bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract LB-387: EZH2 knockdown suppresses the growth of human inflammatory breast cancer cells both in vitro and in vivo in xenograft models
Authors: Mu Zhaomei , Li Hua , Zhang Rugang , Cristofanilli Massimo 
Published: August 2012

Abstract
PURPOSE: Inflammatory breast cancer (IBC) is a rare but very aggressive type of advanced breast cancer with a poor prognosis. Thus, there is an urgent need for novel IBC therapeutics. Enhancer of zeste homolog 2 (EZH2) is of the catalytic subunit of the polycomb repressive complex 2, which silences the expression of its target genes by generating trimethylation of lysine 27 on histone H3 (H3K27Me3). EZH2 is overexpressed in several types of cancer including IBC and its overexpression correlates with a poor prognosis in IBC patients. Here, we investigated the molecular basis by which EZH2 promotes IBC. METHODS: IBC cell lines SUM149 and FC-IBC-02 which were developed from pleural effusion of an IBC patient were used in this study. Specific knockdown of EZH2 was performed using short hairpin RNA (shRNA) specific to the human EZH2 gene. MTS and soft-agar colony formation assays were used for anchorage-dependent and -independent cell growth in vitro, respectively. xCELLigence system was used to determine the cell migration and invasion. For the in vivo tumor growth studies, IBC cells were orthotopically transplanted into the mammary fat pads of immunodeficient mice. RESULTS: EZH2 was expressed at higher levels in all tested human IBC cell lines when compared with non-transformed human mammary epithelial cells. Knockdown of EZH2 caused a significant reduction in the levels of H3K27Me3 in human IBC cell lines. Notably, knockdown of EZH2 expression significantly suppressed both anchorage-dependent and -independent growth of human IBC cells in vitro due to induction of apoptosis. In addition, EZH2 knockdown inhibited the migration and invasion of IBC cells. Significantly, EZH2 knockdown suppressed the growth IBC cells in vivo in an orthotopic IBC model. CONCLUSIONS: EZH2 knockdown suppresses the growth of human IBC cells in vitro and in vivo in an orthotopic IBC model in immunodeficient mice. In addition, EZH2 knockdown inhibits the invasion of human IBC cells. Together, we conclude that EZH2 contributes to IBC by promoting proliferation and invasion of human IBC cells. These results suggest that targeting EZH2 may provide a novel therapeutic strategy for the treatment of patients with IBC.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-387. doi:1538-7445.AM2012-LB-387
Abstract LB-388: Regulation of histone deacethylase 8 expression by inhibitory GTP binding proteins in H1299 non-small-cell lung cancer cells
Authors: Hahn Hwa-jeong , juhnn Yong-sung 
Published: August 2012

Abstract
Histone deacetylases (HDACs) have been reported to regulate the cell growth, cell proliferation, cell cycle, and apoptosis, and increased expression of HDAC (classI) was observed in many kinds of cancer. HDAC8, most recently discovered subtype of HDAC classI, seems to be involved in tumor growth and progression because it is highly expressed in several cell lines and human cancer tissues. Inhibitory heterotrimeric GTP-binding proteins (Gi) are activated by seven transmembrane receptors bound with ligands, and regulate cellular metabolism and proliferation by regulating the activity of adenylate cyclase, activate phospholipase C beta, and ion channels. Thus, we made a hypothesis that Gi signaling system may regulate the expression of HDAC8, and this study investigated the effects of Gi signaling system on the expression of HDAC8 and the underlying mechanism in lung cancer cells. When Gi signaling system was activated by expressing Gαi1Q204L, a constitutively active mutant Gαi1, the expression of both HDAC8 protein and mRNA was increased in H1299 non-small-cell lung cancer (NSCLC) cells. However, the HDAC8 promoter activity did not increased significantly, and treatment with Actinomycin D did not block the increase in mRNA. The degradation of HDAC8 mRNA was facilitated in Gαi1Q204L-expressing cells, indicating Gi signaling system increases HDAC8 expression by stabilizing mRNA. Furthermore, treatment with adenosine or CCPA (2-chloro-N(6)cyclopentyladenosine), which bind to adenosine receptors leading to Gαi1 activation, also increased both HDAC8 mRNA and protein levels in H1299 cells. The effect of adenosine was blocked by treatment with DPCPX (8-Cyclopentyl-1,3-dipropylxanthine), an adenosine A1 receptor antagonist. These results indicate that Gi signaling system increases the HDAC8 expression by stabilizing its mRNA in H1299 NSCLC cells
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-388. doi:1538-7445.AM2012-LB-388
Abstract LB-390: High throughput, quantitative ligand binding assays for human bromodomains
Authors: Quinn Elizabeth , Hunt Jeremy , Wodicka Lisa , Ciceri Pietro , Treiber Daniel K. 
Published: August 2012

Abstract
Post translationally appended acetyl-lysine marks on histone tails are key regulatory features of the epigenetic code. Bromodomains are “readers” of this specific lysine acetylation code, playing an important role in chromatin remodeling and regulation of gene expression. Bromodomains have emerged as an important new druggable target class in small-molecule inhibitor drug discovery, and several bromodomain-containing proteins have been associated with disease. There are 57 bromodomains contained in 41 different proteins, however, few small molecule inhibitors of bromodomains have been identified to date. The primary factor limiting the discovery of new inhibitors is the absence of a comprehensive, biochemical screening platform for bromodomains. Here we describe the application of DiscoveRx Corporation's novel competitive binding assay technology (used to build the KINOMEscan panel of &gt;450 kinase assays) to the development of quantitative ligand binding assays for human bromodomains. By applying our established methodologies, we have rapidly developed an assay panel that covers &gt;15% of the bromodomain family, with the ultimate goal of developing a comprehensive panel, comparable to the KINOMEscan kinase assay panel. A robust bromodomain assay panel suitable for high throughput screening that delivers quantitative ligand binding data will facilitate the identification and optimization of potent and selective small molecule bromodomain inhibitors suitable for both pharmaceutical use and as tool compounds to further elucidate the roles of bromodomains in human disease.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-390. doi:1538-7445.AM2012-LB-390
Abstract LB-391: HDAC6 is a dual enzyme with deacetylase and E3 ligase activities for MSH2 degradation
Authors: Zhang Mu 
Published: August 2012

Abstract
MSH2 is a key DNA mismatch repair (MMR) protein that functions as an MSH2/MSH6 heterodimer (MutSa) in repairing errors after DNA replication as well as sensing certain types of DNA damage. It is believed that reduction of MutSα attenuates recognition of DNA adducts which renders a declined cell cycle arrest and apoptosis upon DNA damage and subsequently leads to chemotolerance. However, the mechanisms of down-regulation of MutSa are largely unknown. Here we show that histone deacetylase 6 (HDAC6) is co-purified with MutSa in HeLa nuclear extracts. Interestingly, we have found that HDAC6 itself serves as a ubiquitin E3 ligase to promote MSH2 polyubiquitination which renders MSH2 degradation by proteasome pathway. Intriguingly, HDAC6 prefers to target MSH2 monomer over MutSa for ubiquitination and degradation. Mechanistically, HDAC6 E3 ligase activity primarily resides in the N-terminal region encompassing the previously identified deacetylase domain 1 (DAC1) whereas its deacetylase activity resides in the deacetylase domain 2 (DAC2). We also showed that HDAC6 E3 ligase activity towards acetylated MSH2 is facilitated by its deacetylase activity in vivo. MSH2 lysine 249 and 892 can be either acetylated or ubiqutinated in vivo. These data suggest that HDAC6 sequentially deacetylates and ubiquitinates MSH2 via its DAC2 and DAC1 domains to target MSH2 degradation in vivo. Moreover, cells lacking or depleted of HDAC6 exhibit elevated levels of MSH2 due to impaired ubiquitin-proteasome-mediated degradation and subsequently prolonged half-life, compared with control cells. In agreement with this, HDAC6 knockout cells display higher MMR activity compared with wild type cells. Importantly, absence or reduction of HDAC6 leads to an increased cellular sensitivity to 6-TG and MNNG, whose DNA lesions were recognized by MutSa, suggesting that HDAC6 governs MSH2-dependent cytotoxicity induced by 6-TG or MNNG. Overall, our results identified a novel ubiquitin E3 ligase activity of HDAC6 and revealed that HDAC6 plays an important role in response to genotoxic stress.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-391. doi:1538-7445.AM2012-LB-391
Abstract LB-393: Genotoxicity of arsenic in primary human bronchial cells
Authors: Xie Hong , Martin Sara , Wise John , Huang Shouping 
Published: August 2012

Abstract
Arsenic originates from both geochemical and numerous anthropogenic activities including mining, combustion of fossil fuels, wood preservation, agriculture and metallurgy. Exposure of the general public to significant levels of arsenic is widespread. Arsenic is a well-documented human carcinogen. Long-term exposure to low levels of arsenic in drinking water have been linked to bladder, lung, kidney, liver, prostate, and skin cancer. Among them, lung cancer is of great public concern. However, little is known about how arsenic causes lung cancer. The purpose of this study was to determine the cytotoxicity and genotoxicity in human primary bronchial fibroblasts cells (NHBF). Our data show that arsenic induces a concentration-dependent increase in cell death after acute (24 h) or chronic (120 h) exposure. 0.1, 1 and 10 uM arsenic for 24 h induced 85, 64 and 35 percent relative survival, respectively, and induced 73, 57 and 11 percent of relative survival, respectively after 120 h treatment. 24 h exposure of 5 and 10 uM arsenic induced 15 and 32 chromosome damage compared to the control. Comet assay was used to measure the formation of DNA double strand breaks. We found that 120 h exposure induced a concentration-dependent increase in double strand breaks. Future study will focus on arsenic cytotoxicity and genotoxicity in primary bronchial epithelial cells.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-393. doi:1538-7445.AM2012-LB-393
Abstract LB-399: Genome-wide expression analysis of subtypes of non-small cell lung carcinoma in highly degraded formalin-fixed paraffin-embedded tissue
Authors: Su Li , Wang Zhaoxi , Wu Chen , Chirieac Lucian R. , Christiani David C. 
Published: August 2012

Abstract
Previous studies demonstrated that gene expression profiles from formalin-fixed paraffin-embedded (FFPE) tissues are largely comparable to fresh frozen matched tissue. This technology can assist in discovering biomarkers of lung cancer prognosis and progression by vastly increasing in the potential resources available for cancer research. In this study, we investigated the potential use of the Whole-Genome DASL HT Assay (Illumina, San Diego, CA) for global expression profiling in FFPE tissues obtained by surgical biopsy from patients with early stage non-small cell lung cancer (NSCLC). We obtained high-quality microarray data on 26 pairs of tumor/non-affected tissues, including 18 pairs of adenocarcinoma and 8 pairs of squamous carcinomas. Among genes differentially expressed between squamous carcinomas and adjacent non-affected lung tissue, we found that the AKR1C1 gene, encoding an aldo-keto reductases, was increased strongly in tumors (fold change: 3.0; p=0.02). This finding was consistent with previous reports that overexpression of AKR1C1 gene as an indicator of poor prognosis and chemoresistance in NSCLC. During pathway-based analysis using GeneGo database, we found that differentially expressed genes of adenocarcinoma were significantly enriched in the pathway of cytoskeleton remodeling_TGF, WNT and cytoskeletal remodeling; and differentially expressed genes of squamous carcinomas were significantly enriched in the pathway of Lung Neoplasms_Signal transduction. Our study demonstrates that with DASL expression profiling technology, genome-wide expression profiles can be successfully generated from FFPE lung tissues. Support: CA092824 and CA CA90578, and CA074386 from NCI
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-399. doi:1538-7445.AM2012-LB-399
Abstract LB-401: Functional impact bias reveals cancer drivers
Authors: Gonzalez-Perez Abel , Lopez-Bigas Nuria 
Published: August 2012

Abstract
Currently, one of the main challenges in cancer genomics is the identification of driver genes and pathways among all the altered genes in a cohort of tumors. Typically, tests of recurrence are applied to identify significantly mutated genes, which are candidates to cancer drivers. These methods assess the probability to observe by chance the number of somatic single nucleotide variants (SNVs) found across a number of tumor samples. Some known limitations of these methods include the difficulty in correctly assessing background mutation rate, as all parameters that affect it are not well-understood, and the fact that they usually fail to identify lowly recurrently mutated driver genes. In addition, methods that compute recurrence treat all observed somatic SNVs equally when clearly their impact on protein function varies widely. We have developed a method which can complement the analysis of recurrence of SNVs across several tumor samples to detect candidate driver genes by taking advantage of the information provided by the analysis of functional impact of SNVs and short frameshift indels. The method is based on the assumption that any bias towards the accumulation of variants with high functional impact (FM bias) is an indication of positive selection and can thus be used to detect candidate driver genes or gene modules. We have called it Oncodrive-fm. We have applied the Oncodrive-fm approach to two datasets of genes with variants in samples of different tumor types: Chronic Lymphocytic Leukemia (cll: from Spanish ICGC Group) and Glioblastoma datasets (gbm: from TCGA). Most of the genes detected by recurrence analysis (i.e MutSig) also show significant FM bias (eg. TP53, EGFR, PTEN in gbm and SF3B1 in cll), we call these clear drivers. However, Oncodrive-fm can also detect lowly recurrent likely driver genes that are overlooked by recurrence analysis (eg. IDH1, FGFR1 and FGFR3 in gbm and CDH9 and CHD2 in cll), and identify genes with high number of mutations that do not show FM bias, which we term as candidate false positives. The application of Oncodrive-fm to the analysis of pathways reveals several pathways with FM bias, such as MAPK and mTOR pathways in gbm and mRNA splicing pathway in cll. In summary we show that FM bias helps to uncover drivers and recommend its computation in conjunction with the analysis of recurrence in a cohort of tumor samples to identify candidate driver genes and gene modules. Oncodrive-fm method is available at http://bg.upf.edu/oncodrive.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-401. doi:1538-7445.AM2012-LB-401
Abstract LB-403: Recurrent fusion transcripts in breast cancer
Authors: Sadanandam Anguraj , Wullschleger Stephan , Spellman Paul , Hanahan Douglas , Gray Joe W. 
Published: August 2012

Abstract
Breast cancer is the second leading cause of cancer deaths among women in the United States. Genome wide analyses in primary breast tumors and ∼50 breast cancer cell lines using gene expression profiling revealed subsets defined as luminal, basal-like, ERBB2 and claudin-low. The general hypothesis is that recurrent fusion transcripts exist and play a central role in the pathophysiology and clinical outcome of breast cancer. We identified recurrent fusion transcripts specific to breast cancer cell lines by performing Solexa based paired-end sequencing of whole-transcriptome (RNAseq) using 9 basal, 9 luminals, 4 ERBB2 and 1 claudin-low breast cancer cell lines. In addition, we cross-compared the predicted fusion transcripts with that of copy number and gene expression changes in the respective cell lines and performed gene ontology (GO) based enrichment analysis using the genes that were involved in the fusion. The sequencing of 19 breast cancer cell lines resulted in a range of ∼15 million to ∼45 million paired-end reads of 76 bp per cell line and out of which 93% to 98.6% had quality reads. On average, we predicted ∼14 fusion genes per cell lines (331 fusion genes in total) that are expressed atleast in one cell line. Interestingly, basal breast cancer cell lines on average have more number of fusion transcripts (∼13 per cell line and 115 in total) whereas luminal cell lines have only ∼9 predicted fusion transcripts per cell line (84 in total). Among the 418 unique genes that were involved in fusion processes, 20% of the genes occurred atleast twice and GO enrichment analysis show similar terms to be significantly enriched. Intriguingly, we identified 24 different recurrent fusion transcripts in total. In summary, the data demonstrates that there is more number of predicted fusion transcripts in breast cancer than initially thought. Also, the data suggest that genes with similar functions or processes fuse together. Currently studies are in progress to test if recurrent gene fusions may have a functional role, which may assist in the design of appropriate strategies to target recurrent events, and may be associated with poor outcome of basal breast cancers. Overall, this may improve the prognosis of breast cancer patients.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-403. doi:1538-7445.AM2012-LB-403
Abstract LB-411: RNA sequencing reveals CUX1 to be a conserved tumor suppressor in acute myeloid leukemia associated with loss or deletion of chromosome 7
Authors: McNerney Megan E. , Brown Christopher D. , Wang Xiaoyue , Karmakar Subhradip , Bandlamudi Chaitanya , Yu Shan , Anastasi John , Le Beau Michelle M. , White Kevin 
Published: August 2012

Abstract
Loss of chromosome 7 and del(7q) [-7/del(7q)] are recurring cytogenetic abnormalities in acute myeloid leukemia (AML), occurring in 9% of de novo AML and 50% of therapy-related myeloid neoplasms (t-MN). Abnormalities of chromosome 7 carry an adverse prognosis. Despite intensive analysis by many laboratories, and the identification of multiple minimally deleted regions on 7q, the putative tumor suppressor(s) on chromosome 7 is currently unknown. We performed transcriptome sequencing on 22 samples and SNP array analysis on 35 samples from patients with myeloid neoplasms, half of which contain -7/del(7q). Copy number analysis identified a 2.17 Mb commonly deleted segment on chromosome band 7q22.1 containing CUX1, a gene encoding a homeodomain-containing transcription factor normally expressed highly in hematopoietic stem cells. CUX1 was found to be disrupted in a translocation resulting in a chimeric RNA fusion transcript in one patient. We found the CUX1 transcript and protein to be expressed at haploinsufficent levels in -7/del(7q) leukemias. To test the tumor suppressor activity of CUX1, the drosophila homologue, CUT, was knocked-down in Drosophila melanogaster hemocytes, which led to significantly increased numbers of hemocytes and melanotic tumor formation. Restoration of CUX1 expression in a human AML cell line with -7 decreased proliferation. These data indicate that CUX1 is a conserved, haploinsufficient, tumor suppressor that promotes leukemogenesis in -7/del(7q) AML.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-411. doi:1538-7445.AM2012-LB-411
Abstract LB-416: Genetic analysis of pediatric brainstem glioma using protein analysis of cerebrospinal fluid
Authors: Saratsis Amanda M. , Nazarian Javad 
Published: August 2012

Abstract
Abstract: Diffuse intrinsic pontine glioma (DIPG) is a leading cause of brain tumor death in children due to lack of effective therapy. Genetic analysis of DIPG has been limited due to the lack of readily available tumor tissue for molecular study. Molecular analysis of cerebrospinal fluid (CSF) could provide information on chromosomal abnormalities in DIPG. Methods: CSF samples from normal and brainstem glioma patients were analyzed by MS/MS label-free proteomic analysis using LTQ-Orbitrap-XL. Proteins were identified using the Sequest algorithm in the Bioworks browser against the Uniprot database and quantitated using ProteoIQ software. Relative protein expression was used to extrapolate potential regions of chromosomal amplification and deletion. Results: Quantitative proteomic analysis revealed 309 proteins detected in DIPG CSF specimens but absent in controls 76% of which correlated to regions of known genomic amplification in pediatric brainstem glioma. Specifically, 1q and 17q were chromosomal regions that showed the greatest amplification as judges by high expression in DIPGs CSF Specimens Moreover, 46 proteins were detected in all controls but absent in DIPG CSF specimens. Of these, 58% mapped to known genomic deletion sites, with X, 5p and 17p the most common abnormal regions. These findings correlate with existing data in the literature on genetic abnormalities of brainstem glioma. Conclusions: Cerebrospinal fluid from children with DIPG and other craniospinal tumors are more readily available than biopsies tumor specimen. Proteomic analysis can reveal potential regions of genomic change that correlates with existing data in the literature and can provide insight to pathways of brainstem gliomagenesis. Further analysis of CSF and validation of observed dysregulation is warranted.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-416. doi:1538-7445.AM2012-LB-416