augmented by serum deprivation and concurrent cytotoxic drug therapy in cell culture
CONCLUSION: BIN1 inactivation may be necessary for MYCN overexpression to lead to cellular proliferation rather than programmed cell death in neuroblastomas with MYCN amplification.

Related: Apoptosis Neuroblastoma


Elliott K, Ge K, Du W, Prendergast GC
The c-Myc-interacting adaptor protein Bin1 activates a caspase-independent cell death program.
Oncogene. 2000; 19(41):4669-84 [PubMed] Related Publications
Cell death processes are progressively inactivated during malignant development, in part by loss of tumor suppressors that can promote cell death. The Bin1 gene encodes a nucleocytosolic adaptor protein with tumor suppressor properties, initially identified through its ability to interact with and inhibit malignant transformation by c-Myc and other oncogenes. Bin1 is frequently missing or functionally inactivated in breast and prostate cancers and in melanoma. In this study, we show that Bin1 engages a caspase-independent cell death process similar to type II apoptosis, characterized by cell shrinkage, substratum detachment, vacuolated cytoplasm, and DNA degradation. Cell death induction was relieved by mutation of the BAR domain, a putative effector domain, or by a missplicing event that occurs in melanoma and inactivates suppressor activity. Cells in all phases of the cell cycle were susceptible to death and p53 and Rb were dispensable. Notably, Bin1 did not activate caspases and the broad spectrum caspase inhibitor ZVAD.fmk did not block cell death. Consistent with the lack of caspase involvement, dying cells lacked nucleosomal DNA cleavage and nuclear lamina degradation. Moreover, neither Bcl-2 or dominant inhibition of the Fas pathway had any effect. In previous work, we showed that Bin1 could not suppress cell transformation by SV40 large T antigen. Consistent with this finding, we observed that T antigen suppressed the death program engaged by Bin1. This observation was interesting in light of emerging evidence that T antigen has roles in cell immortalization and human cell transformation beyond Rb and p53 inactivation. In support of a link to c-Myc-induced death processes, AEBSF, a serine protease inhibitor that inhibits apoptosis by c-Myc, potently suppressed DNA degradation by Bin1. Our findings suggest that the tumor suppressor activity of Bin1 reflects engagement of a unique cell death program. We propose that loss of Bin1 may promote malignancy by blunting death penalties associated with oncogene activation.

Related: TNFRSF6 gene Apoptosis Bone Cancers Liver Cancer Mitochondrial Mutations in Cancer Osteosarcoma RB1 TP53


Ge K, Minhas F, Duhadaway J, et al.
Loss of heterozygosity and tumor suppressor activity of Bin1 in prostate carcinoma.
Int J Cancer. 2000; 86(2):155-61 [PubMed] Related Publications
The genetic events underlying the development of prostate cancer are poorly defined. c-Myc is often activated in tumors that have progressed to metastatic status, so events that promote this process may be important. Bin1 is a nucleocytoplasmic adaptor protein with features of a tumor suppressor that was identified through its ability to interact with and inhibit malignant transformation by c-Myc. We investigated a role for Bin1 loss or inactivation in prostate cancer because the human Bin1 gene is located at chromosome 2q14 within a region that is frequently deleted in metastatic prostate cancer but where no tumor suppressor candidate has been located. A novel polymorphic microsatellite marker located within intron 5 of the human Bin1 gene was used to demonstrate loss of heterozygosity and coding alteration in 40% of informative cases of prostate neoplasia examined. RNA and immunohistochemical analyses indicated that Bin1 was expressed in most primary tumors, even at slightly elevated levels relative to benign tissues, but that it was frequently missing or inactivated by aberrant splicing in metastatic tumors and androgen-independent tumor cell lines. Ectopic expression of Bin1 suppressed the growth of prostate cancer lines in vitro. Our findings support the candidacy of Bin1 as the chromosome 2q prostate tumor suppressor gene.

Related: Prostate Cancer


Ge K, Duhadaway J, Sakamuro D, et al.
Losses of the tumor suppressor BIN1 in breast carcinoma are frequent and reflect deficits in programmed cell death capacity.
Int J Cancer. 2000; 85(3):376-83 [PubMed] Related Publications
Oncogenic activation of MYC occurs often in breast carcinoma and is associated with poor prognosis. Loss or inactivation of mechanisms that restrain MYC may therefore be involved in tumor progression. In this study, we show that the MYC-interacting adaptor protein BIN1 is frequently missing in malignant breast cells and that this loss is functionally significant. BIN1 was expressed in normal and benign cells and tissues but was undetectable in 6/6 estrogen receptor-positive or estrogen receptor-negative carcinoma cell lines examined. Similarly, complete or partial losses of BIN1 were documented in 30/50 (60%) cases of malignant breast tissue analyzed by immuno-histochemistry or RT-PCR. Abnormalities in the organization of the BIN1 gene were apparent in only a minority of these cases, suggesting that most losses were due to epigenetic causes. Nevertheless, they were functionally significant because ectopic BIN1 induced programmed cell death in malignant cells lacking endogenous BIN1 but had no effect on the viability of benign cells. We propose that loss of BIN1 may contribute to breast cancer progression by eliminating a mechanism that restrains the ability of activated MYC to drive cell division inappropriately.

Related: Apoptosis Breast Cancer


Livezey KW, Negorev D, Simon D
Investigation of the expression of Bin1, a putative suppressor, in human hepatoma cells.
Cancer Genet Cytogenet. 2000; 116(1):35-9 [PubMed] Related Publications
Recent data suggest that Bin1, a novel C-MYC interacting protein, is a suppressor gene whose loss of expression is a frequent aberration associated with several malignancies. The mechanism responsible for loss of BIN1 expression is not understood. The purpose of this study is to investigate DNA profile of the BIN1 gene in human hepatoma Hep G2 cells, previously documented with lack of BIN1 expression. Chromosome and molecular analyses of Hep G2 cells were initiated to exclude the possibility of genetic alterations as a factor affecting BIN1 gene expression in these cells. We used Hep G2 cell line and its hepatitis B virus (HBV) transfected variants--Hep G2T14.1 and Hep G2215 cell lines. The cytogenetic localization of BIN1 was identified in the 2q14 region. Fluorescence in situ hybridization (FISH) with the chromosome 2 whole chromosome painting probe (WCP) demonstrated three or four intact copies of chromosome 2 in all three hepatoma cell lines studied. FISH analyses with the BIN1-specific probe of the Hep G2, Hep G2T14.1, and Hep G2215 metaphase chromosomes document no rearrangement of the BIN1 gene on any of the multiple copies of chromosome 2. FISH with the specific HBV probe did not identify the HBV integration site in Hep G2T14.1 and Hep G2215 cells within the BIN1 locus. Southern blot analyses revealed no genetic rearrangements in the BIN1 gene in any of the cell lines studied. Our RNA analyses (northern blot and RT-PCR) document lack of BIN1 message in Hep G2 cells in contrast to the presence of BIN1 in Hep G2T14.1 and Hep G2215 cells. No difference was identified in other transcripts analyzed, including c-myc. Analyses of BIN1 expression of Hep G2 cells at different passages were initiated and document low levels of BIN1 transcript in Hep G2 cells of passage < 85. Furthermore, BIN1 transcript was identified in additional seven HCC cell lines analyzed. Our data indicate that lack of Bin1 expression in HepG2 cells previously documented is a characteristic of cells of passage > 85 and is not due to genetic loss, or rearrangement within the BIN1 DNA sequence. Loss of the BIN1 transcript is not a characteristic of HCCs analyzed.

Related: Chromosome 2 FISH Liver Cancer


Ge K, DuHadaway J, Du W, et al.
Mechanism for elimination of a tumor suppressor: aberrant splicing of a brain-specific exon causes loss of function of Bin1 in melanoma.
Proc Natl Acad Sci U S A. 1999; 96(17):9689-94 [PubMed] Free Access to Full Article Related Publications
Loss of tumor suppressors that restrain important oncoproteins such as c-Myc may contribute to malignant progression. Bin1 is an adapter protein with features of a tumor suppressor that was identified through its interaction with and inhibition of the oncogenic properties of c-Myc. In this study, we analyzed the patterns of Bin1 expression in normal melanocytes and melanoma cells at different stages of tumor progression. Evidence is provided that Bin1 function is abrogated in melanoma cells by a mechanism based on aberrant splicing of a tissue-specific exon. Specifically, most melanoma cells inappropriately expressed exon 12A, which is spliced alternately into Bin1 isoforms found in brain but not into isoforms found in melanocytes and many other nonneuronal cells. Exon 12A sequences abolished the ability of Bin1 to inhibit malignant transformation by c-Myc or adenovirus E1A. Similarly, these sequences abolished the ability of Bin1 to induce programmed cell death in melanoma cells that endogenously expressed exon 12A. Our findings suggest that aberrant splicing of Bin1 may contribute to melanoma progression, and they define a mechanism by which the activity of a tumor suppressor can be eliminated in cells.

Related: Apoptosis Melanoma


Duhadaway J, Rowe F, Elliott K, et al.
Bau, a splice form of Neurabin-I that interacts with the tumor suppressor Bin1, inhibits malignant cell transformation.
Cell Adhes Commun. 1999; 7(2):99-110 [PubMed] Related Publications
Bin1 is a nucleocytoplasmic adaptor protein and tumor suppressor. A novel protein termed Bau was identified through its ability to interact with a region of Bin1 required to inhibit malignant cell transformation by certain oncogenes. Bau is a splice form of Neurabin-I, one of two related F-actin-binding proteins that are proposed to link cadherin-based cell-cell adhesion sites with the growth regulatory kinase p70S6K. Bau lacks actin- and p70S6K-binding domains found in Neurabin-I but includes coiled-coil domains that are part of its central domain as well as additional sequences not found in Neurabin-I. Interaction with Bin1 requires the presence of the U3 region which is alternately spliced in muscle cells. Bau localizes to the nucleus and cytosol. Like Bin1, Bau can suppress oncogene-mediated transformation and inhibit tumor cell growth. We suggest that Bau may link Bin1 to the Neurabin-I/p70S6K system in muscle and other cells, perhaps providing a mechanism to influence adhesion-dependent signals which affect cell fate.


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