bluuebunny/crossref_metadata_2025_split huggingface dataset:
An Evolutionary Perspective on Single-Nucleotide Polymorphism Screening in Molecular Cancer Epidemiology
Authors: Zhu Yong , Spitz Margaret R. , Amos Christopher I. , Lin Jie , Schabath Matthew B. , Wu Xifeng 
Published: September 2005

Abstract
Given that there are millions of single-nucleotide polymorphisms (SNPs) in the entire human genome, a major difficulty faced by scientists in planning costly population-based genotyping is to choose target SNPs that are most likely to affect phenotypic functions and ultimately contribute to disease development. Although it is widely accepted that sequences with important functionality tend to be less variable across species because of selective pressure, to what extent evolutionary conservation is mirrored by epidemiological outcome has never been demonstrated. In this study, we surveyed odds ratios detected for 46 SNPs in 39 different cancer-related genes from 166 molecular epidemiological studies. The conservation levels of amino acid that these SNPs affected were calculated as a tolerance index by comparing sequences from different species. Our results provide evidence of a significant relationship between the detected odds ratios associated with cancer risk and the conservation levels of the SNP-affected amino acids (P = 0.002; R2 = 0.06). Tolerance indices were further calculated for 355 nonsynonymous SNPs identified in 90 human DNA repair genes, of which 103 caused amino acid changes in very conserved positions. Our findings support the concept that SNPs altering the conserved amino acids are more likely to be associated with cancer susceptibility. Using such a molecular evolutionary approach may hold great promise for prioritizing SNPs to be genotyped in future molecular epidemiological studies.
Loss of MSH3 Protein Expression Is Frequent in MLH1-Deficient Colorectal Cancer and Is Associated with Disease Progression
Authors: Plaschke Jens , Krüger Stefan , Jeske Birgit , Theissig Franz , Kreuz Friedmar R. , Pistorius Steffen , Saeger Hans D. , Iaccarino Ingram , Marra Giancarlo , Schackert Hans K. 
Published: September 2005

Abstract
Mononucleotide repeat sequences are particularly prone to frameshift mutations in tumors with biallelic inactivation of the mismatch repair (MMR) genes MLH1 or MSH2. In these tumors, several genes harboring mononucleotide repeats in their coding region have been proposed as targets involved in tumor progression, among which are also the MMR genes MSH3 and MSH6. We have analyzed the expression of the MSH3 and MSH6 proteins by immunohistochemistry in 31 colorectal carcinomas in which MLH1 was inactivated. Loss of MSH3 expression was identified in 15 tumors (48.5%), whereas all tumors expressed MSH6. Frameshift mutations at coding microsatellites were more frequent in MSH3 (16 of 31) than in MSH6 (3 of 31; Fisher’s exact test, P &lt; 0.001). Frameshift mutations and allelic losses of MSH3 were more frequent in MSH3-negative tumors compared with those with normal expression (22 mutations in 30 alleles versus 8 mutations in 28 alleles; χ2, P = 0.001). Biallelic inactivation was evident or inferred for 60% of MSH3-negative tumors but none of the tumors with normal MSH3 expression. In contrast, we did not identify frameshift mutations in the (A)8 tract of MSH3 in a control group of 18 colorectal carcinomas in which the MMR deficiency was based on the inactivation of MSH2. As it has been suggested that mutations of MSH3 might play a role in tumor progression, we studied the association between MSH3 expression and disease stage assessed by lymph node and distant metastases status. Dukes stages C and D were more frequent in primary tumors with loss of MSH3 expression (9 of 13), compared with tumors with retained expression (1 of 14; Fisher’s exact test, P = 0.001), suggesting that MSH3 abrogation may be a predictor of metastatic disease or even favor tumor cell spread in MLH1-deficient colorectal cancers.
Cyclin-Dependent Kinase Inhibition by the KLF6 Tumor Suppressor Protein through Interaction with Cyclin D1
Authors: Benzeno Sharon , Narla Goutham , Allina Jorge , Cheng George Z. , Reeves Helen L. , Banck Michaela S. , Odin Joseph A. , Diehl J. Alan , Germain Doris , Friedman Scott L. 
Published: September 2005

Abstract
Kruppel-like factor 6 (KLF6) is a tumor suppressor gene inactivated in prostate and colon cancers, as well as in astrocytic gliomas. Here, we establish that KLF6 mediates growth inhibition through an interaction with cyclin D1, leading to reduced phosphorylation of the retinoblastoma protein (Rb) at Ser795. Furthermore, introduction of KLF6 disrupts cyclin D1-cyclin-dependent kinase (cdk) 4 complexes and forces the redistribution of p21Cip/Kip onto cdk2, which promotes G1 cell cycle arrest. Our data suggest that KLF6 converges with the Rb pathway to inhibit cyclin D1/cdk4 activity, resulting in growth suppression.
Phosphatidylinositol Triphosphate Kinase-dependent and c-Jun NH2-Terminal Kinase-dependent Induction of Telomerase by Calcium Requires Pyk2
Authors: Alfonso-De Matte Michelle Y. , Kruk Patricia A. 
Published: September 2005

AbstractCalcium signaling has been linked to activation of Pyk2, a calcium-dependent, focal adhesion kinase-related, non-receptor tyrosine kinase. Signaling via Pyk2 can activate c-jun NH2-terminal kinase (JNK). Calcium has also been shown to activate phosphatidylinositol triphosphate kinase and/or JNK. Here, we show that calcium signaling in ovarian surface epithelial cells not only induces telomerase activity via JNK but also activates Pyk2. Moreover, telomerase activation by Pyk2 requires JNK activation. In contrast, a kinase-deficient Pyk2 construct failed to activate either JNK or telomerase. Finally, we demonstrate that Pyk2 is capable of driving the human telomerase reverse transcriptase promoter, resulting in telomerase activation. These data suggest a novel role of Pyk2 for telomerase regulation.
USP6 (Tre2)
Fusion Oncogenes in Aneurysmal Bone Cyst
Authors: Oliveira Andre M. , Hsi Bae-Li , Weremowicz Stanislawa , Rosenberg Andrew E. , Cin Paola Dal , Joseph Nora , Bridge Julia A. , Perez-Atayde Antonio R. , Fletcher Jonathan A. 
Published: September 2005

Abstract
Aneurysmal bone cyst (ABC) is a locally aggressive osseous lesion that typically occurs during the first two decades of life. ABC was regarded historically as a nonneoplastic process, but recent cytogenetic data have shown clonal rearrangements of chromosomal bands 16q22 and 17p13, indicating a neoplastic basis in at least some ABCs. Herein we show that a recurring ABC chromosomal translocation t(16;17)(q22;p13) creates a fusion gene in which the osteoblast cadherin 11 gene (CDH11) promoter region on 16q22 is juxtaposed to the entire ubiquitin-specific protease USP6 (Tre2) coding sequence on 17p13. CDH11-USP6 fusion transcripts were demonstrated only in ABC with t(16;17) but other ABCs had CDH11 or USP6 rearrangements resulting from alternate cytogenetic mechanisms. CDH11 is expressed strongly in bone, and our findings implicate a novel oncogenic mechanism in which deregulated USP6 transcription results from juxtaposition to the highly active CDH11 promoter.
Crystal Structures of Prostaglandin D2 11-Ketoreductase (AKR1C3) in Complex with the Nonsteroidal Anti-Inflammatory Drugs Flufenamic Acid and Indomethacin
Authors: Lovering Andrew L. , Ride Jon P. , Bunce Christopher M. , Desmond Julian C. , Cummings Stephen M. , White Scott A. 
Published: September 2005

Abstract
It is becoming increasingly well established that nonsteroidal anti-inflammatory drugs (NSAID) protect against tumors of the gastrointestinal tract and that they may also protect against a variety of other tumors. These activities have been widely attributed to the inhibition of cylooxygenases (COX) and, in particular, COX-2. However, several observations have indicated that other targets may be involved. Besides targeting COX, certain NSAID also inhibit enzymes belonging to the aldo-keto reductase (AKR) family, including AKR1C3. We have demonstrated previously that overexpression of AKR1C3 acts to suppress cell differentiation and promote proliferation in myeloid cells. However, this enzyme has a broad tissue distribution and therefore represents a novel candidate for the target of the COX-independent antineoplastic actions of NSAID. Here we report on the X-ray crystal structures of AKR1C3 complexed with the NSAID indomethacin (1.8 Å resolution) or flufenamic acid (1.7 Å resolution). One molecule of indomethacin is bound in the active site, whereas flufenamic acid binds to both the active site and the β-hairpin loop, at the opposite end of the central β-barrel. Two other crystal structures (1.20 and 2.1 Å resolution) show acetate bound in the active site occupying the proposed oxyanion hole. The data underline AKR1C3 as a COX-independent target for NSAID and will provide a structural basis for the future development of new cancer therapies with reduced COX-dependent side effects.
Epigenetic Profiling in Chronic Lymphocytic Leukemia Reveals Novel Methylation Targets
Authors: Rush Laura J. , Raval Aparna , Funchain Pauline , Johnson Amy J. , Smith Lisa , Lucas David M. , Bembea Melania , Liu Te-Hui , Heerema Nyla A. , Rassenti Laura , Liyanarachchi Sandya , Davuluri Ramana , Byrd John C. , Plass Christoph 
Published: September 2005

Abstract
CpG island methylation is an epigenetic alteration that contributes to tumorigenesis by transcriptional inactivation of genes. Little is known about the overall levels of CpG island methylation in chronic lymphocytic leukemia (CLL). To provide a baseline estimate of global aberrant methylation and identify target sequences for additional investigation, we performed Restriction Landmark Genomic Scanning on 10 CLL samples. Two methylation-sensitive landmark enzymes were used (NotI and AscI), allowing assessment of over 3000 CpG islands in each sample. Tumor-derived Restriction Landmark Genomic Scanning profiles were compared with profiles from CD19-selected B cells from normal volunteers and matched normal neutrophils from 4 CLL patients. We found 2.5–8.1% (mean 4.8%) of the CpG islands in CLL samples were aberrantly methylated compared with controls, and the methylation events had a nonrandom distribution (P &lt; 0.0001). Furthermore, we identified 193 aberrantly methylated sequences, of which 93% have CpG island characteristics and 90% have homology to genes or expressed sequences. One such gene, the G protein-coupled metabotropic glutamate receptor 7 (GRM7), possibly inhibits cyclic AMP signaling in the induction of apoptosis. Bisulfite sequencing of GRM7 confirmed extensive CpG island methylation, and treatment with 5-aza-2′-deoxycytidine (decitabine) resulted in up-regulated expression of several genes in vitro with concurrent cellular depletion of DNMT1 protein. Our dual-enzyme global methylation study shows that CLL is characterized by widespread nonrandom CpG island methylation similar to other tumors and provides a panel of novel methylation targets that can be used in larger studies designed to assess impact on disease progression and survival.
Polymorphism in the Androgen Receptor and Mammographic Density in Women Taking and Not Taking Estrogen and Progestin Therapy
Authors: Lillie Elizabeth Osth , Bernstein Leslie , Ingles Sue Ann , Gauderman W. James , Rivas Guillermo E. , Gagalang Virgilio , Krontiris Theodore , Ursin Giske 
Published: September 2005

Abstract
There is some evidence that women with a higher number of CAG repeat lengths on the androgen receptor (AR) gene have increased breast cancer risk. We evaluated the association between AR-CAG repeat length and mammographic density, a strong breast cancer risk factor, in 404 African-American and Caucasian breast cancer patients. In postmenopausal estrogen progestin therapy users, carriers of the less active AR-CAG had statistically significantly higher mean percentage of density (41.4%) than carriers of the more active AR-CAG (25.7%; P = 0.04). Our results raise the question of whether the number of AR-CAG repeats predicts breast cancer risk in estrogen progestin therapy users.
Aurora-A Kinase Regulates Telomerase Activity through c-Myc in Human Ovarian and Breast Epithelial Cells
Authors: Yang Hua , Ou Chien Chen , Feldman Richard I. , Nicosia Santo V. , Kruk Patricia A. , Cheng Jin Q. 
Published: September 2005

Abstract
Aurora-A kinase is frequently overexpressed/activated in human ovarian and breast cancers. A rat mammary tumor model study indicates that alterations of Aurora-A are early events during mammary tumor development (T. M. Goepfert et al., Cancer Res., 62: 4115–4122, 2002), suggesting that Aurora-A plays a pivotal role in transformation. However, the molecular mechanism by which Aurora-A induces ovarian and breast cell transformation remains elusive. Here we show that ectopic expression of Aurora-A induces telomerase activity in human ovarian and breast epithelial cell lines HIOSE118 and MCF-10A. The mRNA and promoter activities of human telomerase reverse transcriptase (hTERT) are stimulated by Aurora-A. Furthermore, we have demonstrated that the c-Myc binding sites of hTERT promoter are required for Aurora-A-induced hTERT promoter activity. Ectopic expression of Aurora-A up-regulates c-Myc. Knockdown of c-Myc by RNA interference attenuates Aurora-A-stimulated hTERT expression and telomerase activity. To our knowledge, these findings demonstrate, for the first time, that Aurora-A induces telomerase activity and hTERT by up-regulation of c-Myc and provides an additional mechanism for the role of Aurora-A in malignant transformation in addition to its cell cycle control.
Mammary Tumor Induction in Transgenic Mice Expressing an RNA-Binding Protein
Authors: Tessier Charles R. , Doyle Glenn A. , Clark Brad A. , Pitot Henry C. , Ross Jeff 
Published: September 2005

Abstract
We have analyzed mammary tumors arising in transgenic mice expressing a novel, multifunctional RNA-binding protein. The protein, which we call the c-myc mRNA coding region instability determinant binding protein (CRD-BP), binds to c-myc, insulin-like growth factor II, and β-actin mRNAs, and to H19 RNA. Depending on the RNA substrate, the CRD-BP affects RNA localization, translation, or stability. CRD-BP levels are high during fetal development but low or undetectable in normal adult tissues. The CRD-BP is linked to tumorigenesis, because its expression is reactivated in some adult human breast, colon, and lung tumors. These data suggest the CRD-BP is a proto-oncogene. To test this idea, the CRD-BP was expressed from the whey acidic protein (WAP) promoter in mammary epithelial cells of adult transgenic mice. The incidence of mammary tumors was 95% and 60% in two lines of WAP-CRD-BP mice with high and low relative CRD-BP expression, respectively. Some of the tumors metastasized. Nontransgenic mice did not develop mammary tumors. H19 RNA and insulin-like growth factor II mRNA were up-regulated significantly in non-neoplastic WAP-CRD-BP mammary tissue. WAP-CRD-BP mice are a novel model for mammary neoplasia and might provide insights into human breast cancer biology.
Modulation of Tumor-host Interactions, Angiogenesis, and Tumor Growth by Tissue Inhibitor of Metalloproteinase 2 via a Novel Mechanism
Authors: Feldman Andrew L. , Stetler-Stevenson William G. , Costouros Nick G. , Knezevic Vladimir , Baibakov Galina , Alexander H. Richard , Lorang Dominique , Hewitt Stephen M. , Seo Dong-Wan , Miller Marshall S. , O’Connor Sarah , Libutti Steven K. 
Published: September 2005

Abstract
Solid tumors depend on angiogenesis for sustained growth. Tissue inhibitor of metalloproteinase 2 (TIMP-2) is an angiogenesis inhibitor initially characterized for its ability to block matrix metalloproteinases; however, recent data suggest that the antiangiogenic action of TIMP-2 may rely on matrix metalloproteinase-independent mechanisms. The aim of this study was to identify molecular pathways involved in the effects of TIMP-2 on processes dependent on tumor-host interactions such as angiogenesis. Using in vitro cell culture and a syngeneic murine tumor model, we compared the effects of TIMP-2 overexpression on gene expression profiles in vitro to those observed in vivo. Validating these findings by real-time quantitative PCR and layered protein scanning, we identified up-regulation of mitogen-activated protein kinase phosphatase 1 as an effector of the antiangiogenic function of TIMP-2. Up-regulation of mitogen-activated protein kinase phosphatase 1 in tumors overexpressing TIMP-2 leads to dephosphorylation of p38 mitogen-activated protein kinase and inhibition of tumor growth and angiogenesis. Phosphatase activity appears important in regulating tumor angiogenesis, offering a promising direction for the identification of novel molecular targets and antiangiogenic compounds for the treatment of cancer.
The Prognostic Implication of the Basal-Like (Cyclin Ehigh/p27low/p53+/Glomeruloid-Microvascular-Proliferation+) Phenotype of
BRCA1
-Related Breast Cancer
Authors: Foulkes William D. , Brunet Jean-Sébastien , Stefansson Ingunn M. , Straume Oddbjørn , Chappuis Pierre O. , Bégin Louis R. , Hamel Nancy , Goffin John R. , Wong Nora , Trudel Michel , Kapusta Linda , Porter Peggy , Akslen Lars A. 
Published: September 2005

Abstract
Previous studies have shown that BRCA1-related breast cancers are often high-grade tumors that do not express estrogen receptors, HER2, p27Kip1, or cyclin D1, but do express p53 and cyclin E. In addition, the expression of cytokeratin 5/6 (CK5/6), indicating a basal epithelial phenotype, is frequent in BRCA1-related breast cancer. Here, in a series of 247 breast cancers, we demonstrate that CK5/6 expression was associated with nearly all of the features of BRCA1-related breast cancer and was also associated with a poor prognosis. In a parsimonious multivariable proportional hazards model, protein levels of cyclin E, p27Kip1, p53, and the presence of glomeruloid microvascular proliferation all independently predicted outcome after breast cancer. In this model, only cyclin E and p27Kip1 levels were independent predictors in lymph node-negative cancers, whereas glomeruloid microvascular proliferation and tumor size independently predicted outcome in node-positive disease. The molecular determinants of the basal epithelial phenotype encapsulate many of the key features of breast cancers occurring in germ-line BRCA1 mutation carriers and have independent prognostic value. Basal breast cancer deserves recognition as an important subtype of breast cancer.
Promotion of Microsatellite Instability by Hepatitis C Virus Core Protein in Human Non-neoplastic Hepatocyte Cells
Authors: Naganuma Atsushi , Dansako Hiromichi , Nakamura Takashi , Nozaki Akito , Kato Nobuyuki 
Published: September 2005

Abstract
Hepatitis C virus proteins exert an effect on a variety of cellular functions, including gene expression, signal transduction, and apoptosis, and because they possess oncogenic potentials, they have also been suggested to play an important role in hepatocarcinogenesis. Although the mechanisms of hepatocarcinogenesis remain poorly understood, we hypothesized that the disease may arise because of a disturbance of the DNA repair system by hepatitis C virus proteins. To test this hypothesis, we developed a reproducible microsatellite instability assay system for mismatch-repair using human-cultured cells transducted with pCXpur retrovirus expression vector, in which the puromycin resistance gene was rendered out-of-frame by insertion of a (CA)17 dinucleotide repeat tract immediately following the ATG start codon. Using several human cancer cell lines known to be replication error positive or negative, we demonstrated that this assay system was useful for monitoring the propensity for mismatch-repair in the cells. This assay system was applicable to non-neoplastic human PH5CH8 hepatocytes, which could support hepatitis C virus replication. Using PH5CH8 cells, in which hepatitis C virus proteins were stably expressed by the retrovirus-mediated gene transfer, we found that the core protein promoted microsatellite instability in PH5CH8 cells. Interestingly, such promotion by the core protein only occurred in cells having the core protein belonging to genotype 1b or 2a and did not occur in cells having the core protein belonging to genotype 1a, 2b, or 3a. This is the first report to demonstrate that the core protein may disturb the DNA repair system.
Expression of Focal Adhesion Kinase in Acute Myeloid Leukemia Is Associated with Enhanced Blast Migration, Increased Cellularity, and Poor Prognosis
Authors: Recher Christian , Ysebaert Loïc , Beyne-Rauzy Odile , Mansat-De Mas Véronique , Ruidavets Jean-Bernard , Cariven Pascal , Demur Cécile , Payrastre Bernard , Laurent Guy , Racaud-Sultan Claire 
Published: September 2005

AbstractFocal adhesion kinase (FAK) is a nonreceptor tyrosine kinase playing an important role in cell motility and survival. However, very little is known about FAK in normal and leukemic myeloid cells. In this study, FAK protein expression and mRNA were detected in 25 of 60 cases (42%) of acute myeloid leukemia (AML). Whereas FAK was expressed in 46% of CD34+ AML cells, it was not detected in normal purified CD34+ cells. Conversely, the FAK homologue proline-rich tyrosine kinase 2 (PYK2) was found to be expressed both in normal and leukemic myeloid cells. When expressed, FAK displayed phosphorylation on Tyr-397, an important step for its activation. Moreover, FAK expression was correlated with the phosphorylation of PYK2 on Tyr-881, a critical site for the PYK2 function in cell migration. FAK+ AML cells displayed significantly higher migration capacities and resistance to daunorubicin, compared with FAK− cells. The implication of FAK in both cell motility and drug resistance was demonstrated by small interfering RNA experiments with the FAK-positive KG1 cell line. However, adhesion on fibronectin efficiently protected FAK− AML cells from daunorubicin-mediated killing, suggesting that cellular adhesion mediated-drug resistance is not mediated by FAK. Finally, in a retrospective cohort of 60 AML patients, FAK expression was significantly correlated with high blast cell count, early death, and shorter survival rate. Altogether, this study shows that FAK is aberrantly expressed and activated in about half of the cases of AML and suggests that FAK may contribute to the regulation of AML cell transit from the marrow to blood compartment and that it may influence clinical outcome.
Hypoxia-Inducible Factor-1-Independent Regulation of Vascular Endothelial Growth Factor by Hypoxia in Colon Cancer
Authors: Mizukami Yusuke , Li Jingnan , Zhang Xiaobo , Zimmer Michael A. , Iliopoulos Othon , Chung Daniel C. 
Published: September 2005

Abstract
The induction of vascular endothelial growth factor (VEGF) is an essential feature of tumor angiogenesis, and the hypoxia-inducible factor-1 (HIF-1) transcription factor is known to be a key mediator of this process. In colon cancer, the frequently mutated K-ras oncogene also can regulate VEGF expression, but the role that K-ras may play in hypoxia is unknown. Hypoxia induced VEGF promoter activity, mRNA, and protein levels in colon cancer cells. Although HIF-1α was induced by hypoxia, VEGF reporter constructs with selectively mutated hypoxia-response elements remained responsive to hypoxia. In addition, “knockdown” of HIF-1α by RNA interference only minimally inhibited the hypoxic induction of VEGF. A region of the VEGF promoter between −420 and −90 bp mediated this HIF-independent induction by hypoxia. The introduction of K-rasVal12 augmented the hypoxic induction of VEGF, and this was observed in wild-type and HIF-1α knockdown colon cancer cells. Thus, VEGF may be induced by hypoxia through HIF-dependent and HIF-independent pathways, and K-ras also can induce VEGF in hypoxia independent of HIF-1. These findings suggest the existence of multiple mechanisms regulating the hypoxic induction of VEGF in colon cancer.