bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1246: ELK-1 regulates interferon-alpha8 expression via a polymorphic region in the interferon-alpha8 promoter associated with outcome of glioma patients
Authors: Kohanbash Gary , Ishikawa Eiichi , Fujita Mitsugu , Mckaveney Kayla , Sakaki Masashi , Scheurer Michael , Bondy Melissa , Sarkar Saumendra Narayan , Okada Hideho 
Published: August 2012

Abstract
Several studies have demonstrated a significant immunological impact of single nucleotide polymorphisms in Interferon (IFN)-related genes, such as Toll-Like Receptor (TLR)3 and TLR4. We recently reported that patients with the AA-genotype of a SNP in the IFN-alpha8 (IFNA8) promoter region was associated with better overall survival of patients with WHO grade 2 and 3 gliomas compared to patients with the AC-genotype. Based on these observations we hypothesized that the A-allele in the promoter of IFNA8 allows for enhanced transcription factor binding and expression levels of IFNA8 compared with the C-allele. Analyses of THP-1 cells transfected with a luciferase gene downstream of a short sequence containing the SNP in the IFNA8 promoter demonstrated that the A-allele results in enhanced promoter activity. In silico analysis suggested c-Krox and ELK-1 as likely transcription factors that bind to the IFNA8 polymorphic region. Co-transfection of plasmids encoding the c-Krox or ELK-1 and the luciferase constructs revealed that ELK-1 negatively regulated promoter activity with the A but not C-allele, while c-Krox could not affect activity regardless of allele. Consistently, transfection of ELK-1 siRNA into THP-1 cells resulted in increased promoter activity. To further identify factors that contribute to the enhanced A-allele promoter activity we assessed the effect drugs that inhibit intracellular signaling pathways: PD98059 for inhibiting MEK/ERK, SB203580 a p38 inhibitor, and PPase-2B for de-phosphorylating small molecules. Use of any of the inhibitor resulted in decreased activity of the A-allele promoter activity indicating that multiple proteins or a protein common to multiple pathways seems to be involved. Taken together our data demonstrates that the A-allele in the IFNA8 promoter, which is associated with better glioma patient survival, allows for enhances promoter activation which is negatively regulated by ELK-1 and further regulate by multiple signaling pathways.
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 1246. doi:1538-7445.AM2012-1246
Abstract 1250: Crosstalk between Notch and MAPK signaling regulates proliferation in papillary thyroid cancer
Authors: Yamashita Alex S. , Geraldo Murilo V. , Kimura Edna T. 
Published: August 2012

Abstract
Background: RET/PTC, RAS and BRAF are present in about two thirds of papillary thyroid carcinomas (PTC), activating constitutively the mitogen activated protein kinase (MAPK) signaling pathway. There is practically no overlap between RET/PTC, RAS and BRAF mutations in PTC, the lack of concordance for these mutations provides compelling genetic evidence for the requirement of this signaling system for transformation to PTC. However, the effect of these genetic alterations in other signaling pathways remains unclear, which could, at least in part, cooperates in transformation. Recently, Notch signaling has been implicated in tumorigenesis in other cancer types. In this study, we test the hypothesis that RET/PTC and BRAFT1799A oncogenes crosstalks and regulates Notch pathway. Methods: TPC-1 and BCPAP (human PTC cells harboring RET/PTC1 rearrangement and BRAFT1799A mutation, respectively) were treated with gamma secretase inhibitor (GSI) and proliferation was analyzed by MTT assay and growth curve; cell cycle and apoptosis were analyzed by flow cytometry. PCCL3 cells harboring Doxycycline-inducible RET/PTC3 and BRAFT1799A (PC-BRAF) were used to analyze protein and gene expression by Western blotting and real-time PCR, respectively. Notch1 protein expression was analyzed in transgenic mice (Tg-BRAF) which harbor targeted expression of BRAFT1799A restricted to thyroid gland. Results: PTC cells treated with GSI decreased the percentage of viable cell in a dose-dependent manner and reduced the growth rate. Cell cycle analysis in PTC cells showed enhancement of DNA fragmentation and increased apoptotic cells. Furthermore, the GSI treatment in PTC cells modulates cell cycle related genes, increasing CDKN1A and CDKN1B gene expression and reducing CCND1, MCM6, CKS2, and MADL2 expression. Conditional activation of RET/PTC3 and BRAFT1799A in PTC3-5 and PC-BRAF cells, respectively, showed a sustained enhancement in pERK protein expression, increased Notch1 protein and gene expression and Hes1 gene expression, the target gene of Notch signaling. Furthermore, transgenic mice Tg-BRAF showed a stronger stain for Notch1 in follicular and stromal cells. Treating PTC cells with MEK inhibitors, U0126 or PD96059, reduces NOTCH1 and HES1 gene expression. The combination of GSI with MEK inhibitor enhances the growth suppression promote by MAPK signaling inhibition in PTC cell proliferation. CONCLUSION: Taken together, targeting Notch signaling resulted in anti-proliferative effect, suggesting an important role of Notch signaling in tumorigenesis of MAPK-induced PTC and our results indentify Notch signaling as a potential therapeutic target in thyroid cancer.
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 1250. doi:1538-7445.AM2012-1250
Abstract 1253: Fer is required for mammary tumorigenesis
Authors: Greer Peter A. , Chi Changnian , Gao Yan , LeBrun David , Golbourn Brian , Sangrar Waheed 
Published: August 2012

Abstract
Fer is a ubiquitously expressed cytoplasmic protein-tyrosine kinase (PTK) which is inducibly activated upon engagement of the epidermal and platelet-derived growth factor receptors (EGFR/PDGFR). Fer - and its homologous family member Fps/Fes - are structurally distinguished from other PTKs by a membrane-binding F-BAR domain implicated in regulating membrane-cytoskeletal dynamics during receptor endocytosis. We are investigating the role of Fer in EGFR internalization using both non-transformed mammary epithelial cells (MCF10A) and mammary tumor epithelial cells (MTEC) isolated from an ErbB2 mouse model of breast cancer. MCF10A Fer-knockdown cells (MCF10A-F2) and MTECs harboring a kinase-inactivating knock-in mutation at the fer locus (ferDR/DR) displayed elevated rates of EGF-induced endocytosis suggesting that Fer inhibits EGFR internalization. Elevated endocytic rates correlated with enhanced short-term MAPK signaling in both cell culture models and elevated steady-state Erk activity in ferDR/DR ErbB2 mammary tumors. Systems-level analyses using a physiochemical model of EGFR-MAPK signaling suggested that up-regulation of receptor endocytic rates could potentiate MAPK signal strength and sensitize this pathway to pharmacological inhibition at the receptor level. Inhibition of MAPK signaling with the EGFR/ErbB2 inhibitor, Lapatinib, confirmed this prediction, showing increased Erk signal-sensitivity to this drug in endocytosis-enhanced ferDR/DR MTECs. This correlated with a 10-fold reduction in the EC50 for Lapatinib cytotoxicity on ferDR/DR MTECs. Both the signaling and cytotoxicity phenoytypes were reversible by rescued expression of wild type Fer in ferDR/DR MTECs. These data reveal a novel mechanism by which potentiation of EGFR endocytosis enhances the sensitivity of downstream signaling to inhibition by ErbB inhibitors. In this respect, Fer is a unique kinase target because it provides a direct means of pharmacologically intervening with the mechanism of EGFR endocytosis. The therapeutic significance of potentiating receptor endocytosis by targeting Fer is highlighted by observations of: (1) delayed onset of ErbB2-mediated breast tumorigenesis in ferDR/DR genetic backgrounds in vivo; and; (2) impaired tumor growth of Fer-deficient MDA-MB-231 cells in mammary-fat pad transplantation models. We envisage that anti-Fer based treatments may sensitize breast - and potentially other carcinoma types - to anti-ErbB therapies. These observations provide biological proof-in-principle for developing small molecule inhibitor-based therapies against Fer in breast cancer.
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 1253. doi:1538-7445.AM2012-1253
Abstract 1275: Quantitative proteomic analysis of tumor growth associated proteins in cutaneous malignant melanoma
Authors: Serada Satoshi , Kotobuki Yorihisa , Tanemura Atsushi , Katayama Ichiro , Naka Tetsuji 
Published: August 2012

Abstract
BACKGROUND: The identification of proteins responsible for tumor development and regulation is of great value. In this study, we aimed to identify novel functional proteins associated with tumor progression in malignant melanoma. MATERIAL AND METHODS: The proteins extracted from malignant melanoma and normal skin tissue were labeled with iTRAQ reagent and performed a quantitative mass spectrometric analysis using nano LC-MS/MS system. The detected protein expression and localization in cutaneous malignant melanoma tissue was confirmed by immunohistochemistry. Human melanoma cell line (Mewo) was subcutaneously injected into Rag2-/- mice and POSTN-/-Rag2-/-mice, thereafter implanted tumor growth was compared. RESULTS: Among 1314 identified proteins, 118 proteins were increased more than 5.0-fold and 37 proteins were decreased &lt;0.5-fold in malignant melanoma compared to normal tissue. In these proteins, we found significant upregulation of an extracellular matrix protein, periostin (POSTN). POSTN expression was robustly induced in fibroblast cultured with Mewo and evident on the stroma of advanced melanoma tissue, suggesting the importance of interaction of these cells. As an assessment of functional implication in POSTN in malignant melanoma, we observed significant increase in melanoma cell number in the treatment with recombinant POSTN. Moreover, tumor growth in POSTN-/-Rag2-/- mice was significantly suppressed compared with that in Rag2-/- mice.CONCLUSIONS: We newly identified upregulation of POSTN expression in malignant melanoma tissue. POSTN was induced in the co-culture of fibroblast with melanoma cell and showed the growth promoting effect. These results indicate that periostin might be a potential therapeutic target in malignant melanoma.
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 1275. doi:1538-7445.AM2012-1275
Abstract 1277: Antigen-specific markers for paraneoplastic neurological syndromes obtained by proteomic analysis of patient immunoglobulins
Authors: vanDuijn Martijn M. , Maat Peter , Dekker Lennard J. , Luider Theo M. , Smitt Peter A. Sillevis 
Published: August 2012

Abstract
In the antibody response, as occurs in antitumor immunity, germline sequences are rearranged and mutated to generate a sequence with specificity for an antigen. In earlier work, it was shown that the antigen specificity of immune sera from rats can be distinguished by the proteomic analysis of immunoglobulins. It is hypothesized that the sequence of the antigen binding sites converges to a similar subset in individuals exposed to a given antigen. We therefore tested the applicability of our approach in patients with Paraneoplastic Neurological Syndrome (PNS). In these patients, a tumor triggers a well-characterized auto-immune response against onconeural antigens expressed in tumor and the affected part of the nervous system. These antibodies serve as markers for both the underlying tumor and specific neurological syndromes. Sera of 60 patients with PNS associated with paraneoplastic antibodies were analysed: 20 anti-HuD (18 lung cancer), 20 anti-Yo (6 breast, 9 gynecological and one other cancer), 10 anti-amphiphysin (4 lung, one breast and one other cancer), and anti-CV2 (6 lung cancer) antibodies. Antigen-specific immunoglobulins were collected by affinity enrichment on beads coated with recombinant antigen. The antigen-specific immunoglobulins were digested with trypsin and analyzed by nano-LC and mass spectrometry. From the resulting dataset, peptides were selected that uniquely identified one of the patient groups, and the peptide sequence was deduced from fragmentation spectra. 28 specific and unique peptides were found; 0 specific for amphiphysin, 2 specific for CV2, 11 for HuD and 15 for Yo. Several marker peptide sequences showed homology to known immunoglobulin sequences, and no relations were found to other known proteins from the NCBInr protein database. The data show that immunoglobulin-derived biomarkers can indeed be found in samples from patients and can serve as early markers of cancer and auto-immunity.
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 1277. doi:1538-7445.AM2012-1277
Abstract 1278: Determining the proteomic changes that define progressor and non-progressor clear cell renal cell carcinoma
Authors: Kurban Ghada , Tsavachidou Dimitra , Gallie Brenda , Evans Andrew , Finelli Antonio , Jonasch Eric , Jewett Michael 
Published: August 2012

Abstract
Renal cell carcinoma (RCC) is the most common type of kidney cancer, is increasing in incidence and is the most lethal genitourinary cancer. Due to the increased use of abdominal imaging, small renal masses (SRMs), mostly RCC, are now commonly detected in asymptomatic individuals and are the most common presentation of kidney cancer. Many of these SRMs grow slowly or not at all, while about 30% progress to advanced stages. However, in the absence of factors distinguishing masses that need treatment from those that can be managed by surveillance alone, most SRMs are treated by surgery. Clear cell RCC (ccRCC) is the most common form of RCC, has the worst prognosis and is characterized by inactivation of von Hippel-Lindau tumor suppressor gene (VHL). Systemic therapies developed to treat patients at advanced stages have targeted pVHL regulated genes particularly hypoxia inducible factor (HIF) downstream targets. However, these drugs rarely achieve cures suggesting that other pathways are implicated in ccRCC initiation and progression. Our national clinical trial, “Active Surveillance of Small Renal Masses” provides a unique opportunity to study the genetics and biology of the early stage ccRCC and characterize the genomic and proteomic signatures distinguishing non-progressor from progressor ccRCC-SRMs. Patients with ccRCC-SRMs (&lt;4cm in size) are followed with time and if their mass progresses, they undergo surgical or other forms of intervention as appropriate. In this study, we determine the proteomic differences between a) non-progressor and progressor ccRCC-SRMs by characterizing biopsies taken at the time of diagnosis and recruitment into the surveillance protocol from both groups, and b) progressor ccRCC-SRM (at time of recruitment) and advanced ccRCC by comparing the initial, diagnostic biopsy of ccRCC-SRMs that subsequently progress to the surgical specimen at the time of treatment for progression (advanced stage). Using reverse phase protein array (RPPA), we identify proteomic signatures that distinguish progressor and non-progressor groups. We observed changes mostly in the PI3 kinase and ERK pathways as well as alterations in apoptotic pathways. Our results provide important insight for management of ccRCC-SRMs and define pathways involved in their initiation and progression. This could furthermore identify potential therapeutic targets that would lead to better management of ccRCC 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 1278. doi:1538-7445.AM2012-1278
Abstract 1280: Nano-scale phospho-proteomic analysis to define diagnostic signatures and biomarkers of therapeutic activity in cancer
Authors: Fan Alice C. , Banerjee Prajna , Xu Liwen , Kong Christina , Sabatti Chiara , Wilhelm Francois , Greenberg Peter , Felsher Dean W. 
Published: August 2012

Abstract
The ability to quantify changes in protein activity in a clinical setting is important for the development of therapeutics that target cancer signaling pathways. We have developed the use of a highly sensitive microfluidic nano-immunoassay (NIA, Nanopro1000) to quantify unphosphorylated, single- and multi- phosphorylated isoforms of proteins in clinical specimens including blood, bone marrow, and fine needle aspirates (FNAs). Using as little as 2 nanoliters of cellular lysate, we can measure over 40 proteomic parameters, and assess changes in proteins that mediate signal transduction, cell cycle progression and apoptosis. Using NIA to resolve different phosphorylated isoforms of individual proteins and directly measure percent phosphorylation has led to new hypotheses and approaches to biomarker development. To develop novel diagnostic biomarkers, we have analyzed MAP Kinase phospho-protein profiles for over 200 specimens collected from patients with hematopoietic and solid tumors. We found that quantifying even subtle differences in protein signaling between tumor calls and adjacent non-tumor tissue can distinguish various malignancies. We will also present preclinical and clinical data using NIA to develop biomarkers of therapeutic activity biologic activity of tyrosine kinase inhibitors (TKIs) in myelodysplastic syndrome and leukemia. One unanticipated finding has been that TKIs might preferentially inhibit or activate specific phospho-isoforms of proteins. Our NIA studies also suggest that dynamic changes in protein signaling may better predict therapeutic outcome than profiles from a single, pre-treatment time point. One example is that the decrease in single phospho-ERK2 (p-ERK2) is associated with response to TKIs in chronic myelogenous leukemia. Notably, measurements of the phospho-isoform at a single time point were not sufficient to distinguish the two groups, which may reflect that individual tumors may have different initial “set-points” for the pathway. In contrast, comparison of proteomic signatures serially sampled from patients before and during treatment can provide valuable information regarding degree of target kinase inhibition and also compensatory signaling that can not be gleaned from analysis of a single time point. Our studies using nanoscale proteomic analysis to profile tumor signatures and characterize biologic response to therapies have led to new potential strategies for developing biomarkers, moving us closer to individualized cancer therapy.
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 1280. doi:1538-7445.AM2012-1280
Abstract 1287: High mobility of triple-negative breast cancer cells is due to repression of plakoglobin gene by SLUG
Authors: Bailey Charvann K. , Mittal Mukul K. , Misra Smita , Chaudhuri Gautam 
Published: August 2012

Abstract
One of highly pathogenic breast cancer cell types are the SLUG-high claudin-low triple negative (negative in the expression of estrogen, progesterone and ERBB2 receptors) breast cancer (TNBC) cells. These cells are highly metastatic and have low levels of the motility regulatory catenin plakoglobin. In order to link high levels of the transcriptional repressor SLUG in the TNBC cells with low levels of plakoglobin we found that SLUG inhibits the expression of plakoglobin gene directly in these cells and thus, among other downstream effects, help disseminating these tumor cells. Overexpression of SLUG in the SLUG-deficient cancer cells significantly decreased the levels of mRNA and protein of plakoglobin. On the contrary, knockdown of SLUG in SLUG-high cancer cells elevated the levels of plakoglobin. Overexpression of SLUG in the SLUG-deficient cells elevated the invasiveness and motility of these cells. On the other hand, knockdown of plakoglobin in these low motility non-invasive breast cancer cells did not affect the ability of the cancer cells to penetrate Matrigel matrix but increase the growth and migration rates of these cells. This study thus implicates high levels of SLUG and low levels of plakoglobin as determinants in the progression of highly disseminating breast cancer. Supported in parts by the DOD-CDMRP grants BC050641, BC086542 and BC103645 to GC.
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 1287. doi:1538-7445.AM2012-1287
Abstract 1289: Cooperation between beta-catenin, Snail, Slug, and Twist is required for maximum repression of the human vascular endothelial-cadherin promoter
Authors: Lopez Dayami , Carter W. Bradford 
Published: August 2012

Abstract
Vascular endothelial (VE)-cadherin is a key protein in the adherens junctions. This protein forms homophilic intercellular interactions and is required for the integrity of the endothelial monolayer, endothelial permeability, and control of cell growth. We have previously demonstrated that exposure of endothelial cells to breast cancer cell-conditioned media results in upregulation of Twist, Slug, and Snail expression, which in turn downregulate the activity of the human VE-cadherin promoter through at least two E-box motifs. Since these repressors have been linked to the β-catenin signaling pathway, we chose to determine whether β-catenin could regulate the activity of the human VE-cadherin promoter. Herein, we demonstrate that β-catenin represses the VE-cadherin promoter either alone or in coordination with the repressors Twist, Slug, and Snail. Electrophoretic mobility shift assays showed that the VE-cadherin promoter contains four β-catenin/LEF-1 binding motifs (designated Site-1-4) that appear to be involved in this regulatory process. In addition, we identified TGFβ as one of the factors released by breast cancer cells that could be involved in the regulation of the VE-cadherin gene when HDMEC are exposed to breast cancer cell conditioned medium.
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 1289. doi:1538-7445.AM2012-1289