bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1220: ErbB4: A novel therapeutic target in glioblastoma multiforme
Authors: Donoghue Jacqueline , Kerr Lauren , Longano Anthony , Mischel Paul , Johns Terrance 
Published: August 2012

Abstract
Introduction: Glioblastoma Multiforme or glioma is amongst the most lethal and difficult to cancers to treat and kills 1,000 Australians and 12,000 Americans every year. The average age at diagnosis is 60 years and the death rate for glioma has remained relatively unchanged for the past 20 years; highlighting the need for new therapeutic options for its treatment. ErbB4, the fourth member of the EGFR family has both oncogenic and tumor suppressive activity dependent upon isoform expression and although ErbB4 is universally expressed in glioma, its functional role is somewhat unclear. Aims: The aim of this study was to characterize the expression of ErbB4 in a large cohort of glioma tissues at the protein and mRNA level and determine if ErbB4 expression relates to tumor biology and patient survival. Methods: Immunohistochemistry was performed on paraffin sections of glioma tissue (n=68) and normal brain (n=5) for the immunolocalisation of ErbB4 and EGFR (total and activated) and the ErbB4 ligand heregulin. Using a customized RT-qPCR assay, ErbB4 isoforms were identified in snap frozen glioma (n=23) and normal brain (n=15). Results: Patients diagnosed with glioma (n=68) had a median survival time of 15 months (range 1-120 months) with the average age of 63±2 years (range 21-80 years). ErbB4 and heregulin protein was demonstrated in all our glioma and normal brain samples. At the mRNA level however, ErbB4 expression was reduced in the glioma samples when compared to normal brain tissue. All six ErbB4 isoforms were demonstrated in all tissue samples and ErbB4 was preferentially expressed as the JMa/Cyt2 isoform in glioma. Histologically, ErbB4 activation (independent of EGFR activation) occurred in 16% of patient samples and was localized to sites like the leading edge of the tumor. The mean survival time for patients with high levels of activated ErbB4 was 12 months, while patients with low levels of activated ErbB4 had a mean survival time of 32 months. ErbB4, activated ErbB4 and heregulin were also demonstrated in the vasculature of the glioma but not normal brain. Conclusions: This study demonstrated the preferential expression of the JMa/Cyt-2 isoform of ErbB4 in glioma along with increased ErbB4 activation significantly shortening patient survival times. Due to a potential angiogenic role of ErbB4 in glioma and reduced patient survival times following ErbB4 activation, ErbB4 should be considered a new therapeutic target in glioma.
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 1220. doi:1538-7445.AM2012-1220
Abstract 1222: Met-dependent positive and negative signaling cascades in gastric cancer cells
Authors: Lai Andrea Z. , Zhao Hong , Cory Sean , Bell Emily S. , Hallett Michael , Park Morag 
Published: August 2012

Abstract
Signaling by the Met, hepatocyte growth factor (HGF) receptor tyrosine kinase (RTK) activates multiple downstream signaling pathways that promote cell migration and invasive growth. Cells that overexpress and are “addicted” to Met also require Met signaling to sustain cell survival. Thus, a number of specific small-molecule inhibitors have been developed to target Met in the clinic. Although several successes of RTK-targeted therapies are acknowledged, several have limited long-term success clinically, due to development of drug resistance. Initiation of RTK signaling cascades leads to the activation of a number of downstream signaling molecules, but prolonged activation also triggers negative feedback loops that function in part to abrogate this signaling. Hence, targeted inhibition of Met, in addition to suppressing Met-dependent signaling, may also release cells from negative feedback mechanisms and allow the reactivation of signaling pathways, that may promote resistance to Met inhibition. As MET amplification occurs in 10-20% of gastric cancers, to identify core Met dependent signaling pathways activated in Met dependent cancers we have used four different gastric cancer cell lines that exhibit amplification, overexpression, and constitutive activation of Met. Upon inhibition of Met with a small-molecule inhibitor, we observe abrogation of several downstream signaling pathways at both the protein phosphorylation and transcript level. Interestingly, as Met has been demonstrated to cross-talk with the EGF receptor family, we also observe a decrease in the phosphorylation of EGFR and HER3 upon treatment with Met inhibitor, and a decrease in expression of EGFR ligands. Conversely, Met inhibition results in an elevation in expression of HER3 transcript and protein in all 4 cell lines, implicating Met signaling in HER3 repression, and inhibition of Met may release HER3 from this negative regulation. As increases in HER3 phosphorylation and expression occur in other models (such as breast or lung cancer cell lines) upon treatment with EGFR, HER2, or AKT inhibitors, and high HER3 expression is strongly associated with tumor progression and poor prognosis in gastric cancer; hence, the loss of negative regulation of HER3, downstream from Met, may ultimately contribute to clinical efficacy, or lack thereof, of Met inhibitors.
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 1222. doi:1538-7445.AM2012-1222
Abstract 1224: PDGFR as a novel target for the treatment of malignant peripheral nerve sheath tumors
Authors: Patwardhan Parag , Tap William , de Stanchina Elisa , Schwartz Gary K. 
Published: August 2012

Abstract
Malignant peripheral nerve sheath tumor (MPNST) is a rare and highly aggressive tumor type that accounts for approximately 5-10% of soft tissue sarcomas. MPNSTs arise either spontaneously or in patients with type 1 neurofibromatosis (NF1). These tumors are highly resistant to chemotherapy and there are no effective treatment options. It has been demonstrated that MPNSTs with NF1 mutations are highly sensitive to the mTOR inhibitor rapamycin. However, inhibition of this pathway by rapamycin in sarcomas has been shown to release negative feedback inhibition of IGF-1R and activate AKT (pAKT). We have shown that treatment of MPNST cell lines (MPNST and ST8814) with rapamycin activates AKT, but not through IGF-1R, since IGF-1R is not expressed in these cells. This would suggest an alternate route for rapamycin induced AKT activation. To understand this process, we treated MPNST and ST8814 cells, with or without rapamycin, and used cellular lysates to determine whether the release of negative feedback by mTOR inhibition was mediated by alternate receptor tyrosine kinases (RTKs). Using RTK array profiling (R&D Systems), our results indicate that both p-PDGFRα and p-PDGFRß are activated in response to rapamycin. Using imatinib (STI571) to target both PDGFRα and PDGFRß, we show that imatinib blocks rapamycin induced reactivation of pAKT. In order to rule out off target effects of imatinib, knockdown of PDGFR using siRNA followed by treatment with rapamycin recapitulates the effects observed with imatinib treatment. The combination of imatinib and rapamycin in MPNST cells resulted in a significant decrease in cell proliferation when compared to either of the two drugs alone. Mouse xenograft studies also show that tumor growth volume is decreased significantly when xenografts are treated with imatinib in combination with rapamycin compared to either drug alone. Taken together, our data strongly suggests that in MPNST cells, PDGFR pathway is involved in rapamycin mediated release of the negative feedback loop that activates pAKT. Furthermore, the targeting of PDGFR in combination with inhibitors of mTOR could provide a new therapeutic approach for the treatment of this 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 1224. doi:1538-7445.AM2012-1224
Abstract 1225: Integration of HGF/Met signaling and hypoxia response in cancer cell invasion and proliferation
Authors: Lee Young H. , Bottaro Donald P. 
Published: August 2012

Abstract
The cellular response to hypoxia is a major influence on the aggressiveness of primary tumors, yet much of how this response mechanism integrates with other signaling pathways is unknown. The MET proto-oncogene, which encodes the tyrosine kinase receptor for hepatocyte growth factor (HGF), is often overexpressed in cancers and can drive cell proliferation, invasion, and metastasis. Prior studies demonstrate that the Met tyrosine-kinase receptor drives cell invasion and metastasis under hypoxic conditions, and this invasive phenotype is lost if MET expression is inhibited. Hypoxia also has been shown to sensitize Met-activated pathways to drive HGF-induced invasion through an as yet undefined molecular mechanism. The high mortality rate of metastatic cancer makes it crucial to understand the functional integration of these two prevalent drivers of metastasis, hypoxia and Met signaling, and to identify ways to selectively block cancer cell invasiveness. We show that a chemically generated pseudo-hypoxic condition enhanced HGF-mediated cell migration and invasion in the papillary renal cell (PRC) carcinoma cell lines ACHN and UOK112. Enhanced HGF-driven invasiveness was associated with sensitization of the mitogen-activated protein kinase (MAPK) pathway and increased matrix metalloproteinase activity. HGF-stimulated cell proliferation, in contrast, was phosphoinositide 3-kinase (PI3K) pathway dependent and not enhanced under the same pseudo-hypoxic condition. Furthermore, MAPK activation in the presence of HGF and hypoxia negatively regulated HGF-induced Akt activation and mitochondrial reductase enzymes as detected by MTT assay. These data suggest that hypoxia promotes tumor invasion by sensitizing the MAPK pathway to HGF stimulation in PRC-derived cells while limiting and/or suppressing HGF activation of PI3K-mediated cell proliferation. Identifying the specific effectors responsible for the integration these signals will improve our understanding of pro-metastatic invasiveness and potentially identify novels targets for its selective blockade.
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 1225. doi:1538-7445.AM2012-1225
Abstract 1232: Overcoming resistance to EGFR-tyrosine kinase inhibitor therapy in non-small cell lung cancer
Authors: Sierra J Rafael , Chang Anderson , Moffat Jason , Neel Benjamin G. , Tsao Ming-Sound 
Published: August 2012

Abstract
Lung cancer is the leading cause of cancer death in developed countries both for men and women; and the second most common type of cancer diagnosed, with less than 15% of patients surviving beyond 5 years. Since more than 60% of lung adenocarcinomas and more than 90% of lung squamous cell carcinomas express high levels of EGFR mRNA and protein, it has been the focus of efforts to develop new agents that target the EGFR pathway. Clinical trials have demonstrated that patient selection plays a major role for patient response. Patients that present amplification or activating mutations (L878R or exon 19 deletions) of EGFR, have higher response rates. Selection improved response rates from less than 10% to over 60-80%. Despite the promising results, all patients that receive TKI therapy develop resistance to treatment in less than one year. The mechanisms of resistance to EGFR TKi's described so far are those dependant on the overactivation/amplification of other receptor tyrosine kinases (RTK) capable to sustain anti-apoptotic signaling pathways. Our study proposes the use of genome-wide screenings using an 80,000 shRNA library on EGFR resistant cells can identify new genes that mediate the resistance to EGFR targeted therapy and provide the basis for designing new therapeutic approaches to avoid the emergence of resistance. So far, we have generated a shortlist of gene candidates that confer synergistic synthetic lethal interactions with EGFR targeted therapies and that are also highly expressed in resistant cells. We are currently overexpressing candidate genes in sensitive cells searching for those that can confer resistance to EGFR targeted therapies. Our study proposes target genes that can synergize with the current treatments to create new therapeutical strategies that can avoid the acquisition of resistance to targeted therapies. Overall, the information gained from this type of study can be applicable to tumors where ERBB receptor(s) play an important role and targeted therapies are currently used.
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 1232. doi:1538-7445.AM2012-1232
Abstract 1233: A triad of Brk, HER2 and STAT3 in regulating epithelial and mesenchymal transition and survival of breast cancer cells
Authors: Ai Midan 
Published: August 2012

Abstract
Breast tumor kinase (Brk) is a nonreceptor protein-tyrosine kinase recently shown to be coexpressed with human epidermal growth factor receptor-2 (HER2) at high levels in tumor specimens from patients with invasive ductal breast cancer. Brk is associated with HER2 in breast cancer cells and can directly phosphorylate signal transducers and activators of transcription-3 (STAT3). However, the biological functions of these interactions remain largely unknown. In current study, we developed a subline from HER2-transfected MCF7 breast cancer cells through in vivo selection in nude mice. Overexpression of HER2 led to a higher level of Brk in MCF7 cells and the in vivo selection resulted in a subline with markedly enhanced epithelial and mesenchymal transition (EMT) phenotype and markedly increased migration potential. We named the subline cells EMT1. Both the EMT phenotype and survival of the EMT1 cells heavily depend on Brk, because knockdown of Brk through RNA interference reversed the EMT phenotype, reduced cell migration potential and induced cell death via apoptosis in the EMT1 cells. We further found that the level of activation-specific phosphorylated STAT3 was markedly increased in the EMT1 cells compared with control vector-transfected or HER2-transfected MCF7 cells. Knockdown of Brk significantly reduced the level of STAT3 phosphorylation in the EMT1 cells. Overexpression of a constitutively active STAT3 counteracted Brk knockdown-induced inhibition of cell migration potential and Brk knockdown-induced apoptosis in the EMT1 cells. Together, these preliminary findings support a new paradigm for regulating breast cancer cell EMT and survival that involves interaction and coordination between Brk, HER2, and STAT3.
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 1233. doi:1538-7445.AM2012-1233
Abstract 1238: Gab1 regulates epithelial cell polarity and scattering by acting as a platform for PAR proteins
Authors: Yang Ziqiang , Neel Benjamin 
Published: August 2012

Abstract
Control of cell polarity plays a key role in numerous important biological processes, but the molecules and mechanisms that regulate polarity remain poorly defined. We found that the scaffolding adaptor Gab1, a component of multiple growth factor and cytokine signaling pathways, interacts with two PAR proteins, PAR1 and PAR3. Gab1 binds PAR1 and activates its kinase activity. Acting as a scaffold, Gab1 brings PAR1 and PAR3 into a transient complex, facilitating PAR3 phosphorylation by PAR1. Gab1 and PAR6 bind the PAR3 PDZ1 domain, and thereby compete for PAR3 binding. Consequently, depletion of Gab1 causes PAR3 hypo-phosphorylation and increased PAR3/PAR6 complex formation, resulting in accelerated formation of tight junctions, increased trans-epithelial electrical resistance and a shortened lateral domain in epithelial cells. Conversely, Gab1/PAR1 interaction enhances epithelial cell scattering. Thus, Gab1 is a novel regulator of epithelial cell polarity that acts as a platform for assembling and modulating PAR protein complexes.
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 1238. doi:1538-7445.AM2012-1238
Abstract 1256: Profiling protein-coding RNA and thousands of large non-coding RNAs from nanogram amounts of total RNA using a single microarray design
Authors: Lucas Anne Bergstrom , Kulkarni Vinayak , LeProust Emily , Srinivasan Maithreyan , Fulmer-Smentek Stephanie 
Published: August 2012

Abstract
Large intergenic non-coding RNAs (lincRNAs) are emerging as key regulators of diverse cellular processes, yet determining the function of individual lincRNAs remains challenging. Recently, more than 8,000 human lincRNAs were annotated and cataloged from more than 4 billion RNA-Seq reads across 24 tissues and cell types by scientists at the Broad Institute of MIT and Harvard. Data from this project indicates that lincRNA expression is highly tissue-specific as compared to protein coding gene expression. As researchers continue to investigate the function of lincRNAs, there is a need for tools that can rapidly and accurately measure the expression of the recently annotated lincRNAs along with mRNA expression. We have previously developed and recently updated the content of the human SurePrint G3 microarrays so that they are comprised of all known protein-coding mRNAs and lincRNAs, to enable systematic profiling and simultaneous detection of coding and non-coding gene expression from a single sample. To demonstrate the utility of the new microarray design we used low nanogram amounts RNA from matched tumor and adjacent normal tissues to produce cyanine-labeled cRNA. The labeled cRNA was applied to the microarrays to detect differences in coding and non-coding gene expression profiles. Using the GeneSpring GX software we are able to identify differentially expressed lincRNAs and protein-coding RNAs in the tumor and normal samples in less than two days. Comparisons of probe signals from technical replicate samples demonstrated high reproducibility with wide dynamic ranges and high sensitivity. Data from the microarrays correlates well with whole transcriptome sequencing of the same matched tumor/normal samples. Using this approach we show that lincRNA expression coincides with key genes known to regulate biological processes involved in cancer progression and this work demonstrates how profiling mRNA and lincRNA from matched tumor and adjacent normal samples can enable researchers to further define the role of lincRNAs in gene regulation.
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 1256. doi:1538-7445.AM2012-1256
Abstract 126: miR-221 promotes tumorigenesis in human triple negative breast cancer cells
Authors: Yin Min-Jean , Nassirpour Rounak , Mehta Pramod P. , Baxi Sangita M. 
Published: August 2012

Abstract
MicroRNAs (miRNAs) are non-coding, single-stranded RNAs of ∼22 nucleotides that act as agents of the RNA interference pathway and negatively regulate their targets by either cleaving mRNA molecules or by inhibiting their translation. miRNAs are frequently located at fragile sites and genomic regions susceptible to amplification, deletion, or translocation during tumor development, and growing evidence indicates that miRNAs can function as tumor suppressors and oncogenes. Additionally, miRNA expression profiling analyses have revealed characteristic miRNA signatures in human cancers. MicroRNA-221 (miR-221) is up-regulated in many cancers including HCC, glioblastoma, pancreatic cancer, prostate cancer, and tamoxifin-resistant breast cancer. Overexpression of miR-221 has previously been shown to promote cancer cell proliferation, most likely by its ability to modulate the expression of the oncogenic proteins c-kit and cyclin dependent kinase inhibitor (CDKI) CDKN1B/p27. In this study, we demonstrate that in comparison to normal mammary tissues, miR-221 is overexpressed in triple negative breast cancer cell lines (TNBC) and downregulated in non-TNBC breast cancer cell lines. Stable knockdown of miR-221 expression reduced cell proliferation and induced apoptosis in TNBC cell lines. Overexpression of miR-221 promoted cell migration and cell invasion, while knockdown of miR-221 inhibited both cell migration and cell invasion and increased E-cadherin expression in TNBC lines but not in the non-TNBC lines. Furthermore, downregulation of miR-221 in MDA-MB-231 xenografts decreased the tumor growth rate in mice. Therefore, our results suggest that miR-221 is a potential oncomiR that promotes cell proliferation, migration, and invasion in triple negative breast cancer cells, and that knockdown of miR-221 is able to induce in vitro and in vivo anti-tumor activity in these TNBC cell lines.
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 126. doi:1538-7445.AM2012-126
Abstract 1263: Affinity-based proteomics reveal cancer-specific networks coordinated by Hsp90
Authors: Gomes-DaGama Erica M. , Moulick Kamalika , Ahn James H. , Zong Hongliang , Rodina Anna , Cerchietti Leandro , Lopes-Vazquez Maria E. Caldas , Beebe Kristin , Perna Fabiana , Katerina Chatzi , Vu Ly P. , Zhao Xinyang , Zatorska Danuta , Taldone Tony , Smith-Jones Peter , Alpaugh Mary , Gross Steven S. , Pillarsetty Nagavarakishore , Ku Thomas , Lewis Jason S. , Larson Steven M. , Ross Levine , Erdjument-Bromage Hediye , Guzman Monica L. , Nimer Stephen D. , Melnick Ari M. , Neckers Len , Chiosis Gabriela 
Published: August 2012

Abstract
Most cancers are characterized by multiple molecular alterations, but identification of the key proteins involved in these signaling pathways is currently beyond reach. We show that the inhibitor PU-H71 preferentially targets tumor-enriched Hsp90 complexes and affinity captures Hsp90-dependent oncogenic client proteins. We have used PU-H71 affinity capture to design a proteomic approach that, when combined with bioinformatic pathway analysis, identifies dysregulated signaling networks and key oncoproteins in chronic myeloid leukemia. The identified interactome overlaps with the well-characterized altered proteome in this cancer, indicating that this method can provide global insights into the biology of individual tumors, including primary patient specimens. In addition, we show that this approach can be used to identify previously uncharacterized oncoproteins and mechanisms, potentially leading to new targeted therapies.
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 1263. doi:1538-7445.AM2012-1263