bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Selective Estrogen Receptor Modulator Arzoxifene and the Rexinoid LG100268 Cooperate to Promote Transforming Growth Factor β-Dependent Apoptosis in Breast Cancer
Authors: Rendi Mara H. , Suh Nanjoo , Lamph William W. , Krajewski Stan , Reed John C. , Heyman Richard A. , Berchuck Andrew , Liby Karen , Risingsong Renee , Royce Darlene B. , Williams Charlotte R. , Sporn Michael B. 
Published: September 2005

Abstract
We show that the selective estrogen receptor modulator arzoxifene (Arz) and the rexinoid LG100268 (268) synergize to promote apoptosis in a rat model of estrogen receptor-positive breast carcinoma and in estrogen receptor-positive human breast cancer cells in culture. We also show that it is not necessary to administer Arz and 268 continuously during tumor progression to prevent cancer in the rat model because dosing of these drugs in combination for relatively short periods, each followed by drug-free rests, is highly effective. This new approach to chemoprevention uses high doses of drugs that are too toxic for long-term administration. However, when given for short periods, the agents are nontoxic and still induce apoptosis in breast cancer cells. We also show that the ability of the two drugs to induce apoptosis is the combined result of induction of transforming growth factor β by Arz, together with inhibition of the prosurvival nuclear factor κB and phosphatidylinositol 3′ kinase signaling pathways by 268. The new protocol we have developed for chemoprevention allows the efficacious and safe administration of 268 and Arz, and these agents now should be considered for clinical use.
DNA Hypomethylation and Ovarian Cancer Biology
Authors: Widschwendter Martin , Jiang Guanchao , Woods Christian , Müller Hannes M. , Fiegl Heidi , Goebel Georg , Marth Christian , Müller-Holzner Elisabeth , Zeimet Alain G. , Laird Peter W. , Ehrlich Melanie 
Published: September 2005

Abstract
Hypomethylation of some portions of the genome and hypermethylation of others are very frequent in human cancer. The hypomethylation often involves satellite 2 (Sat2) DNA in the juxtacentromeric (centromere-adjacent) region of chromosome 1. In this study, we analyzed methylation in centromeric and juxtacentromeric satellite DNA in 115 ovarian cancers, 26 non-neoplastic ovarian specimens, and various normal somatic tissue standards. We found that hypomethylation of both types of satellite DNA in ovarian samples increased significantly from non-neoplastic toward cancer tissue. Furthermore, strong hypomethylation was significantly more prevalent in tumors of advanced stage or high grade. Importantly, extensive hypomethylation of Sat2 DNA in chromosome 1 was a highly significant marker of poor prognosis (relative risk for relapse, 4.1, and death, 9.4) and more informative than tumor grade or stage. Also, comparing methylation of satellite DNA and 15 5′ gene regions, which are often hypermethylated in cancer or implicated in ovarian carcinogenesis, we generally found no positive or negative association between methylation changes in satellite DNA and in the gene regions. However, hypermethylation at two loci, CDH13 (at 16q24) and RNR1 (at 13p12), was correlated strongly with lower levels of Sat2 hypomethylation. The CDH13/Sat2 epigenetic correlation was seen also in breast cancers. We conclude that satellite DNA hypomethylation is an important issue in ovarian carcinogenesis as demonstrated by: (a) an increase from non-neoplastic tissue toward ovarian cancer; (b) an increase within the ovarian cancer group toward advanced grade and stage; and (c) the finding that strong hypomethylation was an independent marker of poor prognosis.
Global Expression Profiling Identifies Signatures of Tumor Virulence in MMTV-PyMT-Transgenic Mice
Authors: Qiu Ting Hu , Chandramouli Gadisetti V. R. , Hunter Kent W. , Alkharouf Nawal W. , Green Jeffrey E. , Liu Edison T. 
Published: September 2005

Abstract
FVB/N-Tg (MMTV-PyMT)634Mul-transgenic mice develop multifocal mammary tumors with a high incidence of pulmonary metastasis. We have demonstrated previously that mammary tumors derived from transgene-positive F1 progeny in particular inbred strains display altered latency, tumor growth rates, and metastatic rates when compared with the FVB/NJ homozygous parent. To identify genes with expression that might be critical in modifying the biological behavior of MMTV-PyMT tumors, we performed a detailed comparative analysis of expression profiles from mammary tumors arising in the parental FVB/NJ background and F1 progeny from crosses with I/LnJ, LP/J, MOLF/Ei, and NZB/B1NJ mice. Compared with normal mammary glands, gene expression profiles of tumors from all five strains exhibited up-regulation of genes involved in cell growth (e.g., Cks1 and CDC25C) and down-regulation of cell adhesion molecules, with many genes associated previously with human breast cancer such as STAT2, CD24 antigen, gelsolin, and lipocalin2. To identify genes with significant variation in expression between the five different genotypes, significance analysis of microarrays (SAM) and one-way ANOVA were used. Three definable groupings of tumors were identified: (a) tumors derived in the LP/J F1 and MOLF/Ei F1 strains in which tumor growth and dissemination are suppressed and latency prolonged; (b) the most aggressive tumors from the FVB/NJ parental strain and I/LnJ F1 genomic backgrounds; and (c) an intermediate virulence phenotype with tumors from NZB/B1NJ–F1 crosses. These array based assessments correlated well with a composite phenotype ranking using a “virulence” index. The gene expression signature that is associated with a high metastatic rate in the mouse contains the same 17 genes described recently as the signature gene set predictive of metastasis in human tumors (1) with 16 of the 17 genes exhibiting the same directional change in expression associated with human metastases. These results demonstrate that the genetic analysis of mouse models of tumorigenesis may be highly relevant to human cancer and that the metastatic phenotype of a tumor may be affected by the germline genetic configuration of the host.
Polymorphisms in DNA Double-Strand Break Repair Genes and Skin Cancer Risk
Authors: Han Jiali , Colditz Graham A. , Samson Leona D. , Hunter David J. 
Published: September 2005

Abstract
UV can cause a wide range of DNA lesions. UVA-induced oxidative DNA damage and blocked DNA replication by UVB-induced photoproducts can lead to double-strand breaks (DSBs). We selected 11 haplotype-tagging single nucleotide polymorphisms in three DSB repair genes XRCC2, XRCC3, and LigaseIV and evaluated their associations with skin cancer risk in a nested case-control study within the Nurses’ Health Study [219 melanoma, 286 squamous cell carcinoma (SCC), 300 basal cell carcinoma (BCC), and 873 controls]. We observed that the XRCC3 18085T (241Met) allele and its associated haplotype were significantly inversely associated with the risks of SCC and BCC, whereas the XRCC3 4552C allele along with its associated haplotype and the XRCC2 30833A allele were significantly associated with increased BCC risk. The LigaseIV 4044T and 4062T alleles were associated with decreased BCC risk; two of four haplotypes were significantly associated with altered BCC risk. A trend toward decreased risk of nonmelanoma skin cancer was found in those harboring a greater number of putative low risk alleles (P for trend, 0.05 for SCC, &lt;0.0001 for BCC). The main effects of these genotypes were essentially null for melanoma risk. This study provides evidence to suggest the role of the DSB repair pathway in skin cancer development, especially for BCC.
A Fully Synthetic Therapeutic Vaccine Candidate Targeting Carcinoma-Associated Tn Carbohydrate Antigen Induces Tumor-Specific Antibodies in Nonhuman Primates
Authors: Lo-Man Richard , Vichier-Guerre Sophie , Perraut Ronald , Dériaud Edith , Huteau Valérie , BenMohamed Lbachir , Diop Ousmane M. , Livingston Philip O. , Bay Sylvie , Leclerc Claude 
Published: September 2005

AbstractWe recently developed an efficient strategy based on a fully synthetic dendrimeric carbohydrate display (multiple antigenic glycopeptide; MAG) to induce anticarbohydrate antibody responses for therapeutic vaccination against cancer. Here, we show the superior efficacy of the MAG strategy over the traditional keyhole limpet hemocyanin glycoconjugate to elicit an anticarbohydrate IgG response against the tumor-associated Tn antigen. We highlight the influence of the aglyconic carrier elements of such a tumor antigen for their recognition by the immune system. Finally, we additionally developed the MAG system by introducing promiscuous HLA-restricted T-helper epitopes and performed its immunological evaluation in nonhuman primates. MAG:Tn vaccines induced in all of the animals strong tumor-specific anti-Tn antibodies that can mediate antibody-dependent cell cytotoxicity against human tumor. Therefore, the preclinical evaluation of the MAG:Tn vaccine demonstrates that it represents a safe and highly promising immunotherapeutic molecularly defined tool for targeting breast, colon, and prostate cancers that express the carbohydrate Tn antigen.
Transcriptional Regulation of Signal Regulatory Protein α1 Inhibitory Receptors by Epidermal Growth Factor Receptor Signaling
Authors: Kapoor Gurpreet S. , Kapitonov Dmitri , O’Rourke Donald M. 
Published: September 2005

Abstract
Signal regulatory protein (SIRP) α1 is a membrane glycoprotein and a member of the SIRP receptor family. These transmembrane receptors have been shown to exert negative effects on signal transduction by receptor tyrosine kinases via immunoreceptor tyrosine-based inhibitory motifs in the carboxyl domain. Previous work has demonstrated that SIRPs negatively regulate many signaling pathways leading to reduction in tumor migration, survival, and cell transformation. Thus, modulation of SIRP expression levels or activity could be of great significance in the field of cancer therapy. The aim of the present study was to determine the factors that regulate levels of SIRPα1 in human glioblastoma cells that frequently overexpress the epidermal growth factor receptor (EGFR) because SIRPs have been shown to negatively regulate EGFR signaling. Northern blot analysis and immunoprecipitation assays showed variable expression levels of endogenous SIRPα transcripts in nine well-characterized glioblastoma cell lines. We examined SIRPα1 regulation in U87MG and U373MG cells in comparison with clonal derivatives that express a truncated form of erbB2, which negatively regulates EGFR signaling by inducing the formation of nonfunctional heterodimeric complexes. Mutant erbB2-expressing cells contained more SIRPα1 mRNA when compared with the parental cells in presence or absence of serum. Similarly, immunoprecipitation assays showed increased SIRPα1 protein levels in erbB-inhibited cells when compared with parental cells. Messenger RNA stability assays revealed that the increased mRNA levels in EGFR-inhibited cells were due to an induction of transcription. Consistent with this finding, expression of the erbB2 mutant receptor up-regulated SIRPα1 promoter activity in all cell lines tested. Interestingly, pharmacological inhibition of the kinase activities of EGFR, erbB2, and src and activation of mitogen-activated protein kinase, but not phosphatidylinositol 3′-kinase, significantly up-regulated SIRPα1 promoter activity. Based on these observations, we hypothesize that down-modulation of EGFR signaling leads to transcriptional up-regulation of the inhibitory SIRPα1 gene. These data may be important in the application of erbB-inhibitory strategies and for design of therapies for the treatment of glial tumors and other epithelial malignancies.
Assessing Tumor Angiogenesis
Authors: Rabascio Cristina , Muratori Elisabetta , Mancuso Patrizia , Calleri Angelica , Raia Valentina , Foutz Thomas , Cinieri Saverio , Veronesi Giulia , Pruneri Giancarlo , Lampertico Pietro , Iavarone Massimo , Martinelli Giovanni , Goldhirsch Aron , Bertolini Francesco 
Published: September 2005

Abstract
No markers are currently available to indicate the angiogenic profile of a specific malignant disease nor to predict response to antiangiogenic therapies. Nevertheless, many different antiangiogenic drugs are presently being tested in many clinical trials, with an obvious scarcity of useful endpoints for treatment outcome beside survival. By means of a quantitative reverse transcription-PCR approach, we measured VE-cadherin (VE-C), Tie-2, vascular endothelial growth factor receptor 2 and CD133 RNA in the blood of 14 healthy controls, 3 pregnant women, and 84 newly diagnosed (or relapsed) cancer patients. Circulating VE-C RNA was increased in pregnant women and cancer patients (P = 0.0002). VE-C RNA was particularly increased in patients affected by hematological malignancies and decreased to normal values in patients achieving complete remission. Conversely, circulating RNA levels of other endothelial or progenitor cell-specific markers Tie-2, vascular endothelial growth factor receptor 2, and CD133 were not significantly increased in either pregnant women or cancer patients. Comparison of various surrogate angiogenesis markers indicated a switch toward increased plasma vascular endothelial growth factor (VEGF) levels, viable circulating endothelial cells, and circulating VE-C RNA levels in patients affected by hematological malignancies. Taken together, our data indicate that the quantitative evaluation of circulating VE-C RNA is a specific and highly promising tool with which to investigate the angiogenic phenotype of cancer patients.
Phosphorylation of Akt (Ser473) is an Excellent Predictor of Poor Clinical Outcome in Prostate Cancer
Authors: Kreisberg Jeffrey I. , Malik Shazli N. , Prihoda Thomas J. , Bedolla Roble G. , Troyer Dean A. , Kreisberg Suzanne , Ghosh Paramita M. 
Published: September 2005

Abstract
We previously showed, by immunohistochemistry with phospho-specific antibodies, increased phosphorylation (activation) of Akt (Ser473) [phosphorylated Akt (pAkt)] in high-Gleason grade prostate cancer (Malik SN, et al., Clin Cancer Res 2002;8:1168–71). Elevation of pAkt was accompanied by decreased phosphorylation of extracellular signal-regulated kinase (ERK) 1/2 (Thr202/Tyr204) [phosphorylated ERK (pERK)], indicative of inactivation. In this report, we determined whether increased pAkt and decreased pERK predicted clinical outcome. Prostate-specific antigen (PSA) failure (detectable and rising PSA) versus PSA non-failure (undetectable PSA 5 years after prostatectomy) was used as a surrogate for clinical outcome. Prostate tumors from cases of PSA failure versus non-failure were stained for pAkt and pERK. A significant increase in mean pAkt staining (P &lt; 0.001) in the PSA failures versus non-failures was seen based on the Wilcoxon signed ranks test [222.18 ± 33.9 (n = 37) versus 108.79 ± 104.57 (n = 16)]. Using the best-fitting multiple logistic regression equation, a 100-point increase in pAkt staining resulted in a 160% increase in the odds of being a PSA failure. There was decreased staining for pERK in PSA failures versus non-failures: a 100-point decrease resulted in an 80% increase in the odds of being a PSA failure. Each of these effects assumed the other biomarker was held constant. The area under the receiver-operating characteristic curve for these two biomarkers predicting PSA failure was 0.84, indicating excellent discrimination between PSA failure and non-failure cases. These data indicate that increased pAkt, alone or together with decreased pERK, is an important predictor of probability of PSA failure. However, pERK alone was not a significant predictor of PSA failure.
KAI1 COOH-Terminal Interacting Tetraspanin (KITENIN), a Member of the Tetraspanin Family, Interacts with KAI1, a Tumor Metastasis Suppressor, and Enhances Metastasis of Cancer
Authors: Lee Ji Hee , Park Sei Ryun , Chay Kee-Oh , Seo Young-Woo , Kook Hyun , Ahn Kyu Youn , Kim Young Jin , Kim Kyung Keun 
Published: September 2005

Abstract
We cloned recently an alternatively spliced variant of KAI1 mRNA that lacked exon 7 at the COOH-terminal region and showed differences in metastasis suppression when compared with the wild-type KAI1. These findings indicated that the COOH-terminal region of KAI1 is critical for its metastasis suppressor function. In this study, we isolated a cDNA clone of VANGL1, a member of the tetraspanin protein family, which interacted specifically with the COOH-terminal cytoplasmic domain of KAI1 in the yeast two-hybrid system. We renamed it KAI1 COOH-terminal interacting tetraspanin (KITENIN). We found that KITENIN-overexpressing CT-26 mouse colon cancer cells showed increased tumorigenicity and early hepatic metastasis in vivo, as well as increased invasiveness and adhesion to fibronectin in vitro compared with parental cells. Moreover, increased levels of KITENIN were observed in a human gastric tumor and its metastatic tissues, compared with the normal adjacent mucosa. Our results indicate that KITENIN promotes adhesion and invasion of cancer cells in vitro and in vivo, and suggest that KITENIN participates in the regulation of the tumor formation and metastasis by interacting with KAI1, a metastasis suppressor and antisense KITENIN strategy that can be used to inhibit metastasis in various cancers.
Hyperforin Inhibits Cancer Invasion and Metastasis
Authors: Donà Massimo , Dell’Aica Isabella , Pezzato Elga , Sartor Luigi , Calabrese Fiorella , Barbera Mila Della , Donella-Deana Arianna , Appendino Giovanni , Borsarini Anna , Caniato Rosy , Garbisa Spiridione 
Published: September 2005

AbstractHyperforin (Hyp), the major lipophilic constituent of St. John’s wort, was assayed as a stable dicyclohexylammonium salt (Hyp-DCHA) for cytotoxicity and inhibition of matrix proteinases, tumor invasion, and metastasis. Hyp-DCHA triggered apoptosis-associated cytotoxic effect in both murine (C-26, B16-LU8, and TRAMP-C1) and human (HT-1080 and SK-N-BE) tumor cells; its effect varied, with B16-LU8, HT-1080, and C-26 the most sensitive (IC50 = 5 to 8 μmol/L). At these concentrations, a marked and progressive decline of growth was observed in HT-1080 cells, whereas untransformed endothelial cells were only marginally affected. Hyp-DCHA inhibited in a dose-dependent and noncompetitive manner various proteinases instrumental to extracellular matrix degradation; the activity of leukocyte elastase was inhibited the most (IC50 = 3 μmol/L), followed by cathepsin G and urokinase-type plasminogen activator, whereas that of the matrix metalloproteinases (MMPs) 2 and 9 showed an IC50 &gt; 100 μmol/L. Nevertheless, inhibition of extracellular signal-regulated kinase 1/2 constitutive activity and reduction of MMP-2 and MMP-9 secretion was triggered by 0.5 μmol/L Hyp-DCHA to various degrees in different cell lines, the most in C-26. Inhibition of C-26 and HT-1080 cell chemoinvasion (80 and 54%, respectively) through reconstituted basement membrane was observed at these doses. Finally, in mice that received i.v. injections of C-26 or B16-LU8 cells, daily i.p. administration of Hyp-DCHA—without reaching tumor-cytotoxic blood levels—remarkably reduced inflammatory infiltration, neovascularization, lung weight (−48%), and size of experimental metastases with C-26 (−38%) and number of lung metastases with B16-LU8 (−22%), with preservation of apparently healthy and active behavior. These observations qualify Hyp-DCHA as an interesting lead compound to prevent and contrast cancer spread and metastatic growth.
The Human Glutathione
S
-Transferase P1 Protein Is Phosphorylated and Its Metabolic Function Enhanced by the Ser/Thr Protein Kinases, cAMP-Dependent Protein Kinase and Protein Kinase C, in Glioblastoma Cells
Authors: Lo Hui-Wen , Antoun Gamil R. , Ali-Osman Francis 
Published: September 2005

Abstract
We report here that the human glutathione S-transferase P1 (GSTP1) protein, involved in phase II metabolism of many carcinogens and anticancer agents and in the regulation of c-Jun NH2-terminal kinase-mediated cell signaling, undergoes phosphorylation by the Ser/Thr protein kinases, cAMP-dependent protein kinase (PKA) and protein kinase C (PKC), resulting in a significant enhancement of its metabolic activity. GSTP1 phosphorylation by PKA was glutathione (GSH)-dependent, whereas phosphorylation by PKC did not require but was significantly enhanced by GSH. In the presence of GSH, the stoichiometry of phosphorylation was 0.4 ± 0.03 and 0.53 ± 0.02 mol incorporated phosphate per mole of dimeric GSTP1 protein. The GSTP1 protein was phosphorylated, in the presence of GSH, by eight different PKC isoforms (α, βΙ, βΙΙ, δ, ε, γ, η, and ζ), belonging to the three major PKC subclasses, albeit with various efficiencies. The catalytic efficiency, kcat/Km, of the phosphorylated GSTP1 was more than double that of the unphosphorylated protein. In MGR3 human glioblastoma cells, PKA and PKC activation resulted in a significant increase in the level of phosphorylation of the GSTP1 protein and was accompanied by a 2.1- and 2.7-fold increase, respectively, in specific GSTP1 activity in the cells. Peptide phosphorylation analyses and both phosphorylation and enzyme kinetic studies with GSTP1 proteins mutated at candidate amino acid residues established Ser-42 and Ser-184 as putative phospho-acceptor residues for both kinases in the GSTP1 protein. Together, these findings show PKA- and PKC-dependent phosphorylation as a significant post-translational mechanism of regulation of GSTP1 function. The GSH-dependence of the phosphorylation suggests that under high intracellular GSH conditions, such as is present in most drug-resistant tumors, the GSTP1 protein will exist in a hyper-phosphorylated and enzymatically more active state. In normal cells, the functional activation of the GSTP1 protein by PKA- and PKC-dependent phosphorylation could represent a potentially important mechanism of cellular protection, whereas in tumors, increased phase II metabolism of anticancer drugs by the more active phosphorylated GSTP1 protein could contribute to the drug resistance and therapeutic failure frequently associated with increased activities of these Ser/Thr kinases.
Antiangiogenic Properties of Fibstatin, an Extracellular FGF-2–Binding Polypeptide
Authors: Bossard Carine , Berghe Loic Van den , Laurell Henrik , Castano Caroline , Cerutti Martine , Prats Anne-Catherine , Prats Hervé 
Published: September 2005

Abstract
By using the two-hybrid system with basic fibroblast growth factor (FGF-2) as bait, we isolated and characterized fibstatin, an endogenous Mr 29,000 human basement membrane-derived inhibitor of angiogenesis and tumor growth. Fibstatin, a fragment containing the type III domains 12–14 of fibronectin, was produced as a recombinant protein and was shown to inhibit the proliferation, migration, and differentiation of endothelial cells in vitro. Antiangiogenic activity of fibstatin was confirmed in a Matrigel angiogenesis assay in vivo, and electrotransfer of the fibstatin gene into muscle tissue resulted in reduced B16F10 tumor growth. Taken together, these results suggest that fibstatin could act as a powerful molecule for antiangiogenic therapy.