bluuebunny/crossref_metadata_2025_split huggingface dataset:
TheEws/Fli-1Fusion Gene Switches the Differentiation Program of Neuroblastomas to Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumors
Authors: Rorie Checo J. , Thomas Venetia D. , Chen Pengchin , Pierce Heather Hanson , O’Bryan John P. , Weissman Bernard E. 
Published: September 2005

AbstractNeuroblastoma (NB) and the Ewing sarcoma (ES)/peripheral primitive neuroectodermal tumor (PNET) family are pediatric cancers derived from neural crest cells. Although NBs display features of the sympathetic nervous system, ES/PNETs express markers consistent with parasympathetic differentiation. To examine the control of these differentiation markers, we generated NB × ES/PNET somatic cell hybrids. NB-specific markers were suppressed in the hybrids, whereas ES/PNET-specific markers were unaffected. These results suggested that the Ews/Fli-1 fusion gene, resulting from a translocation unique to ES/PNETs, might account for the loss of NB-specific markers. To test this hypothesis, we generated two different NB cell lines that stably expressed the Ews/Fli-1 gene. We observed that heterologous expression of the Ews/Fli-1 protein led to the suppression of NB-specific markers and de novo expression of ES/PNET markers. To determine the extent of changes in differentiation, we used the Affymetrix GeneChip Array system to observe global transcriptional changes of genes. This analysis revealed that the gene expression pattern of the Ews/Fli-1-expressing NB cells resembled that observed in pooled ES/PNET cell lines and differed significantly from the NB parental cells. Therefore, we propose that Ews/Fli-1 contributes to the etiology of ES/PNET by subverting the differentiation program of its neural crest precursor cell to a less differentiated and more proliferative state.
Phosphorylation of Tuberin as a Novel Mechanism for Somatic Inactivation of the Tuberous Sclerosis Complex Proteins in Brain Lesions
Authors: Han Sangyeul , Santos Túlio M. , Puga Ana , Roy Jenn , Thiele Elizabeth A. , McCollin Mia , Stemmer-Rachamimov Anat , Ramesh Vijaya 
Published: September 2005

AbstractTuberous sclerosis complex is caused by mutations in tumor suppressor genes TSC1 or TSC2 and is characterized by the presence of hamartomas in many organs. Although tuberous sclerosis complex is a tumor suppressor gene syndrome with classic “second hits” detectable in renal tumors, conventional genetic analysis has not revealed somatic inactivation of the second allele in the majority of human brain lesions. We demonstrate a novel mechanism of post-translational inactivation of the TSC2 protein, tuberin, by physiologically inappropriate phosphorylation, which is specific to tuberous sclerosis complex-associated brain lesions. Additional analysis shows that tissue specificity is due to abnormal activation of the Akt and mitogen-activated protein kinase pathways in brain but not in renal tumors. These results have widespread implications for understanding the tissue specificity of tumor suppressor gene phenotypes.
Human Papillomavirus Type 16 and
TP53
Mutation in Oral Cancer
Authors: Dai Min , Clifford Gary M. , le Calvez Florence , Castellsagué Xavier , Snijders Peter J. F. , Pawlita Michael , Herrero Rolando , Hainaut Pierre , Franceschi Silvia ,   for the IARC Multicenter Oral Cancer Study Group
Published: September 2005

Abstract
TP53 mutations were analyzed in 35 human papillomavirus (HPV) type 16 DNA-positive cancers of the oral cavity and oropharynx and in 35 HPV DNA-negative cancers matched by subsite, country, sex, age, and tobacco and alcohol consumption. Wild-type TP53 was found more frequently in cancer specimens that contained HPV16 DNA than in those that did not. All 14 HPV16 DNA-positive cancers in HPV16 E6 antibody-positive patients contained wild-type TP53, compared with 50% of corresponding HPV DNA-negative cancers (matched odds ratio, ∞; 95% confidence interval, 1.4–∞). In contrast, for HPV16 DNA-positive cancers in E6-negative patients, wild-type TP53 frequency was similar to that in corresponding HPV DNA-negative cancers (matched odds ratio, 1.0; 95% confidence interval, 0.2–5.4). TP53 inactivation is a major mechanism of HPV-related carcinogenesis in the oral cavity and oropharynx. The role of HPV in cancers also containing TP53 mutations remains to be clarified.
Tbx2 Directly Represses the Expression of the p21WAF1 Cyclin-Dependent Kinase Inhibitor
Authors: Prince Sharon , Carreira Suzanne , Vance Keith W. , Abrahams Amaal , Goding Colin R. 
Published: September 2005

Abstract
T-box factors play a crucial role in the development of many tissues, and mutations in T-box factor genes have been implicated in multiple human disorders. Some T-box factors have been implicated in cancer; for example, Tbx2 and Tbx3 can suppress replicative senescence, whereas Tbx3 can cooperate with Myc and Ras in cellular transformation. The p21WAF1 cyclin-dependent kinase inhibitor plays a key role in senescence and in cell cycle arrest after DNA damage. Here, using a combination of in vitro DNA-binding, transfection, and chromatin immunoprecipitation assays, we show that Tbx2 can bind and repress the p21 promoter in vitro and in vivo. Moreover, small interfering RNA-mediated down-regulation of Tbx2 expression results in a robust activation of p21 expression. Taken together, these results implicate Tbx2 as a novel direct regulator of p21 expression and have implications for our understanding of the role of T-box factors in the regulation of senescence and oncogenesis, as well as in development.
An Integrated View of Copy Number and Allelic Alterations in the Cancer Genome Using Single Nucleotide Polymorphism Arrays
Authors: Zhao Xiaojun , Li Cheng , Paez J. Guillermo , Chin Koei , Jänne Pasi A. , Chen Tzu-Hsiu , Girard Luc , Minna John , Christiani David , Leo Chris , Gray Joe W. , Sellers William R. , Meyerson Matthew 
Published: September 2005

AbstractChanges in DNA copy number contribute to cancer pathogenesis. We now show that high-density single nucleotide polymorphism (SNP) arrays can detect copy number alterations. By hybridizing genomic representations of breast and lung carcinoma cell line and lung tumor DNA to SNP arrays, and measuring locus-specific hybridization intensity, we detected both known and novel genomic amplifications and homozygous deletions in these cancer samples. Moreover, by combining genotyping with SNP quantitation, we could distinguish loss of heterozygosity events caused by hemizygous deletion from those that occur by copy-neutral events. The simultaneous measurement of DNA copy number changes and loss of heterozygosity events by SNP arrays should strengthen our ability to discover cancer-causing genes and to refine cancer diagnosis.
Identification of Aryl Hydrocarbon Receptor as a Putative Wnt/β-Catenin Pathway Target Gene in Prostate Cancer Cells
Authors: Chesire Dennis R. , Dunn Thomas A. , Ewing Charles M. , Luo Jun , Isaacs William B. 
Published: September 2005

Abstract
Recent genetic and functional analyses have implicated the wnt/β-catenin signaling pathway in prostate cancer (CaP) pathogenesis. Thus, there is much interest in understanding the consequences of wnt signaling in CaP; target gene expression is one important area of inquiry and is the focus of this report. Adenoviral-mediated overexpression of a mutant, hyperactive form of β-catenin in CWR22-Rv1 CaP cells led to increased aryl hydrocarbon receptor (AhR, or dioxin receptor) and transmembrane protein 2 RNA transcript expression, as detected by cDNA-microarray analyses. Validating these results, reverse transcription-PCR assays demonstrated that in CWR22-Rv1 cells as well as in LAPC-4 CaP cells, increased putative target gene RNA expression occurs with transient overexpression of mutant β-catenin, treatment of cells with lithium chloride, or with wnt3a-conditioned medium, three distinct modes of experimental wnt/β-catenin pathway activation. This β-catenin-associated expression of AhR and transmembrane protein 2 does not require de novo protein synthesis and may only involve a certain subset of CaP cell lines. Western and immunofluorescence analyses were undertaken to assess the relationship between the wnt/β-catenin-stimulated increase in AhR transcripts and AhR protein expression; we provide evidence that an association exists whereby up-regulation of AhR RNA by wnt or β-catenin is coupled with augmented AhR protein levels. Intriguingly, these studies also demonstrated that nuclear β-catenin staining may not be a sole deciding factor when predicting the status of wnt/β-catenin signaling in CaP cells. Finally, the extent to which wnt signaling may synergize with an environmental agonist of AhR (2,3,7,8-tetrachlorodibenzo-p-dioxin) to potentiate AhR transcriptional activity was examined. Considering previous work linking AhR to processes of development and carcinogenesis, our data may highlight one particular role for wnt/β-catenin signaling in prostate tumor biology.
Selective Estrogen Receptor Modulators
Authors: Frasor Jonna , Stossi Fabio , Danes Jeanne M. , Komm Barry , Lyttle C. Richard , Katzenellenbogen Benita S. 
Published: September 2005

Abstract
Selective estrogen receptor modulators (SERMs) such as tamoxifen are effective in the treatment of many estrogen receptor-positive breast cancers and have also proven to be effective in the prevention of breast cancer in women at high risk for the disease. The comparative abilities of tamoxifen versus raloxifene in breast cancer prevention are currently being compared in the Study of Tamoxifen and Raloxifene trial. To better understand the actions of these compounds in breast cancer, we have examined their effects on the expression of ∼12,000 genes, using Affymetrix GeneChip microarrays, with quantitative PCR verification in many cases, categorizing their actions as agonist, antagonist, or partial agonist/antagonist. Analysis of gene stimulation and inhibition by the SERMs trans-hydroxytamoxifen (TOT) and raloxifene (Ral) or ICI 182,780 (ICI) and by estradiol (E2) in estrogen receptor-containing MCF-7 human breast cancer cells revealed that (a) TOT was the most E2-like of the three compounds, (b) all three compounds either partially or fully antagonized the action of E2 on most genes, with the order of antagonist activity being ICI &gt; Ral &gt; TOT, (c) TOT and Ral, but not ICI, displayed partial agonist/partial antagonist activity on a number of E2-regulated genes, (d) several stimulatory cell cycle-related genes were down-regulated exclusively by ICI, (e) the estrogen-like activity of Ral nearly always overlapped with that of TOT, indicating that Ral has little unique agonist activity different from that of TOT, and (f) some genes were specifically up-regulated by TOT but not Ral, ICI, or E2. Hence, gene expression profiling can discern fundamental differences among SERMs and provides insight into the distinct biologies of TOT, Ral, and ICI in breast cancer.
Menin Inactivation Leads to Loss of Transforming Growth Factor β Inhibition of Parathyroid Cell Proliferation and Parathyroid Hormone Secretion
Authors: Sowa Hideaki , Kaji Hiroshi , Kitazawa Riko , Kitazawa Sohei , Tsukamoto Tatsuo , Yano Shozo , Tsukada Toshihiko , Canaff Lucie , Hendy Geoffrey N. , Sugimoto Toshitsugu , Chihara Kazuo 
Published: September 2005

Abstract
Primary hyperparathyroidism is a common endocrine disorder caused by parathyroid gland enlargement and excessive parathyroid hormone (PTH) secretion. However, the precise mechanisms of tumorigenesis of the parathyroids are unknown. Here we have investigated the roles of transforming growth factor (TGF)-β and menin, the product of the multiple endocrine neoplasia type 1 (Men1) gene, in the proliferation and PTH production of parathyroid cells from either patients with secondary hyperparathyroidism or Men1. TGF-β was expressed in the parathyroid endocrine cells. Addition of TGF-β to parathyroid cells from patients with secondary hyperparathyroidism inhibited their proliferation and PTH secretion. These responses to TGF-β were lost when menin was specifically inactivated by antisense oligonucleotides. Moreover, TGF-β did not affect the proliferation and PTH production of parathyroid cells from a Men1 patient. These results indicate that menin is required for TGF-β action in the parathyroid. We conclude that TGF-β is an important autocrine/paracrine negative regulator of parathyroid cell proliferation and PTH secretion and that loss of TGF-β signaling due to menin inactivation contributes to parathyroid tumorigenesis.
Survival Efficacy of Adjuvant Cytosine-Analogue CS-682 in a Fluorescent Orthotopic Model of Human Pancreatic Cancer
Authors: Katz Matthew H. , Bouvet Michael , Takimoto Shinako , Spivack Daniel , Moossa Abdool R. , Hoffman Robert M. 
Published: September 2005

Abstract
Adjuvant treatment with the cytosine analogue 1-(2-C-cyano-2-deoxy-β-d-arabino-pentofuranosyl)-N4-palmitoylcytosine (CS-682) results in a highly significant increase in survival in the aggressive orthotopic MIA-PaCa-2 human pancreatic cancer mouse model. Seven days after implantation, mice were randomized into eight groups, depending on whether they were to be treated by tumor resection, 5 weeks of CS-682 chemotherapy at 40–60 mg/kg once daily, or both. Throughout the course of treatment, noninvasive optical whole-body imaging based on brilliant red fluorescent protein expression of the tumor permitted visualization and quantification of primary, metastatic, and recurrent disease. Total tumor burden negatively correlated with survival. Untreated mice died of disseminated disease with a median survival of 26 days. Surgical resection alone conferred a small but significant survival advantage (median survival, 28 days, P = 0.03). Primary CS-682 treatment at all doses also significantly prolonged survival compared with untreated animals (P &lt; 0.05) and was more effective than surgery alone at doses of 50 and 60 mg/kg (median survival, 34 days, P = 0.045, and 38.5 days, P = 0.03, respectively). Maximal survival (median, 48 days, with 30% of animals surviving longer than 60 days) was achieved by adjuvant CS-682 (50 mg/kg), given after surgical resection of the primary pancreatic tumor (P = 0.004 compared with surgery alone). The results demonstrate that adjuvant oral administration of CS-682 for pancreatic cancer is highly effective with acceptable toxicity, suggesting its potential for cure of this disease in appropriate combinations.
Impact of Types of Lymphocyte Chromosomal Aberrations on Human Cancer Risk
Authors: Hagmar Lars , Strömberg Ulf , Bonassi Stefano , Hansteen Inger-Lise , Knudsen Lisbeth Ehlert , Lindholm Carita , Norppa Hannu 
Published: September 2005

Abstract
The frequency of cells with structural chromosomal aberrations (CAs) in peripheral blood lymphocytes is the first genotoxicity biomarker that has shown an association with cancer risk. CAs are usually divided into chromosome-type (CSAs) and chromatid-type aberrations (CTAs), with different mechanisms of formation. From a mechanistic point of view, it is of interest to clarify whether the cancer predictivity of CAs is different with respect to CSAs and CTAs. We report here cancer risk for cytogenetically tested, healthy subjects with respect to frequency of CAs, CSAs, and CTAs in peripheral blood lymphocytes, using Nordic (1981 subjects with CA data, 1871 subjects with CSA/CTA data) and Italian (1573 subjects with CA data, 877 subjects with CTA/CSA data) cohorts, with a median follow-up of 17 years. High levels of CAs at test were clearly associated with increased total cancer incidence in the Nordic cohorts and increased total cancer mortality in the Italian cohort. In the Nordic cohorts, significantly elevated cancer risks were observed for subjects with both high CSAs and high CTAs at test, and these variables showed equally strong cancer predictivity. The results of the Italian cohort did not indicate any clear-cut difference in cancer predictivity between the CSA and CTA biomarkers. There was no significant effect modification by age at test, gender, country, or time since test. The results suggest that both DNA double-strand breaks and other initial DNA lesions responsible for CSAs and CTAs are associated with cancer risk.
An Increase in the Expression of Ribonucleotide Reductase Large Subunit 1 Is Associated with Gemcitabine Resistance in Non-Small Cell Lung Cancer Cell Lines
Authors: Davidson Jennifer D. , Ma Liandong , Flagella Michael , Geeganage Sandaruwan , Gelbert Lawrence M. , Slapak Christopher A. 
Published: September 2005

Abstract
The mechanisms of resistance to the antimetabolite gemcitabine in non-small cell lung cancer have not been extensively evaluated. In this study, we report the generation of two gemcitabine-selected non-small cell lung cancer cell lines, H358-G200 and H460-G400. Expression profiling results indicated that there was evidence for changes in the expression of 134 genes in H358-G200 cells compared with its parental line, whereas H460-G400 cells exhibited 233 genes that appeared to be under- or overexpressed compared with H460 cells. However, only the increased expression of ribonucleotide reductase subunit 1 (RRM1), which appeared in both resistant cell lines, met predefined analysis criteria for genes to investigate further. Quantitative PCR analysis demonstrated H358-G200 cells had a greater than 125-fold increase in RRM1 RNA expression. Western blot analysis confirmed high levels of RRM1 protein in this line compared with the gemcitabine-sensitive parent. No significant change in the expression of RRM2 was observed in either cell line, although both gemcitabine-resistant cell lines had an approximate 3-fold increase in p53R2 protein. A partial revertant of H358-G200 cells had reduced levels of RRM1 protein (compared with G200 cells), without observed changes in RRM2 or p53R2. In vitro analyses of ribonucleotide reductase activity demonstrated that despite high levels of RRM1 protein, ribonucleotide reductase activity was not increased in H358-G200 cells when compared with parental cells. The cDNA encoding RRM1 from H358-G200 cells was cloned and sequenced but did not reveal the presence of any mutations. The results from this study indicate that the level of RRM1 may affect gemcitabine response. Furthermore, RRM1 may serve as a biomarker for gemcitabine response.
Differential Activation of the Phosphatidylinositol 3′-Kinase/Akt Survival Pathway by Ionizing Radiation in Tumor and Primary Endothelial Cells
Authors: Zingg Daniel , Riesterer Oliver , Fabbro Doriano , Glanzmann Christoph , Bodis Stephan , Pruschy Martin 
Published: September 2005

Abstract
Ionizing radiation induces an intracellular stress response via activation of the phosphatidylinositol 3′-kinase (PI3K)/Akt survival pathway. In tumor cells, the PI3K/Akt pathway is induced through activation of members of ErbB receptor tyrosine kinases. Here, we investigated the receptor dependence of radiation-induced PI3K/Akt activation in tumor cells and in endothelial cells. The integrity of both the ErbB and the vascular endothelial growth factor (VEGF) ligand-activated PI3K/Akt pathway in endothelial cells was demonstrated using specific ErbB and VEGF receptor tyrosine kinase inhibitors. Irradiation of endothelial cells resulted in protein kinase B (PKB)/Akt activation in a similar time course as observed in response to VEGF. More importantly, radiation-induced PKB/Akt phosphorylation in endothelial cells was strongly down-regulated by the VEGF receptor tyrosine kinase inhibitor, whereas the ErbB receptor tyrosine kinase inhibitor did not affect PKB/Akt stimulation in response to irradiation. An opposite receptor dependence for radiation-induced PKB/Akt phosphorylation was observed in ErbB receptor-overexpressing A431 tumor cells. Furthermore, direct VEGF receptor phosphorylation was detected after irradiation in endothelial cells in absence of VEGF, which was almost completely inhibited after irradiation in presence of the VEGF receptor tyrosine kinase inhibitor. These data demonstrate that ionizing radiation induces VEGF ligand-independent but VEGF receptor-dependent PKB/Akt activation in endothelial cells and that PI3K/Akt pathway activation by radiation occurs in a differential cell type and receptor-dependent pattern.
A Genetically Defined Model for Human Ovarian Cancer
Authors: Liu Jinsong , Yang Gong , Thompson-Lanza Jennifer A. , Glassman Armand , Hayes Kimberly , Patterson Andrea , Marquez Rebecca T. , Auersperg Nelly , Yu Yinhua , Hahn William C. , Mills Gordon B. , Bast Robert C. 
Published: September 2005

AbstractDisruptions of the p53, retinoblastoma (Rb), and RAS signaling pathways and activation of human telomerase reverse transcriptase (hTERT) are common in human ovarian cancer; however, their precise role in ovarian cancer development is not clear. We thus introduced the catalytic subunit of hTERT, the SV40 early genomic region, and the oncogenic alleles of human HRAS or KRAS into human ovarian surface epithelial cells and examined the phenotype and gene expression profile of those cells. Disruption of p53 and Rb pathway by SV40 early genomic region and hTERT immortalized but did not transform the cells. Introduction of HRASV12 or KRASV12 into the immortalized cells, however, allowed them to form s.c. tumors after injection into immunocompromised mice. Peritoneal injection of the transformed cells produced undifferentiated carcinoma or malignant mixed Mullerian tumor and developed ascites; the tumor cells are focally positive for CA125 and mesothelin. Gene expression profile analysis of transformed cells revealed elevated expression of several cytokines, including interleukin (IL)-1β, IL-6, and IL-8, that are up-regulated by the nuclear factor-κB pathway, which is known to contribute to the tumor growth of naturally ovarian cancer cells. Incubation with antibodies to IL-1β or IL-8 led to apoptosis in the ras-transformed cells and ovarian cancer cells but not in immortalized cells that had not been transformed. Thus, the transformed human ovarian surface epithelial cells recapitulated many features of natural ovarian cancer including a subtype of ovarian cancer histology, formation of ascites, CA125 expression, and nuclear factor-κB-mediated cytokine activation. These cells provide a novel model system to study human ovarian cancer.
T-bet Regulates Metastasis Rate in a Murine Model of Primary Prostate Cancer
Authors: Peng Stanford L. , Townsend Michael J. , Hecht Jonathan L. , White Ian A. , Glimcher Laurie H. 
Published: September 2005

Abstract
The local progression of primary tumors is extrinsically controlled by type 1 immune responses, particularly via the cytokine IFN-γ, whose secretion is highly dependent on helper T cells. The T-box transcription factor T-bet (Tbx21) plays a critical role in the development of type 1 helper T cells and is essential for the production of IFN-γ. Here, the T-bet pathway in the autochthonous transgenic adenocarcinoma mouse prostate model is demonstrated to have only a modest effect on the characteristics of primary prostate cancers but rather exerts a significant suppressor function in the development of metastatic disease.