bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A54: CnABP, a novel modulator of the Calcineurin-NFAT signaling pathway, is overexpressed in Wilms' tumors and promotes cell migration
Authors: Nguyen Alana H.T. , Beland Melanie , Gaitan Yaned , Bouchard Maxime 
Published: May 2012

Abstract
Wilms' tumor (WT) is a classical cancer type that arises from abnormal differentiation of kidney progenitor cells, and occurs at a frequency of 1 in 10,000 live births, accounting for approx. 90% of childhood kidney cancer. Abnormally high levels of Pax2 (paired-box protein 2), a key regulator of kidney development, have been observed in both WT and renal cell carcinoma, which correlate with proliferation and increased invasiveness. Therefore the misexpression of Pax2 and its target genes may play an important role in tumor initiation and/or progression. To test this, we screened for target genes of Pax2 by cDNA microarray in the embryonic kidney. We identified CnABP (Calcineurin A Binding Protein), a novel gene under Pax2 regulation. In situ hybridization indicates that CnABP coexpresses with Pax2 in the condensing mesenchyme, the abnormal differentiation of which gives rise to WT. Furthermore, expression analysis by quantitative PCR indicates that CnABP is overexpressed in more than 70% of Wilms' tumors. Interestingly, in the proportion of tumors with upregulated PAX2 expression, more than 80% also overexpress CnABP. We characterized CnABP as a membrane-anchored protein that primarily promotes cell proliferation and migration. Mediators of these activities were investigated by Yeast-two-hybrid and immunoprecipitation, which identified an interaction between CnABP and Calcineurin A, the catalytic subunit of a calcium-responsive serine/threonine phosphatase Calcineurin. We showed that CnABP modulates phosphatase activities of Calcineurin, which consequently inhibits calcium/Calcineurin-dependent NFAT nuclear translocation. We further demonstrated that the inhibition of NFAT nuclear localization results in reduced NFAT-specific transcriptional activity. Components of the Calcineurin complex have been reported as differentially expressed genes distinguishing recurrent from non-recurrent Wilms' tumors. This is in line with the evidence we presented, as CnABP is upregulated in Wilms' tumors and is shown to promote proliferation and migration.
Citation Information: Cancer Res 2009;69(23 Suppl):A54.
Abstract A58: Cdk6 association with a transcriptional coactivator indicates a potential role for this cyclin dependent kinase in regulating differentiation
Authors: Crary Jennifer I. , Grossel Martha J. , Hinds Phil W. 
Published: May 2012

Abstract
Cdk6 is a well characterized cyclin dependent kinase that regulates the transition from G1 phase to S phase during the cell cycle with the assistance of the D-type cyclins. Cdk6 is an oncogene and has long been considered to be functionally redundant to cdk4. Yet recent studies have shown functional discrepancies between the two kinases, with cdk6 often displaying distinct roles in development. In this study, a yeast two-hybrid analysis was used to identify potential binding partners for cdk6 from a human fetal brain library. We have confirmed the association with one designated protein, Eya2, via an in vitro GST pull-down assay. Eya2 is a mammalian homologue of the Drosophila gene eya, which is best known for its role as a co-activator involved in transcriptional regulation during eye development. Initial comparison of cdk4 and cdk6 in the GST pull-down assay indicate that cdk6 has a higher binding affinity for Eya2 than cdk4; interestingly, the yeast two-hybrid experiments failed to demonstrate an interaction between cdk4 and Eya2. Additional experiments are underway to confirm this interaction with several in vivo approaches that may further our understanding of mechanisms involved in cancer and development.
Citation Information: Cancer Res 2009;69(23 Suppl):A58.
Abstract A6: Dissecting mechanisms of RANKL dependency in osteosarcoma
Authors: Beristain Alexander G. , Molyneux Sam , Di Grappa Marco A. , Khokha Rama 
Published: May 2012

Abstract
Osteosarcoma is the most common bone tumor in adolescents, severely impacts quality of life, and ∼40% of patients die of metastases to lungs and liver. In an effort to study this poorly understood cancer, we have generated a novel transgenic mouse model of osteosarcoma (designated MOTO) through osteocalcin promoter-driven SV40 T-antigen expression. The MOTO model is 100% penetrant and recapitulates all critical features of the human disease including skeletal tumor distribution, radiology, histology, genomic instability and metastasis. Using genomic screens, we have identified the cytokine RANKL (Receptor Activator of Nuclear Factor kappa B Ligand), and its receptor RANK, to be aberrantly expressed in MOTO tumors and cell lines. Genetic studies using RANKL deficient MOTO mice reveal osteosarcoma to be broadly dependent on its expression. To further dissect the role of RANKL signaling in osteosarcoma, we have performed gain- and loss-of-function studies to determine if RANKL affects classic oncogenic cell parameters. Specifically, loss of RANKL in MOTO tumor cell lines inhibits invasion and soft agar colony formation, indicating its ability to contribute to tumorigenesis in a cell autonomous manner. To support this hypothesis, we are testing the effects of de novo RANK expression on the tumorigenic properties of osteoblastic cells. Together, these studies are dissecting the individual contributions of RANKL and RANK in controlling primary bone tumorigenesis.
Citation Information: Cancer Res 2009;69(23 Suppl):A6.
Abstract A67: Regulation of Eag1 expression by steroid hormones in cervical cancer cells
Authors: Rodriguez-Rasgado Jesus Adrian , Diaz Lorenza , Garcia-Becerra Rocio , Avila Euclides , Camacho Javier 
Published: May 2012

Abstract
Introduction: Ether à go-go 1 (Eag1) channels have oncogenic properties. This channel is widely expressed in human tumors. It has been shown that inhibition of its expression and/or activity reduces cellular proliferation. Some cancer-associated factors up-regulate Eag1 expression; including estradiol and the E6 and E7 human papilloma virus (HPV) oncogenes. On the other hand, calcitriol (the most active metabolite of vitamin D) has shown antiproliferative properties and it has been considered as a potential anticancer treatment. In this work, we studied Eag1 regulation by estradiol, tamoxifen, ICI 182 780, genistein and calcitriol in the cervical cancer cell line SiHa, that express E6 an E7 HPV oncogenes.
Methods: SiHa cells were cultivated with DMEM without phenol red and were treated with estradiol, tamoxifen, ICI 182 780, genistein or calcitriol during 48 hours. Total RNA was obtained with Trizol reagent, and cDNA was synthesized. Eag1 expression was evaluated by real time PCR. Eag1 expression was normalized against the housekeeping gene GAPDH. Using XTT colorimetric assay we evaluated the effect of calcitriol on SiHa cells proliferation.
Results: Calcitriol decreased cell proliferation after 5 days of culture. We also identified estrogen receptors α and β and VDR (vitamin D receptor) proteins by Western blot. Estradiol, antiestrogens, genistein and calcitriol down-regulated Eag1 mRNA expression. Concomitant treatment of SiHa cells with estradiol and calcitriol seems to potentiate such Eag1 down-regulation. On the other hand, SiHa cells expressed higher levels of ERβ than ERα.
Conclusions: Our data suggest that down regulation of Eag1 by calcitriol could be a new mechanism by which calcitriol reduce tumor cells proliferation. Together, estradiol, antiestrogens, genistein and calcitriol could be used as treatment for cancers that present ER pattern expression silimar to SiHa cells.
Citation Information: Cancer Res 2009;69(23 Suppl):A67.
Abstract A70: Oncogenic potential of multiple splicing isoforms of the prostate-cancer specific TMPRSS2-ERG gene fusion product
Authors: Zammarchi Francesca , Boutsalis George , Gerald William , Cartegni Luca 
Published: May 2012

Abstract
Genetic rearrangements are key events in cancer development, as seen by the recurrent chromosomal translocations characteristic of some hematological and mesenchymal tumors. It has been recently reported, however, that a majority of prostate cancer tumors appear to carry specific translocation, in which a transcription factor of the ETS (E26 transformation-specific) family (namely ERG, ETV1, ETV4, ETV5) is expressed under the control of TMPRSS2, a prostate-specific, androgen-dependent protease. In particular, the fusion of TMPRSS2 exon 1 to ERG exon 4 has been observed in approximately 50% of human prostate cases, suggesting a causative role in PC development, but its specific functions remain unclear. This is further complicated by the presence of ERG splicing variants, and by the use of alternative promoters or polyadenylation sites in both the normal and fusion contexts, which could generate over 50 different isoforms. Interestingly, the presence of specific isoforms seems to correlate with tumor aggressiveness.
ERG is already known to be involved in oncogenic fusion, such as EWS-ERG fusion in Ewing sarcoma, which activates targets involved in proliferation, metastasis and angiogenesis, suggesting that the androgen-dependent over-expression of ERG following the TMPRSS2 fusion could be a driving mechanism of prostate carcinogenesis.
We have identified multiple novel splicing isoforms of both the wild-type ERG gene and the TMPRSS2:ERG fusion gene in prostate tumors and we are currently investigating their respective biological roles and mechanism of action in order to determine their function and oncogenic potential in vitro and in vivo.
Citation Information: Cancer Res 2009;69(23 Suppl):A70.
Abstract A72: Stat3 is a negative regulator of intestinal tumor progression in APCmin mice
Authors: Musteanu Monica , Blaas Leander , Mair Markus , Casanova Emilio , Kenner Lukas , Poli Valeria , Eferl Robert 
Published: May 2012

Abstract
The transcription factor Stat3 has been considered to promote progression and metastasis of intestinal cancers. We investigated the role of Stat3 in intestinal tumors using mice with conditional ablation of Stat3 in intestinal epithelial cells (Stat3ΔIEC). In the APCmin mouse model of intestinal cancer, genetic ablation of Stat3 reduced the multiplicity of early adenomas. However, loss of Stat3 promoted tumor progression at later stages leading to formation of invasive carcinomas which significantly shortened the lifespan of Stat3ΔIEC APCmin/+ mice. Interestingly, loss of Stat3 in tumors of APCmin/+ mice had no significant impact on cell survival and angiogenesis but promoted cell proliferation. A genome-wide expression analysis of Stat3-deficient tumors suggested that Stat3 negatively regulates intestinal cancer progression via the cell adhesion molecule Ceacam1. Therefore, detrimental effects on tumor progression have to be considered upon therapeutic targeting of the Stat3 signaling pathway in intestinal cancer.
Citation Information: Cancer Res 2009;69(23 Suppl):A72.
Abstract A8: Role of the WWOX gene in non-small cell lung cancer
Authors: Buyru Nur , Baykara Onur , Demirkaya Ahmet , Kaynak Kamil , Toker Alper , Tanju Serhat 
Published: May 2012

Abstract
Lung cancer is the most common cause of cancer-related deaths worldwide and like many other cancers is affected by different genetic, epigenetic and environmental factors. The WWOX gene is a tumor supressor gene located on 16q23.3–24.1. It has been shown that it loses its function due to differences in genetic and epigenetic mechanisms.
In this study we investigated whether the presence of WWOX gene mutations in lung cancer. The entire coding exons and flanking intronic sequences of the gene were analysed by PCR amplification from the genomic DNA and direct sequencing in 50 patients with non-small cell lung cancer (NSCLC). WWOX gene mutations were detected in five out of 50 primary tumors (10%). One of these mutations was an insertion in exon 4 at the third nucleotide of codon 120. This mutation was observed in 2 patients and leads to a frameshift creating a stop codon at codon 133. The second mutation was an insertion at position 2583 which also causes a shift in the reading frame. Finally, heterozygous C→G transitions on position 2807 at the first nucleotide of codon 282 (exon 8) were identified in 2 patients. This mutation affecting codon 282 leads to the substitution of alanine instead of proline. We also observed a previously defined G to A polymorphism at the nucleotide 2196 in homozygous and heterozygous form in 20 and 5 patients, respectively. Additionally we detected 12 different intronic substitutions. In addition to inactivating mutations target genes may also be silenced epigenetically. Therefore, besides mutation screening we also analyzed the methylation profile of the promoter region of the WWOX gene in tumor tissue and adjacent non-cancerous tissue samples by bisulphite modification and methylation-specific PCR. Promoter methylation was detected in 76% of the tumor tissue samples. While 20% of the samples displayed partial methylation 56% were completely methylated. In the adjacent normal tissue samples partial and complete methylation frequencies were 6% and 58%, respectively. Methylation frequency was significantly higher in the tumor tissue samples than in normal tissue samples (p=0.014).
The high frequency of mutations and epigenetic modifications suggest that the WWOX gene may play a significant role in the etiology of NSCLC.
Citation Information: Cancer Res 2009;69(23 Suppl):A8.
Abstract A9: Importance of C17orf37 prenyl modification in cancer cell migration and invasion
Authors: Dasgupta Subhamoy , Vishwanatha Jamboor K. 
Published: May 2012

Abstract
C17orf37 is a novel gene located in the hot spot locus of human chromosomal region 17q12-21. C17orf37 is frequently amplified in breast cancer patients along with ERBB2, and expression correlates with grade and stage of cancer. C17orf37 gene is also found to be activated in certain cancer cells and tissues irrespective of ERBB2 status, compared to minimal expression in normal cells. Recently, we have reported that C17orf37 is highly overexpressed in prostate cancer cells and tissues, and expression of the gene positively correlates with the migratory and invasive potential of cancer cells. Moreover C17orf37 acts as a signaling molecule via Akt/NF-κB pathway modulating the expression of key metastasis-related genes uPA, MMP-9 and VEGF. We identified a putative prenylation motif ‘CVIL’ at the C-terminal end of C17orf37 protein. Using confocal, total internal reflection fluorescence microscopy (TIRFM) and cellular fractionation studies we show C17orf37 is post-translationally modified by GGTase-I enzyme, which translocates the protein to the inner leaflet of plasma membrane. Mutation of the cys-112 or entire deletion of the ‘CVIL’ motif of C17orf37 protein blocks the protein localization to the membrane. Based on this, we hypothesize that prenylation at ‘CVIL’ motif is important for activation of C17orf37 protein and subsequent downstream signaling. To study the importance of prenylated C17orf37 in cancer cells, we generated stable cells expressing either wild type or mutant C17orf37 protein. Our studies show that prenylated C17orf37 protein (wild type) preferentially localize to the leading edge of migrating cancer cells (directional) thereby activating nucleation of F-actin, formation of lamellipodia and increased migration of cancer cells. Cells expressing mutant C17orf37 protein are mostly localized in the cytosol and fail to localize to the edge of the migrating cancer cells. In addition, we identified a canonical immunoreceptor tyrosine-based activation motif (ITAM) at the N-terminus of C17orf37 protein. Currently we are investigating the importance of ITAM domain for downstream signaling of C17orf37 through Akt/NF-κB pathway.
Citation Information: Cancer Res 2009;69(23 Suppl):A9.
Abstract B12: RB1-mediated regulation of osteoblast migration
Authors: Gunduz Volkan , Cardona Pedro Santiago , Hinds Philip W. 
Published: May 2012

Abstract
Alterations involving loss or gain of function of components of the retinoblastoma (RB1) tumor suppressor pathway are observed in a wide range of human cancers. They include loss of p16INK4a expression in melanomas and overexpression of cyclin D1 in breast tumors. RB1 itself, however, is inactivated in a reduced subset of tumors including retinoblastomas, osteosarcomas and small cell lung carcinomas. A common characteristic of these tumors is the lack of well-organized adherens junctions. Thus, in retinoblastoma, the cadherin/catenin complex fails to anchor to the actin cytoskeleton leading to loss of cell-cell contact inhibition. Likewise, osteosarcomas and small cell lung carcinomas show reduced expression of cadherins and beta-catenin. In addition, a strong correlation has been found between abnormal adherens junction structures and the invasive capacity of these tumors. In this study, we aim to investigate the role of RB1 on cell-cell adhesion and migration using calvarial osteoblasts that are deficient in RB1 expression. We observe that RB1-deficient immortal osteoblasts (MC3T3 cells) lack membrane localization of N-cadherin and Beta-catenin and display an increased migratory phenotype compared to the RB1 expressing counterparts. In addition, RB1-deficient MC3T3 osteoblasts express and secrete higher levels of IGF1 leading to the activation of the IGF1 receptor (IGF1R). Interestingly, the opposite pattern of expression/secretion was observed for IGFBP-2, with higher levels observed in RB1-expressing MC3T3 cells. Moreover, activation of the IGF signaling pathway correlated with higher levels of phosphorylated Akt in RB1-deficient MC3T3s and, accordingly, treatment of RB1-deficient MC3T3 osteoblasts with either a neutralizing antibody against IGF1 or an inhibitor of IGF1 receptor led to impaired migration. We have also observed reduced phospho-Akt levels in RB1-deficient MC3T3 osteoblasts that were exposed to the conditioned medium (CM) from RB1 wild type MC3T3 osteoblasts. This reduction in phospho-Akt levels correlated well with a reduced migratory phenotype of RB1-deficient MC3T3 osteoblasts under these conditions. Taken together our data suggest that IGF signaling is one of the mechanisms that might contribute to increased migration in RB1-deficient MC3T3 osteoblasts.
Citation Information: Cancer Res 2009;69(23 Suppl):B12.
Abstract B19: An integrative in vivo analysis of PIK3CA, PTEN and AKT alterations in head and neck squamous cell carcinoma
Authors: Bornstein Sophia , Owens Philips , Ruth White , Li Yuexin , Weber Stephen , Wang Xiao-Jing , Lu Shi-Long 
Published: May 2012

Abstract
In vitro studies indicate that deregulation of the PI3K/AKT pathway is important in head and neck squamous cell carcinoma (HNSCC) tumorigenesis, as has been observed in several other cancers. However, the in vivo role of PI3K/AKT pathway deregulation in HNSCC remains unknown. The objective of this study was to investigate the in vivo roles of PIK3CA, PTEN and AKT alterations in head and neck tumorigenesis. To this end, we developed inducible head and neck specific transgenic PIK3CA and AKT mice, and inducible head and neck specific knockout PTEN mice under the control of an RU486-responsive Keratin 5 promoter. Both PIK3CA or AKT transgene expression was induced in mouse head and neck epithelia, i.e. buccal mucosa, tongue, and esophagus, upon RU486 application in a dose- and time- dependent manner. PTEN deletion was also achieved in mouse head and neck epithelia after five consecutive RU486 applications. The PIK3CA and AKT inducible transgenic mice exhibited severe head and neck epithelial hyperplasia, dysplasia, and carcinoma in situ, but no visible tumor formation after one year of observation. Further, the inducible head and neck specific PTEN knockout mice developed oral, but not esophageal SCCs. To investigate whether the inducible PIK3CA or AKT mice harbored higher cancer susceptibility upon tobacco carcinogen exposure, we applied a subcarcinogenic dose of 4NQO, a surrogate of a tobacco carcinogen, to the PIK3CA and AKT mice. Both PIK3CA and AKT mice developed oral and/or esophageal SCCs as early as one month after 4NQO exposure, and by 4 months, all PIK3CA and AKT transgenic mice developed oral and/or esophageal SCCs. Interestingly, a higher incidence of esophageal in comparison with oral SCC (93% versus. 19% of mice) was observed in the AKT transgenic mice, while a higher incidence of oral versus esophageal SCC (74% vs. 44% of mice) was found in the PIK3CA mice, suggesting a tissue specificity of AKT and PIK3CA in head and neck tumorigenesis. Studies investigating the underlying molecular mechanism of each molecule in head and neck tumorigenesis are currently underway. In conclusion, our data demonstrate an oncogenic role of PIK3CA and AKT, and a tumor suppressive role of PTEN in head and neck tumorigenesis in vivo. Our inducible head and neck specific mouse models are powerful tools to evaluate the roles of PIK3CA, PTEN, and AKT during each stage and site involved in head and neck tumorigenesis, and to test novel therapeutics targeting this important signaling pathway.
Citation Information: Cancer Res 2009;69(23 Suppl):B19.
Abstract B2: Coup-tf1 is suppressed by androgen receptor in prostate cancer epithelial and normal stromal cells
Authors: Perets Ruth , Hidas Guy , Simon Itamar , Pikarsky Eli 
Published: May 2012

Abstract
Chicken ovalbumin upstream promoter-transcription factor 1 (Coup-tf1) is a transcription repressor previously known to play a role in neurogenesis and adipogenesis. It mainly acts through suppression of thyroid hormone receptor and vitamin D receptor. Coup-tf1 was implicated before in breast cancer as a negative regulator of the Aromatase gene, and in gastric cancer cell lines as a positive regulator of vegf-d.
We performed a genome wide location analysis of androgen receptor (AR) target genes in prostate cancer cells treated with androgen, an AR antagonist or androgen deprivation. This analysis revealed ligand dependent binding of the coup-tf1 promoter and enhancer by the AR which was confirmed by specific chromatin immunoprecipitation studies. AR activation by a ligand is correlated with decreasing mRNA levels implying that AR is a negative regulator of coup-tf1 in prostate cancer cells.
Using immunohistochemistry we have seen coup-tf1 staining in 21/28 primary human prostate cancer samples, regardless of Gleason score or prognosis. Coup-tf1 staining was in a nucleolar pattern and its levels in malignant cells were substantially higher than in the adjacent benign prostate glands. Stromal cells both in human and mouse prostate show nuclear coup-tf1 staining. There is an inverse correlation between Coup-tf1 staining and the rising levels of androgen with advancing puberty.
These results implicate coup-tf1 in prostate cancer for the first time, and show a novel AR repressed gene, that might play a role in prostate cancer.
Citation Information: Cancer Res 2009;69(23 Suppl):B2.