bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3120: Aberrant activation of ERBB3 oncogenic signaling in human hepatocellular carcinoma
Authors: Hsieh Sen-Yung , He Jung-Ru , Hsu Chih-Yun , Yu Ming-Chin , Weng Wen-Hui , Huang Shiu-Fen 
Published: February 2011

Abstract
Background & aims: Recent evidence that ERBB3 is responsible for tumor resistance to EGFR or ERBB2 targeted therapies highlighted its crucial role in the oncogenic signaling of EGFR family. However, its roles in hepatocelluar carcinoma (HCC) remain unclear. Methods: Expression and phosphorylation of ERBB3 was examined in HCC tissues and cells. Gene number was determined using fluorescence in situ hybridization. Roles of EGEF, ERBB2, and neuregulin in phosphorylation of ERBB3 were evaluated via small-interference RNAs to silence their expression. The effects of ERBB3 on cell proliferation, invasion and tumorigenesis were assayed in vitro and in vivo. Results: Overexpression of ERBB3 was associated with a higher recurrence (P=0.000), and a worse prognosis (P=0.004). Gain of ERBB3 gene number was found in most HCC cells. EGFR, ERBB2, neuregulin and phosphorylated ERBB3 were detected in HCC cells. Phosphorylation of ERBB3 was induced by treatment with the conditioned media of HCC cells, while it was abolished by pre-treatment of the conditioned media with the anti-neuregulin antibodies or by silencing neuregulin expression. Phosphorylation of ERBB3 was suppressed by silencing the expression of ERBB2 but not EGFR. Induction of ERBB3 phosphorylation promoted cell proliferation, invasion and colony formation, while silencing ERBB3 expression suppressed xenograft tumor formation and growth in nude mice. Conclusions: Overexpression of ERBB3, primarily attributable to gene amplification, was associated with a poor prognosis of HCC. Aberrant activation of ERBB3, via an autocrine mechanism by dimerization with ERBB2, enhanced tumorigenesis in vitro and in vivo. The oncogenic signaling of ERBB3 can be the target for anti-HCC therapy.
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 3120.
Abstract 3122: Her4 and Her2/neu tyrosine kinase domains dimerize and activate in a reconstituted in vitro system
Authors: Monsey John , Shen Wei , Schlesinger Paul S. , Bose Ron 
Published: February 2011

Abstract
Her4 (ErbB-4) and Her2/neu (ErbB-2) are receptor tyrosine kinases belonging to the Epidermal Growth Factor Receptor (EGFR) family. Crystal structures of EGFR and Her4 kinase domains have demonstrated kinase dimerization and activation through an allosteric mechanism. The kinase domains form an asymmetric dimer, where the C-lobe surface of one monomer contacts the N-lobe of the other monomer. In vitro studies of EGFR tyrosine kinase dimerization and activation were previously reported using a nickel-chelating lipid - liposome system, and we now demonstrate this system can be broadly applied to all other members of the EGFR family. Polyhistidine tagged-Her4, Her2/neu, and Her3 kinase domains are bound to these nickel-chelating lipid containing liposomes and are brought to a high local concentration, mimicking what happens to the full-length receptors in vivo following ligand binding. Addition of Nickel-liposomes to Her4 kinase domain results in a 40-fold activation in kinase specific activity and a marked enhancement in C-terminal tail autophosphorylation. Activation of Her4 shows a sigmoidal dependence on kinase concentration, consistent with a cooperative process that requires kinase dimerization. Her2/neu kinase activity is also activated by Nickel-liposomes, and further increases in Her2/neu activity are achieved by heterodimerization with either Her3 or Her4. The ability of Her3 and Her4 to heterodimerize and activate other family members is studied in vitro. Her3 kinase domain readily activates Her2/neu but is a poor activator of Her4, which differs from the prediction made by the asymmetric dimer model, and suggests that the mode of dimerization of Her3 needs to be further studied.
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 3122.
Abstract 3123: Insulin-like Growth Factor-I Suppresses Bone Morphogenetic Protein Signaling through a Phosphatidylinositol 3-Kinase, Akt and mTOR-Dependant Mechanism
Authors: Wahdan-Alaswad Reema S. , Song Kyung , Krebs Tracy L. , Danielpour David 
Published: February 2011

Abstract
Bone morphogenetic proteins (BMPs) and insulin-like growth factor-I (IGF-I) function as critical regulators of prostate tumor cell growth. BMPs have recently been shown to be pivotal in controlling prostate tumorigenesis, and loss of BMP receptor function has been correlated to a higher Gleason grade in prostate cancer patients. The mechanism of such loss of BMP function in prostate cancer is unclear, and is likely to occur through multiple mechanisms. One likely candidate we are investigating is the tumor suppressor PTEN, which is lost up to 50% of patients with advanced prostate cancer. Loss of PTEN leads to enhanced activation of PI3K, Akt signaling and suppression of apoptosis. We provide the first evidence that IGF-I intercepts BMP4-induced apoptosis in prostate epithelial cell lines, as shown by changes in cell number, Hoechst 33342 staining, cell viability and flow cytometry. We show that IGF-I suppresses BMP4-induced activation of Smads 1, 5 and/or 8, and that such suppression is reversed by chemical inhibitors of PI3K, Akt or mTOR, or by wild-type PTEN or a dominant-negative PI3K expression construct efficiently delivered to cells by transduction adenoviral. We further show that IGF-I represses BMP4-induced transcriptional activation of the BMP targets, Id-1, Id-2, and Id-3. These results suggest that IGF-I signaling via a PI3K, Akt and mTOR-dependent mechanism inhibits transcriptional activity and apoptosis by BMP4 through suppressing the activation of Smads 1, 5 and/or 8 in prostate epithelial cells. All in all, our findings have important implications in the therapeutic intervention of prostate cancer by restoring BMP-mediated tumor suppressive capabilities by blocking IGF-I signaling pathway's oncogenic activity.
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 3123.
Abstract 3129: Regulation of expression and role of the pigment epithelium derived factor in Ras-mediated pancreatic oncogenesis
Authors: Maya Joanna , Robin Tyler , Crawford Susan , Campbell Paul M. , Der Channing J. , Grippo Paul , Repasky Gretchen A. 
Published: February 2011

Abstract
Mutated and constitutively activated Ras oncoproteins are found in ∼33% of all human cancers. In particular, Ras mutations are found in a majority of pancreatic cancers (90%), and aberrant Ras activation has been shown to be critical for promoting pancreatic adenocarcinomas. Ras-mediated transformation is associated with downregulation of Pigment Epithelium Derived Factor (PEDF), an anti-angiogenic and lipid regulatory factor shown to suppress oncogenic K-Ras-induced invasive disease in vivo. PEDF has also been shown to have anti-tumorigenic activity on tumor cells themselves. Specifically, mice with chronically active mutant KRAS(12D) background form precancerous lesions with high frequency, and knockout of PEDF expression specifically in pancreatic tissue resulted in a significant aggravation of the precancerous phenotype. The mechanism(s) of this biological phenotype is unclear and the specific role of PEDF as a potential tumor suppressor gene in Ras-mediated oncogenesis remains unresolved. Western analyses were used in this study to investigate the expression of PEDF in K-Ras-transformed and nontransformed human pancreatic duct-derived cells (HPNE) and their surrounding cell culture growth media. We observe that PEDF is upregulated both intracellularly under growth and serum-starved conditions and extracellularly under serum-starved conditions in K-Ras-transformed human pancreatic cells. We are also investigating the role of exogenous PEDF in cell proliferation induced by oncogenic variants of K-Ras. While no significant difference was observed in cell proliferation between the PEDF-treated and nontreated cells (whether they be K-Ras-transformed and nontransformed cells) in growth conditions, a decrease in cell proliferation was observed in the PEDF-treated K-Ras-transformed cells under serum-starved conditions. By better understanding the link between Ras and PEDF we will be able to assess the contribution and therapeutic potential of PEDF to formation and progression of pancreatic cancer while investigating novel targets for therapeutic intervention.
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 3129.
Abstract 3141: Hyperglycemia modulates the Wnt /b-catenin signaling pathway in breast cancer
Authors: Vaira Sergio , Friday R. Ellen , Scott Keith , Conrad Steven , Mills Glenn , Turturro Francesco 
Published: February 2011

Abstract
Hyperglycemia represents one of the early events in the development of diabetes type 2. Susceptibility to this disease has been linked to Wnt/β-catenin signaling pathway that also controls breast cancer progression. We had previously analyzed the effects of hyperglycemia on gene expression profile (GEP) by Affimetrix analysis in breast cancer derived MDA-MB-231 cells (Turturro F. et al., BMC Cancer 2007, 7:96). Wnt/βcatenin signaling pathway had emerged as one of the most prominent signaling pathway regulated by increased glucose in culture media (5 mM versus 20 mM).
The aim of the present study was to validate the GEP data by assessing the mRNA levels of both GSK-3b and Wnt1 by RT-PCR in response to hyperglycemia as previously described. We analyzed the levels of RT-PCR products of the target genes relative to the control mRNA of β-actin in MDA-MB-231 cells, cultured in the same conditions as previously illustrated (Turturro F. et al., BMC Cancer 2007, 7:96). The values were expressed as densitometric readings. Relative levels of GSK-3b mRNA raised from 0.14 + 0.053 for 5 mM glucose to 0.308 + 0.0476 for 5/20 shift (p&lt; 0.05 at 5 vs. 5/20 mM) and to 0.432 + 0.0321 for 20 mM (p&lt; 0.05 at 5 vs. 20 mM) resulting in an overall 3 fold increase. We also examined the effect of hyperglycemia on gene expression of Wnt-1 which inhibits the expression and activity of GSK-3b. The relative levels of mRNA of Wnt-1 assessed by RT-PCR, were decreased from 0.163 + 0.0322 for 5 mM glucose to 0.068 + 0.001 for 20 mM glucose, with an overall 2.7 fold reduction (p&lt;.05 at 5 vs. 20 mM).
These data confirmed the GEP results in terms of relationship between hyperglycemia and gene expression of the Wnt signaling pathway in this particular breast cancer cell line. Our study supports further investigation in the area of diabetes and breast cancer invasiveness and progression.
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 3141.
Abstract 3142: Abnormal expression of the ALK protein in ovarian carcinoma is associated with low copy number amplification of the 2p23 locus
Authors: Merkel Patricia , Grubinska Barbara , Drew Allison , Szilvassy Stephen J. , Gyuris Tibor , Merriam Kim , Tsui Kim , Rottman James , Parker Alex , Brake Rachael 
Published: February 2011

Abstract
Anaplastic lymphoma kinase (ALK) is predominantly expressed in the brain and spinal cord during neonatal development and is subsequently down-regulated in the adult. In cancer, ALK is ectopically expressed as a consequence of one of several different cytogenetic translocations or inversions that lead to the expression of an oligomerized, constitutively active, intracellular tyrosine kinase. The resulting fusion protein has been identified in anaplastic large cell lymphomas, non small cell lung carcinomas and more recently breast and colorectal carcinomas. Preclinical data convincingly demonstrates that fusion transcripts can drive tumorigenesis and inhibition of ALK in vitro and in vivo leads to inhibition of cellular growth. Full length (fl) ALK is also expressed in a variety of other tumor types, and recent data suggest that at least in neuroblastoma, the flALK transcript contains activating point mutations in the tyrosine kinase domain. These data suggest that flALK may also be a therapeutic target in cancer. Here we demonstrate that a significant subset of ovarian carcinoma cell lines and biopsy specimens aberrantly express ALK. Gene expression analysis in 126 ovarian carcinoma samples demonstrated a prevalence of ALK expression of 19%. Analysis of the histological subtypes within this study, showed specific enrichment of ALK transcript in papillary ovarian carcinoma (15 of 42 samples). This subtype showed a range of ALK expression between 2 - 4 fold increase above normal ovarian tissue. We have also confirmed that in a subset of ovarian tumor cell lines and primary tumor samples that ALK transcript is converted into ALK protein. DNA sequence analysis has revealed that in these patient samples and cell lines, ALK is predominantly wild type. Single nucleotide polymorphism (SNP) analysis and fluorescent in situ hybridization (FISH) suggest that over expression may occur as a consequence of low copy number amplification. These preliminary findings suggest that ALK expression in cancer has now been observed in ovarian carcinomas by a mechanism distinct from cytogenetic translocations or inversions. Currently, we are attempting to correlate the aberrant expression of ALK with ovarian cancer prognosis as well as understand the value of inhibiting ALK expression in this cell type.
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 3142.
Abstract 3145: Non-coding promoter-associated RNAs (PARs) orchestrate the epigenetic control of CDH1 transcription in cancer cells
Authors: Magistri Marco , Pastori Chiara , Napoli Sara , Carbone Giuseppina M. , Catapano Carlo V. 
Published: February 2011

Abstract
DNA in eukaryotic cells is wrapped around histones to form chromatin fibers. Chromatin can assume different conformations that dictate its biological activity. The equilibrium between distinct chromatin states is achieved via a cascade of epigenetic events involving DNA and histone modifications. However, the underlying mechanisms determining the timing and selectivity of these epigenetic events are not fully understood. Alterations in epigenetic patterns are common in cancer leading to the aberrant silencing of tumor suppressor genes. The CDH1 gene encodes the epithelial cell adhesion molecule E-cadherin and is frequently silenced in epithelial tumors. CDH1 silencing is associated with cell transformation, tumor invasiveness and metastatic dissemination along with epithelial-mesenchymal transition and acquisition of stem cell properties. Recently, non-protein coding RNAs (ncRNAs) and components of the RNA interference machinery have been proposed as important elements in epigenetic mechanisms that might assist in targeting epigenetic effectors to specific genomic loci. In this study, we investigated the role of non-coding promoter-associated RNA (PARs) in the transcriptional regulation of the CDH1 gene. PARs with both sense and antisense orientation relative to the protein-coding RNA were found in the CDH1 gene using strand-specific RT-PCR and 5’RACE. Sense and antisense PARs were positively and negatively correlated, respectively, to the level of CDH1 RNA in different cell lines, suggesting a functional link between coding and non-coding RNAs. RNA immunoprecipitation showed binding of the Argonaute protein Ago1 to the sense PAR in PC3 cells, in which the CDH1 gene was silenced. Knock-down of Ago1 led to re-expression of CDH1 along with increased histone H3 acetylation and decreased histone H3K9 methylation in the CDH1 promoter. Similar changes in the histone code and re-expression of CDH1 were induced by knocking down the H3K9 histone methyltransferase SUV39H1 and HDAC1. Moreover, Ago1 knock-down reduced binding of both SUV39H1 and HDAC1 to the CDH1 promoter, indicating a critical role of Ago1 in establishing their association with the promoter. Consistent with a role of the PARs in CDH1 transcriptional control, targeting the sense PAR with small interfering RNAs induced chromatin remodeling and CDH1 re-expression, supporting the hypothesis that PARs can direct epigenetic effectors to gene promoters through their interaction with Ago1. These findings suggest the existence of endogenous ncRNA-based mechanisms of transcriptional control that cooperate with and complement DNA and protein based epigenetic pathways in human cells.
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 3145.
Abstract 3146: The role of SUMO on the stabilization of estrogen receptor β cx in hypoxic conditions
Authors: Dey Prasenjit , Strom Anders M. , Gustafsson Jan-Ake 
Published: February 2011

Abstract
Estrogen receptor (ER) βcx is a 495 amino acid splice variant of estrogen receptor (ER) β. It is highly expressed in testes and hypoxic brain, with small amount of expression observed in prostate, thymus and ovary. Clinical studies in breast cancer, shows that, increased expression/stabilization and cytosolic localization of ERβcx have a bad prognosis compared with nuclear localization. We believe that hypoxia play a role in the stabilization of ERβcx. As hypoxia is central to cancer tumorigenesis, the role played by ERβcx in hypoxic environment can elucidate, at least partially, cancer progression and prognosis. We found that, HEK293T cells transiently transfected with YFP-ERβcx fusion protein show more intense fluorescence in the presence of 100 μM CoCl2 (a hypoxia mimetic) indicating the stabilization of the YFP-ERβcx protein. As a control the YFP-ERβ do not show any change after treatment with CoCl2. The ERβcx differ from ERβ by an alternatively spliced last exon. It is well known from previous studies that hypoxic condition stabilizes HIF1α, a transcriptional regulator of a cell's adaptive response to hypoxia. This may causes upregulation of small ubiquitin-related modifier (SUMO) pathway. A close examination of the unique CX exon reveals a SUMOylation consensus sequence. Mutation of this sequence abolishes the hypoxic regulation of ERβcx. Elucidating the regulatory mechanism of ERβcx might give clues to its role in cancer.
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 3146.
Abstract 3150: The SCFFbw7 E3 Ubiquitin Ligase Complex Targets KLF5 for Ubiquitination and Degradation in a Phosphorylation Dependent Manner
Authors: Zheng Han-Qiu , Zhao Dong , Zhou Zhongmei , Chen Ceshi 
Published: February 2011

Abstract
The KLF5 transcription factor is overexpressed in ERα negative basal type breast cancer and promotes breast cell proliferation, survival, and tumorigenesis through upregulating its target gene FGF-BP. We previously identified WWP1 as an E3 ubiquitin ligase for KLF5. However, the regulation mechanisms of KLF5 protein degradation through the ubiquitin proteasome pathway are still poorly understood. In this study, we demonstrate that the Skp1-Cul1-Fbw7 E3 ubiquitin ligase complex (SCFFbw7) targets KLF5 for ubiquitin-mediated degradation in a KLF5 phosphorylation dependent manner. Fbw7 interacts with KLF5 through the WD40 repeats of Fbw7 and a cdc-4 phospho-degron(CPD domain, 303SPPSS) of KLF5 and promotes KLF5 ubiquitination and degradation. Both the F-box and WD40 repeats of Fbw7 are required for KLF5 ubiquitination and degradation. Mutation of the critical Ser303 residue in the KLF5 CPD motif into Ala abolishes the protein interaction, ubiquitination, and degradation by Fbw7. In addition, the interaction between wild type KLF5 and Fbw7 can be abrogated by alkaline phosphotase (CIP) treatment. Using a KLF5 S303 phosphorylation specific antibody, we demonstrate that the S303 residue is phosphorylated. We further demonstrate that the KLF5 S303 can be phosphorylated by GSK3 in vitro. Inhibition of GSK3 activity by LiCl delays the KLF5 S303 phosphorylation and the KLF5 protein degradation. This new regulatory mechanism of KLF5 degradation may result in useful diagnostic and therapeutic targets for breast cancer and other cancers.
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 3150.