bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract LB-19: Involvement of aryl hydrocarbon receptor nuclear translocator in EGF-induced c-Jun/Sp1-mediated gene expression
Authors: Chen Ben-Kuen , Huang Wan-Chen 
Published: February 2011

Abstract
Aryl hydrocarbon receptor nuclear translocator (ARNT)/ hydroxia-inducible factor-1β (HIF-1β) is a basic helix-loop-helix Per/AhR/ARNT/Sim (bHLH-PAS) that forms dimeric transcriptional regulatory complexes with other bHLH-PAS proteins to regulate various biological pathways. Our previous report has shown that ARNT is also involved in epidermal growth factor (EGF)-induced COX-2 gene expression. By using pull-down and protein-DNA interaction assays, we herein report that ARNT is associated with transcription factors c-Jun/Sp1, and it regulates gene expression. We find that EGF stimulated the formation of the c-Jun/ARNT/Sp1 complex and the binding of the transcription protein complex to the Sp1 site of the gene promoter in a time-dependent manner. In addition, the promoter activity and the mRNA level of 12(S)-lipoxygenase upon EGF stimulation were inhibited by ARNT small interfering RNA (siRNA). Notably, ARNT cooperated with c-Jun to regulate gene expression. Although both c-Jun and ARNT have a transactivation domain, c-Jun was responsible for the EGF-induced transcriptional activation because a dominant negative c-Jun mutant, TAM-67, blocked ARNT-mediated 12(S) lipoxygenase expression, but not the binding of ARNT to the promoter. ARNT knockdown attenuated the association between c-Jun and Sp1 and the downregulation of gene expression. Furthermore, ARNT siRNA also inhibited other EGF-induced c-Jun/Sp1 mediated gene expression, such as p21WAF1/CIP1. Our results revealed a novel mechanism by which ARNT acts as a modulator to bridge the c-Jun/Sp1 interaction and plays a role in EGF-mediated gene expression under normoxic conditions.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-19.
Abstract LB-2: Cullin-2 facilitates EGFR ubiquitination and degradation after trafficking of the receptor to the nucleus
Authors: Kim Jayoung , Freeman Michael R. 
Published: February 2011

Abstract
Objectives of the study: The epidermal growth factor receptor (EGFR) can be overexpressed in bladder cancer and other malignancies and is a molecular risk factor associated with poor prognosis. Surface EGFR is able to traffic to the nucleus, where it can regulate gene expression as a component of transcription complexes. This non-canonical function for the EGFR correlates with tumor aggressiveness and unfavorable clinical outcome. We have identified cullin-2, a ubiquitin E3 ligase cofactor that associates with the Von Hippel-Lindau tumor suppressor protein (pVHL) and elongin B/C, by mass spectrometry as a putative component of an EGFR nuclear trafficking complex in human bladder cancer cells. The goal of the present study was to determine the potential role of cullin-2 in EGFR nuclear trafficking and function.
Methodology: Various biochemical approaches, including co-IP/Western blotting and fluorescence imaging, were performed to analyze the association of EGFR and ubiquitin E3 ligase components, including cullin-2 and pVHL. Forced expression or silencing of cullin-2 was also performed.
Results: Accumulation of EGFR in nuclei was shown within 30min after treatment of TCCSUP bladder cancer cells with the EGFR ligand HB-EGF. Ubiquitination and degradation of nuclear EGFR were observed 1h after stimulation. Cullin-2 binds to EGFR in the nucleus, leading to recruitment of pVHL upon HB-EGF treatment. The association of nuclear EGFR with the Rpt10/S5a and Rpt1 proteasome subunits implicates the proteasome in nuclear EGFR degradation, which is consistent with data indicating that nuclear EGFR degradation was suppressed by proteasomal inhibition. Silencing of endogenous cullin-2 or pVHL suppressed the degradation of nuclear EGFR. Collectively, these results suggest that cullin-2 is a mediating factor that connects nuclear EGFR to the ubiquitin E3 ligase and the proteasome, leading to proper feedback regulation after EGFR activation. Our findings provide new insight into the diverse intracellular mechanisms in which the EGFR participates and, in particular, its signaling roles in the nucleus in bladder cancer and possibly other cell types.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-2.
Abstract LB-20: Transcriptionally inactive PAX3-FKHR fails to induce ARMS cells differentiation
Authors: Jothi Mathivanan , Keller Charles , Mal Asoke K 
Published: February 2011

Abstract
Alveolar rhabdomyosarcoma (ARMS) is an aggressive muscle cancer of childhood and believed to arise from committed muscle progenitor cells that have arrested during the process of skeletal muscle differentiation. One of the most established genetic signatures in ARMS is the presence of chimeric aberrant transcription factor PAX3-FKHR generated by fusion of PAX3 and FKHR genes. The stronger transcriptional activity of this fusion PAX3-FKHR protein has previously been attributed to the deregulation of genes, which are known to be associated with tumorigenesis and suppression of skeletal muscle differentiation. Currently, we are investigating the relative contribution of PAX3-FKHR's transcriptional activity in abrogating ARMS cells differentiation using mouse ARMS cells as an in vitro model differentiation readout system. Here, we show that transactivation potential of PAX3-FKHR is declined in mouse ARMS cells that have been induced to differentiate by growing these cells in mitogens-deficient in vitro differentiation-permissible condition. Moreover, this diminished activity of PAX3-FKHR is not due to the alteration of its sub-cellular localization or changes in the level of either mRNA or protein in these ARMS cells. Results also show the lack of muscle-specific gene activation in these ARMS cells despite the reduced transcriptional activity of PAX3-FKHR under condition of differentiation. We also observed that decrease in transcriptional activity of PAX3-FKHR is coincided with the activation of PI3/AKT pathway. The results further show that blockade of PI3/AKT pathway sustains the transcriptional activity of PAX3-FKHR whereas forced activation of AKT inhibits this activity. Together, our results signify that transcriptionally inactive PAX3-FKHR by AKT is incompetent to induce mouse ARMS cells differentiation.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-20.
Abstract LB-21: Emergence of castration resistant prostate cancer class defined by recurrent ERG fusion
Authors: Rickman David S. , Chen Ying-bei , Banerjee Samprit , Pan Yihang , Moss Benjamin , Sboner Andrea , Yu Jindan , Perner Sven , Lafargue Christopher , VanDoren Vanessa , Mertz Kirsten , Setlur Sunita , Sircar Kanishka , Gerstein Mark , Chinnaiyan Arul , Bismar Tarek , Rubin Mark , Demichelis Francesca 
Published: February 2011

Abstract
The role of recurrent ETS gene fusions in castration resistant prostate cancer (CRPC) is poorly understood. We characterized the transcriptome of CRPC by interrogating a cohort of 54 men with locally advanced or metastatic CRPC using a gene expression profiling method recently established for formalin-fixed paraffin-embedded tissue. We found increased expression of multiple genes in ERG rearranged tumors which suggests a selective growth advantage under oxygen poor conditions. We discovered that trefoil factor 3 (TFF3) is the top differentially regulated gene by both ERG rearrangement and resistance to therapy. Conventional chromatin immunoprecipitation (ChIP)-PCR and ChIP-seq data revealed direct binding of ERG to ETS binding sites in the TFF3 promoter in ERG rearranged prostate cancer cell lines, which was confirmed in ERG rearranged hormone naïve prostate cancer (HNPC) and CRPC tissue samples. In vitro data suggested that ERG has an inhibitory effect on TFF3 expression in hormone naïve cancer, which was relieved in CRPC depending on the level of AR expression. These findings reveal an interplay between ERG rearrangement and AR signaling in CRPC, and provide perspective towards novel therapeutic targets.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-21.
Abstract LB-210: A multiplexed serum biomarker immunoassay panel discriminates clinical lung cancer patients from cancer-free high-risk subjects in a CT-screened cohort
Authors: Bigbee William L. , Gopalakrishnan Vanathi , Dacic Sanja , Hauskrecht Milos , Weissfeld Joel L. , Wilson David O. , Siegfried Jill M. , Lokshin Anna E. 
Published: February 2011

Abstract
Clinical decision making in the setting of CT screening could benefit from accessible biomarkers that help predict the level of lung cancer risk in high-risk subjects with indeterminate pulmonary nodules commonly found by screening. The specificity and sensitivity needed to improve interpretation of CT images in the setting of a suspicious pulmonary nodule would be less stringent than those needed for lung cancer screening in the general population. As a first step in identifying and characterizing serum protein biomarkers to more accurately identify individuals with lung cancer in populations of high-risk tobacco-exposed individuals, we measured 70 cancer-related proteins by Luminex xMAP® multiplexed immunoassays in a training set of sera from 56 patients with biopsy-proven primary lung cancer diagnosed in a clinical setting and sera from 56 age-, sex- and smoking-matched CT-screened controls. These controls are drawn from a cohort of participants in the Pittsburgh Lung Screening Study (PLuSS) who have undergone CT screening and are known to be cancer-free after a minimum of 3 years follow-up. We found a profile of 8 biomarkers - PRL, TTR, THSP, SELE, CCL5, MIF, and SERPINE1 and ERBB2 - that distinguished lung cancer from controls in the training set with a sensitivity (SN) of 92.9% and specificity (SP) of 87.5%. The balanced accuracy (average of SN and SP) from 20-fold internal cross-validation of the training set was 82.5% ± 4.8%. We then applied this 8 biomarker model to an independent test set of 10 additional clinically detected lung cancer cases and 83 randomly selected PLuSS participants who were known to be cancer-free. These PLuSS controls in the test set included subjects with and without CT-detected pulmonary nodules and a range of airflow obstruction and radiographic emphysema. The biomarker model classified these test set cases and controls with a balanced accuracy of 83.6% (90.0% SN and 77.1% SP). Importantly, the misclassified PLuSS controls in the test set displayed no significant association with airway function variables or level of suspicion of pulmonary nodule. Taken together, these data suggest that the 8 biomarker panel classified lung cancer independently of pulmonary function abnormalities and the presence of non-cancerous pulmonary nodules, and thus may provide clinical utility in ruling out lung cancer in tobacco-exposed individuals screened by CT imaging. [Supported by NCI SPORE in Lung Cancer P50 CA090440 (JMS) and NCI Early Detection Research Network Biomarker Discovery Laboratory U01 CA084968 (WLB)].
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-210.
Abstract LB-213: Plasma soluble VEGFR1 is a potential dual biomarker of response and toxicity for bevacizumab with chemoradiation in locally advanced rectal cancer
Authors: Duda Dan G. , Willett Christopher G. , Ancukiewicz Marek , di Tomaso Emmanuelle , Shah Mira , Czito Brian G. , Bentley Rex , Poleski Martin , Lauwers Gregory Y. , Carroll Madeline , Tyler Douglas , Mantyh Christopher , Shellito Paul , Clark Jeffrey W. , Jain Rakesh K. 
Published: February 2011

Abstract
We explored plasma and urinary concentration of four members of the vascular endothelial growth factor (VEGF) family as potential response and toxicity biomarker of bevacizumab with neoadjuvant chemoradiation in patients with localized rectal cancer.
The levels of VEGF, placental growth factor (PlGF) and soluble VEGF receptors 1 and −2 (sVEGFR1 and sVEGFR2) were measured by multiplex array in plasma and urine at baseline and during treatment. Pre-treatment values and changes over time were analyzed as potential biomarkers of pathological response to treatment (evaluated histologically using ypT, Mandard and N scoring at surgery) as well as for all acute toxicities in patients with locally advanced rectal cancer treated prospectively from 2002 to 2008 with bevacizumab, 5-fluorouracil and radiation therapy prior to surgery in a phase I/II trial (N=32 patients).
Of all biomarkers, the pretreatment plasma sVEGFR1 - an endogenous blocker of VEGF and a factor linked with “vascular normalization” - was strikingly associated with both tumor regression and with the number of adverse events after preoperative (neoadjuvant) bevacizumab and chemoradiation. Thus, plasma sVEGFR1 is a strong candidate as the first biomarker to stratify patients for bevacizumab therapy.
Therefore, future studies of bevacizumab and/or cytotoxics should be further explore sVEGFR1 as biomarker in neoadjuvant setting as well as in metastatic disease.
This study was partially supported by NIH grants R21-CA99237, P01-CA80124, R01-CA115767, R01-CA85140, R01-CA126642 and Federal Share/NCI Proton Beam Program Income grants, and by the National Foundation for Cancer Research.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-213.
Abstract LB-216: CSLEX (sialyl LewisX) is an important and useful tumor marker in monitoring breast cancer patients
Authors: Fujita Tomoyuki , Nagura Naoya , Koshikawa Kayoko , Nishimura Hajime , Ito Ken-ichi , Fujimori Minoru 
Published: February 2011

Abstract
Background: CSLEX-1 is one of the monoclonal antibodies for which the structure of the antigen is known. This antigen is called CSLEX (Sialyl Le X). It has been reported that CSLEX may be more useful than CEA in combination with CA15-3 in monitoring breast cancer patients.
Methods: We measured and evaluated the serum levels of some tumor markers, including CSLEX, in a total of 482 breast cancer patients with or without metastasis who consecutively visited the outpatient clinic of the Division of Breast and Endocrine Surgery, Shinshu University Hospital, between April 2007 and September 2007.
Results: All serum levels of tumor markers in a single measurement correlated significantly with the status of metastasis (P &lt; 0.01). All combinations of combined measurements, such as CEA and CA15-3, CEA and NCC-ST439, CEA and CSLEX, CA15-3 and NCC-ST439, and CA15-3 and CSLEX, also correlated significantly with the status of metastasis (P &lt; 0.01). The sensitivity, specificity, positive-predictive value, negative-predictive value and accuracy were almost the same between CSLEX and NCC-ST439, which belongs to the type II carbohydrate antigens. The cut-off values of serum CSLEX and NCC-ST439 were 38.8 ± 52.7 U/ml and 22.1 ± 27.8 U/ml, respectively (P = 0.16). Conclusions: These data support there are no differences between CSLEX and NCC-ST439 as diagnostic parameters in single or combined measurements. The cut-off value of serum CSLEX tended to be higher compared with that of NCC-ST439.Patient characteristics Without MetastasisWith MetastasisP-valueNumber363119 Mean Age ± SD (years)56.5 ± 11.758.9 ± 12.60.06CEA2.5 ± 6.311.9 ±34.50.008CA15-311.9 ± 11.166.4 ± 162.50.001BCA22561.0 ±51.5139.4 ± 228.60.001NCCST-4392.0 ± 2.234.2 ± 108.20.003CSLEX3.4 ± 3.765.6 ± 223.10.005Diagnostic parameters for the detection of breast cancer metastasis using tumor markers (%) SensitivitySpecificityPPVNPVAccuracySingle measurement CEA3095688179CA15-33498828282BCA2251698707878NCC-ST4392497727979CSLEX2397697978Combined measurement CEAandCA15-34893698482CEA and NCC-ST4394392648380CEA and CSLEX4392658380CA15-3 and NCC-ST4394595758483CA15-3 and CSLEX4495738482
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-216.
Abstract LB-220: Molecular predictors of sensitivity to an IGF1R inhibitor in pre-clinical models of lung and colon cancers
Authors: Lira Maruja E. , Pavlicek Adam , Lee Nathan V. , Ching Keith O. , Ye Jingjing , Cao Joan , Garza Scott , Hook Kenneth , Ozeck Mark , Shi Stephanie , Yuan Jing , Zheng Xianxian , Rejto Paul , Gualberto Antonio , Kan Julie , Christensen James G. 
Published: February 2011

Abstract
Targeting the insulin like growth factor receptor (IGF1R) signaling pathway is a promising approach against a variety of cancers and several clinical trials are now underway designed to evaluate the efficacy of IGF1R inhibitors singly or in combination with chemotherapeutic agents. Identification of the optimal patient population likely to respond is critical to the success of this class of targeted agents. To identify potentially predictive biomarkers, we sought to correlate response to figitumumab (CP-751,871), a fully human monoclonal antibody against IGF1R with molecular characteristics across a panel of cell lines. Growth inhibition to CP-751,871 was assessed in a panel of non-small cell lung carcinoma (NSCLC) (n=27) and colon cancer cell lines (n=21) cultured in anchorage and anchorage-independent conditions. Mutation status, whole-genome mRNA expression and DNA copy number were correlated to drug sensitivity. In addition, RNA expression of key genes in relevant signaling pathways was also interrogated via real time PCR. In the present studies, the frequency of response was greater in colon cancer cell lines than in NSCLC. Tissue or cell origin-specific expression levels of insulin-like growth factor binding proteins (IGFBPs) were associated with sensitivity. Low IGFBP3 expression [p=0.0035] correlated with response in NSCLC cell lines whereas low IGFBP6 [p=0.013] and IGF2BP3 [p=0.038] expression correlated with response in colon cancer lines. Increased IGF1R mRNA [p=0.045] levels, microsatellite stability, and PIK3CA wild-type status were also correlated with sensitivity in colon cancer lines. In addition, high expression of erbB2 [p=0.04] and erbB3 [p=0.04] were also associated with sensitivity of colon cancer lines. Collectively, findings from these studies are of potential value to identify patient populations with increased probability of benefit from IGF1R targeted agents. Our results further indicate that molecular predictors associated with the IGF1R pathway are potentially distinct between lung and colon cancer lines and additional studies to extend to other tumor types are warranted.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-220.
Abstract LB-229: PTEN modulates EGFRvIII-mediated SHP-2 activation and translocation to affect glioblastoma sensitivity to tyrosine kinase inhibitors (TKI)
Authors: Kapoor Gurpreet Singh , O'Rourke Donald M. 
Published: February 2011

Abstract
EGFRvIII, a constitutively active truncated mutant of epidermal growth factor receptor (EGFR), has been associated with increase neoplastic transformation and poor overall survival (OS). An earlier report showed that expression of EGFRvIII in gliomas provides resistance to chemotherapy. Co-expression of EGFRvIII and PTEN in a small subset of recurrent GBMs has been shown to increase sensitivity to tyrosine kinase inhibitors (TKI), including Erlotinib (tarceva) and Geftinib. However, the exact mechanism of EGFRvIII and PTEN interaction in response to TKI is still unresolved. Our recent reports showed that SHP-2 PTPase and its phosphatase activity are required for the EGFRvIII-mediated transformation. The aim of the present work was to investigate the molecular interaction between EGFRvIII/SHP-2 activation complex and PTEN in response to tarceva treatment and its effect on glioblastoma transformation. Our recent report demonstrated an increased SHP-2 phosphorylation in U87MG. EGFRvIII (PTEN-deficient) when compared to PTEN-intact LN229.EGFRvIII cells. In the present study, we show that tarceva treatment abolished EGFRvIII, EGFR, SHP-2 and Erk1/2, but Src family kinase (SFK), phosphorylation in LN229.EGFRvIII cells at all time intervals ranging from 30 minutes to 6 hours. On the contrary, phosphorylation of EGFRvIII, Src and Erk1/2 in U87MG. EGFRvIII cells was inhibited in early time points, but was restored in 2 to 6 hours. Surprisingly, phosphorylation of SHP-2 at Tyr542 residue was unaffected by tarceva treatment, but EGFR phosphorylation was inhibited in a time-dependent manner. PTEN deficiency resulted in resistance to tarceva treatment as assessed by MTT proliferation and soft agar transformation assays. Immunofluorescent labeling of U87MG. EGFRvIII cells with anti-phospho-SHP-2 (Tyr542) antibody showed perinuclear localization of SHP-2, whereas LN229.EGFRvIII cells exhibited membrane staining of phosphorylated SHP-2 (Tyr542). Our results showed that tarceva increased perinuclear SHP-2 Tyr542 in U87MG. EGFRvIII cells. Interestingly, stable expression of PTEN in U87MG. EGFRvIII cells conferred relocalization of phospho-SHP-2 to the membrane, a phenotype resembling LN229.EGFRvIII cells. Moreover, PTEN-expressing U87MG. EGFRvIII clones grew slower and showed a partially untransformed phenotype. These results suggest that SHP-2 is downstream effectors of PTEN and that PTEN deficiency may lead to SHP-2 activation and perinuclear localization by EGFRvIII, which may results in increased resistance to TKIs. Therefore, targeting SHP-2 may provide a new and effective therapeutic approach for treatment of glioblastoma.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-229.