bluuebunny/crossref_metadata_2025_split huggingface dataset:
Gene Amplification and Overexpression of PRDM14 in Breast Cancers
Authors: Nishikawa Noriko , Toyota Minoru , Suzuki Hiromu , Honma Toshio , Fujikane Tomoko , Ohmura Tousei , Nishidate Toshihiko , Ohe-Toyota Mutsumi , Maruyama Reo , Sonoda Tomoko , Sasaki Yasushi , Urano Takeshi , Imai Kohzoh , Hirata Koichi , Tokino Takashi 
Published: October 2007

Abstract
Several genes that encode PR (PRDI-BF1 and RIZ) domain proteins (PRDM) have been linked to human cancers. To explore the role of the PR domain family genes in breast carcinogenesis, we examined the expression profiles of 16 members of the PRDM gene family in a panel of breast cancer cell lines and primary breast cancer specimens using semiquantitative real-time PCR. We found that PRDM14 mRNA is overexpressed in about two thirds of breast cancers; moreover, immunohistochemical analysis showed that expression of PRDM14 protein is also up-regulated. Analysis of the gene copy number revealed that PRDM14 is a target of gene amplification on chromosome 8q13, which is a region where gene amplification has frequently been detected in various human tumors. Introduction of PRDM14 into cancer cells enhanced cell growth and reduced their sensitivity to chemotherapeutic drugs. Conversely, knockdown of PRDM14 by siRNA induced apoptosis in breast cancer cells and increased their sensitivity to chemotherapeutic drugs, suggesting that up-regulated expression of PRDM14 may play an important role in the proliferation of breast cancer cells. That little or no expression of PRDM14 is seen in noncancerous tissues suggests that PRDM14 could be an ideal therapeutic target for the treatment of breast cancer. [Cancer Res 2007;67(20):9649–57]
Thymic Stromal-Derived Lymphopoietin Induces Proliferation of Pre-B Leukemia and Antagonizes mTOR Inhibitors, Suggesting a Role for Interleukin-7Rα Signaling
Authors: Brown Valerie I. , Hulitt Jessica , Fish Jonathan , Sheen Cecilia , Bruno Marlo , Xu Qing , Carroll Martin , Fang Junjie , Teachey David , Grupp Stephan A. 
Published: October 2007

AbstractUnderstanding the pathogenesis of leukemia in the context of lymphopoiesis may reveal novel therapeutic targets. Previously, we have shown that mTOR inhibitors (MTI) show activity in vitro and in preclinical models of both human and murine precursor B acute lymphoblastic leukemia (pre-B ALL), inhibiting cell proliferation and inducing apoptosis. These MTI-mediated effects can be reversed by interleukin-7 (IL-7), an important regulator of early B-cell development. This observation led us to examine the contribution of signaling via the IL-7Rα chain, which is shared by the receptor complexes of IL-7 and thymic stromal-derived lymphopoietin (TSLP). TSLP is closely related to IL-7 and active in lymphopoiesis, but an effect of TSLP on leukemia cells has not been described. We examined the effect of TSLP on pre-B ALL cells and their response to MTIs. Here, we show that TSLP stimulates proliferation of pre-B ALL cell lines. TSLP also partially reverses the effects of MTI on proliferation, apoptosis, and ribosomal protein S6 and 4E-BP1 phosphorylation in cell lines, with similar biological effects seen in some primary human lymphoblast samples. These data show that TSLP can promote survival of pre-B ALL cells and antagonize the effects of MTIs. These findings suggest that IL-7Rα chain is responsible for transducing the survival signal that overcomes MTI-mediated growth inhibition in pre-B ALL. Thus, further exploration of the IL-7Rα pathway may identify potential therapeutic targets in the treatment of ALL. Our data illustrate that growth-factor–mediated signaling may provide one mechanism of MTI resistance. [Cancer Res 2007;67(20):9963–70]
Opposing Roles of Murine Duffy Antigen Receptor for Chemokine and Murine CXC Chemokine Receptor-2 Receptors in Murine Melanoma Tumor Growth
Authors: Horton Linda W. , Yu Yingchun , Zaja-Milatovic Snjezana , Strieter Robert M. , Richmond Ann 
Published: October 2007

AbstractThe Duffy antigen receptor for chemokines (DARC) has been classified as a “silent” receptor, as it can bind CXC and CC chemokines to undergo ligand-induced receptor internalization, but is not coupled to trimeric G proteins required for the classic G protein–coupled receptor–mediated signaling. CXC chemokine receptor-2 (CXCR2) has been shown to play a major role in tumor angiogenesis. To test the hypothesis that these two chemokine receptors might play opposing roles in the growth of melanoma tumors, we developed a transgenic mouse model, where the preproendothelin promoter/enhancer (PPEP) is used to drive expression of either murine DARC (mDARC) or murine CXCR2 (mCXCR2) in endothelial cells. We show herein that the growth of melanoma tumor xenografts, established from s.c. injection of immortalized murine melanocytes overexpressing macrophage inflammatory protein-2, was inhibited or enhanced in the PPEP-mDARC and PPEP-mCXCR2 transgenic mice, respectively, compared with control mice. The early tumors formed in mDARC transgenic mice exhibited a significantly higher number of infiltrating leukocytes compared with either the control or mCXCR2 transgenic mice, suggesting a potential role for DARC expressed on endothelial cells in leukocyte migration. In addition, the tumor-associated angiogenesis in mDARC transgenic mice was reduced when compared with the control. Conversely, tumor angiogenesis was significantly increased in mCXCR2 transgenic mice. Results indicate that endothelial cell overexpression of mDARC increased leukocyte trafficking to the tumor, reduced the growth of blood vessels into the tumor, and reduced the growth rate of the tumor, whereas endothelial cell overexpression of mCXCR2 had the reverse effect on tumor angiogenesis and growth. [Cancer Res 2007;67(20):9791–9]
CUL7 Is a Novel Antiapoptotic Oncogene
Authors: Kim Sam S. , Shago Mary , Kaustov Lilia , Boutros Paul C. , Clendening James W. , Sheng Yi , Trentin Grace A. , Barsyte-Lovejoy Dalia , Mao Daniel Y.L. , Kay Robert , Jurisica Igor , Arrowsmith Cheryl H. , Penn Linda Z. 
Published: October 2007

Abstract
Using an expression cloning approach, we identify CUL7, a member of the cullin family, as a functional inhibitor of Myc-induced apoptosis. Deregulated expression of the Myc oncogene drives cellular proliferation yet also sensitizes cells to undergo p53-dependent and p53-independent apoptosis. Here, we report that CUL7 exerts its antiapoptotic function through p53. CUL7 binds directly to p53, and small interfering RNA–mediated knockdown of CUL7 results in the elevation of p53 protein levels. This antiapoptotic role of CUL7 enables this novel oncogene to cooperate with Myc to drive transformation. Deregulated ectopic expression of c-Myc and CUL7 promotes Rat1a cell growth in soft agar, and knockdown of CUL7 significantly blocks human neuroblastoma SHEP cell growth in an anchorage-independent manner. Furthermore, using public microarray data sets, we show that CUL7 mRNA is significantly overexpressed in non–small cell lung carcinoma and is associated with poor patient prognosis. We provide experimental evidence to show CUL7 is a new oncogene that cooperates with Myc in transformation by blocking Myc-induced apoptosis in a p53-dependent manner. [Cancer Res 2007;67(20):9616–22]
Batracylin (NSC 320846), a Dual Inhibitor of DNA Topoisomerases I and II Induces Histone γ-H2AX as a Biomarker of DNA Damage
Authors: Rao V. Ashutosh , Agama Keli , Holbeck Susan , Pommier Yves 
Published: October 2007

Abstract
Batracylin (8-aminoisoindolo [1,2-b]quinazolin-10(12H)-one; NSC320846) is an investigational clinical anticancer agent. Previous animal studies showed activity against solid tumors and Adriamycin-resistant leukemia. We initially sought to test the proposed Top2-mediated DNA cleavage activity of batracylin and identify potential biomarkers for activity. COMPARE analysis in the NCI-60 cell lines showed batracylin activity to be most closely related to the class of Top2 inhibitors. The 50% growth inhibition (GI50) value for batracylin in HT29 colon carcinoma cells was 10 μmol/L. DNA-protein cross-links, consistent with Top2 targeting, were measured by alkaline elution. DNA single-strand breaks were also detected and found to be protein associated. However, only a weak induction of DNA double-strand breaks was observed. Because batracylin induced almost exclusively DNA single-strand breaks, we tested batracylin as a Top1 inhibitor. Batracylin exhibited both Top1- and Top2α/β-mediated DNA cleavage in vitro and in cells. The phosphorylation of histone (γ-H2AX) was tested to measure the extent of DNA damage. Kinetics of γ-H2AX “foci” showed early activation with low μmol/L concentrations, thus presenting a useful early biomarker of DNA damage. The half-life of γ-H2AX signal reversal after drug removal was consistent with reversal of DNA-protein cross-links. The persistence of the DNA-protein complexes induced by batracylin was markedly longer than by etoposide or camptothecin. The phosphorylated DNA damage–responsive kinase, ataxia telangiectasia mutated, was also found activated at sites of γ-H2AX. The cell cycle checkpoint kinase, Chk2, was only weakly phosphorylated. Thus, batracylin is a dual Top1 and Top2 inhibitor and γ-H2AX could be considered a biomarker in the ongoing clinical trials. [Cancer Res 2007;67(20):9971–9]
A Human CD4 Monoclonal Antibody for the Treatment of T-Cell Lymphoma Combines Inhibition of T-Cell Signaling by a Dual Mechanism with Potent Fc-Dependent Effector Activity
Authors: Rider David A. , Havenith Carin E.G. , de Ridder Ruby , Schuurman Janine , Favre Cedric , Cooper Joanne C. , Walker Simon , Baadsgaard Ole , Marschner Susanne , vandeWinkel Jan G.J. , Cambier John , Parren Paul W.H.I. , Alexander Denis R. 
Published: October 2007

AbstractZanolimumab is a human IgG1 antibody against CD4, which is in clinical development for the treatment of cutaneous and nodal T-cell lymphomas. Here, we report on its mechanisms of action. Zanolimumab was found to inhibit CD4+ T cells by combining signaling inhibition with the induction of Fc-dependent effector mechanisms. First, T-cell receptor (TCR) signal transduction is inhibited by zanolimumab through a fast, dual mechanism, which is activated within minutes. Ligation of CD4 by zanolimumab effectively inhibits early TCR signaling events but, interestingly, activates signaling through the CD4-associated tyrosine kinase p56lck. An uncoupling of p56lck from the TCR by anti-CD4 allows the kinase to transmit direct inhibitory signals via the inhibitory adaptor molecules Dok-1 and SHIP-1. Second, CD4+ T cells are killed by induction of antibody-dependent cell-mediated cytotoxicity, to which CD45RO+ cells are more sensitive than CD45RA+ cells. Finally, zanolimumab induces down-modulation of CD4 from cell surfaces via a slow Fc-dependent mechanism. In conclusion, zanolimumab rapidly inhibits T-cell signaling via a dual mechanism of action combined with potent Fc-dependent lysis of CD4+ T cells and may act long-term by down-regulating CD4. [Cancer Res 2007;67(20):9945–53]
A Novel Small Molecule Inhibitor of Signal Transducers and Activators of Transcription 3 Reverses Immune Tolerance in Malignant Glioma Patients
Authors: Hussain S. Farzana , Kong Ling-Yuan , Jordan Justin , Conrad Charles , Madden Timothy , Fokt Isabella , Priebe Waldemar , Heimberger Amy B. 
Published: October 2007

AbstractOvercoming the profound immunosuppression in patients with solid cancers has impeded efficacious immunotherapy. Signal transducers and activators of transcription 3 (STAT3) has recently emerged as a potential target for effective immunotherapy, and in this study, we describe a novel small molecule inhibitor of STAT3 that can penetrate the central nervous system (CNS) in mice and in physiologically relevant doses in vitro and reverse tolerance in immune cells isolated from glioblastoma multiforme (GBM) patients. Specifically, it induces the expression of costimulatory molecules on peripheral macrophages and tumor-infiltrating microglia, stimulates the production of the immune-stimulatory cytokines interleukin 2 (IL-2), IL-4, IL-12, and IL-15, and induces proliferation of effector T cells from GBM patients that are refractory to CD3 stimulation. We show that the functional enhancement of immune responses after STAT3 inhibition is accompanied by up-regulation of several key intracellular signaling molecules that critically regulate T-cell and monocyte activation. Specifically, the phosphorylation of Syk (Tyr352) in monocytes and ZAP-70 (Tyr319) in T cells are enhanced by the STAT-3 inhibitor in marked contrast to toll-like receptor and T-cell receptor agonists, respectively. This novel small molecule STAT3 inhibitor has tremendous potential for clinical applications with its penetration into the CNS, easy parental administration, direct tumor cytotoxicity, and potent immune adjuvant responses in immunosuppressed cancer patients. [Cancer Res 2007;67(20):9630–6]
In vivo Functional Analysis of the Counterbalance of Hyperactive Phosphatidylinositol 3-Kinase p110 Catalytic Oncoproteins by the Tumor Suppressor PTEN
Authors: Andrés-Pons Amparo , Rodríguez-Escudero Isabel , Gil Anabel , Blanco Ana , Vega Ana , Molina María , Pulido Rafael , Cid Víctor J. 
Published: October 2007

Abstract
The signaling pathways involving class I phosphatidylinositol 3-kinases (PI3K) and the phosphatidylinositol-(3,4,5)-trisphosphate phosphatase PTEN regulate cell proliferation and survival. Thus, mutations in the corresponding genes are associated to a wide variety of human tumors. Heterologous expression of hyperactive forms of mammalian p110α and p110β in Saccharomyces cerevisiae leads to growth arrest, which is counterbalanced by coexpression of mammalian PTEN. Using this in vivo yeast-based system, we have done an extensive functional analysis of germ-line and somatic human PTEN mutations, as well as a directed mutational analysis of discrete PTEN functional domains. A distinctive penetrance of the PTEN rescue phenotype was observed depending on the levels of PTEN expression in yeast and on the combinations of the inactivating PTEN mutations and the activating p110α or p110β mutations analyzed, which may reflect pathologic differences found in tumors with distinct alterations at the p110 and PTEN genes or proteins. We also define the minimum length of the PTEN protein required for stability and function in vivo. In addition, a random mutagenesis screen on PTEN based on this system allowed both the reisolation of known clinically relevant PTEN mutants and the identification of novel PTEN loss-of-function mutations, which were validated in mammalian cells. Our results show that the PI3K/PTEN yeast-based system is a sensitive tool to test in vivo the pathologic properties and the functionality of mutations in the human p110 proto-oncogenes and the PTEN tumor suppressor and provide a framework for comprehensive functional studies of these tumor-related enzymes. [Cancer Res 2007;67(20):9731–9]
Suppression of Epidermal Growth Factor Receptor Signaling by Protein Kinase C-α Activation Requires CD82, Caveolin-1, and Ganglioside
Authors: Wang Xiao-qi , Yan Qiu , Sun Ping , Liu Ji-Wei , Go Linda , McDaniel Shauntae M. , Paller Amy S. 
Published: October 2007

Abstract
Activation of protein kinase C (PKC)-α decreases normal and neoplastic cell proliferation by inhibiting epidermal growth factor receptor (EGFR)-related signaling. The molecular interactions upstream to PKC-α that influence its suppression of EGFR, however, are poorly understood. We have found that caveolin-1, tetraspanin CD82, and ganglioside GM3 enable the association of EGFR with PKC-α, ultimately leading to inhibition of EGFR signaling. GM3- and CD82-induced inhibition of EGFR signaling requires PKC-α translocation and serine/threonine phosphorylation, which eventually triggers EGFR Thr654 phosphorylation and receptor internalization. Within this ordered complex of signaling molecules, the ability of CD82 to associate with PKC-α requires the presence of caveolin-1, whereas the interaction of caveolin-1 or PKC-α with EGFR requires the presence of CD82 and ganglioside GM3. Disruption of the membrane with methyl-β-cyclodextrin dissociates the EGFR/GM3/caveolin-1/CD82/PKC-α complex and prevents the inhibitory effect of PKC-α on EGFR phosphorylation, suggesting that caveolin-1, CD82, and ganglioside interact with EGFR and PKC-α within intact cholesterol-enriched membrane microdomains. Given the role of these membrane molecules in suppressing EGFR signaling, up-regulation of GM3, caveolin-1, and CD82 function may be an effective adjunctive therapy for treating epithelial cell malignancies. [Cancer Res 2007;67(20):9986–95]
MAGE-A, mMage-b, and MAGE-C Proteins Form Complexes with KAP1 and Suppress p53-Dependent Apoptosis in MAGE-Positive Cell Lines
Authors: Yang Bing , O'Herrin Sean M. , Wu Jianqiang , Reagan-Shaw Shannon , Ma Yongsheng , Bhat Kumar M.R. , Gravekamp Claudia , Setaluri Vijayasaradhi , Peters Noel , Hoffmann F. Michael , Peng Hongzhuang , Ivanov Alexey V. , Simpson Andrew J.G. , Longley B. Jack 
Published: October 2007

Abstract
The MAGE-A, MAGE-B, and MAGE-C protein families comprise the class-I MAGE/cancer testes antigens, a group of highly homologous proteins whose expression is suppressed in all normal tissues except developing sperm. Aberrant expression of class I MAGE proteins occurs in melanomas and many other malignancies, and MAGE proteins have long been recognized as tumor-specific targets; however, their functions have largely been unknown. Here, we show that suppression of class I MAGE proteins induces apoptosis in the Hs-294T, A375, and S91 MAGE-positive melanoma cell lines and that members of all three families of MAGE class I proteins form complexes with KAP1, a scaffolding protein that is known as a corepressor of p53 expression and function. In addition to inducing apoptosis, MAGE suppression decreases KAP1 complexing with p53, increases immunoreactive and acetylated p53, and activates a p53 responsive reporter gene. Suppression of class I MAGE proteins also induces apoptosis in MAGE-A–positive, p53wt/wt parental HCT 116 colon cancer cells but not in a MAGE-A–positive HCT 116 p53−/− variant, indicating that MAGE suppression of apoptosis requires p53. Finally, treatment with MAGE-specific small interfering RNA suppresses S91 melanoma growth in vivo, in syngenic DBA2 mice. Thus, class I MAGE protein expression may suppress apoptosis by suppressing p53 and may actively contribute to the development of malignancies and by promoting tumor survival. Because the expression of class I MAGE proteins is limited in normal tissues, inhibition of MAGE antigen expression or function represents a novel and specific treatment for melanoma and diverse malignancies. [Cancer Res 2007;67(20):9954–62]
Nek2 as an Effective Target for Inhibition of Tumorigenic Growth and Peritoneal Dissemination of Cholangiocarcinoma
Authors: Kokuryo Toshio , Senga Takeshi , Yokoyama Yukihiro , Nagino Masato , Nimura Yuji , Hamaguchi Michinari 
Published: October 2007

Abstract
We investigated the role of Nek2, a member of the serine/threonine kinase family, Nek, in the tumorigenic growth of cholangiocarcinoma cells. Expression of Nek2 is elevated in cholangiocarcinoma in a tumor-specific manner as compared with that of normal fibroblast cells. Expression of exogenous Nek2 did not perturb the growth of cholangiocarcinoma cells, whereas suppression of the Nek2 expression with siRNA resulted in the inhibition of cell proliferation and induced cell death. In xenograft-nude mouse model, s.c. injection of Nek2 siRNA around the tumor nodules resulted in reduction of tumor size as compared with those of control siRNA injection. In peritoneal dissemination model, Nek2 siRNA–treated mice showed statistically longer survival periods in comparison with those of the control siRNA–treated mice. Taken together, our data indicate a pivotal role of Nek2 in tumorigenic growth of cholangiocarcinoma. [Cancer Res 2007;67(20):9637–42]
Bcl-2 Orchestrates a Cross-talk between Endothelial and Tumor Cells that Promotes Tumor Growth
Authors: Kaneko Tomoatsu , Zhang Zhaocheng , Mantellini Maria G. , Karl Elisabeta , Zeitlin Benjamin , Verhaegen Monique , Soengas María S. , Lingen Mark , Strieter Robert M. , Nunez Gabriel , Nör Jacques E. 
Published: October 2007

AbstractThe current understanding of the interaction between the endothelium and cancer cells is fundamentally based on the concept that endothelial cells are responsive to differentiation and survival signals originating from the tumor cells. Whereas the effect of tumor cell–secreted factors on angiogenesis is well established, little is known about the effect of factors secreted by endothelial cells on tumor cell gene expression and tumor progression. Here, we show that bcl-2 gene expression is significantly higher in the tumor-associated endothelial cells of patients with head and neck squamous cell carcinomas (HNSCC) as compared with endothelial cells from the normal oral mucosa. Bcl-2 induces vascular endothelial growth factor (VEGF) expression in neovascular endothelial cells through a signal transducer and activator of transcription 3 (STAT3)–mediated pathway. Endothelial cell–derived VEGF signals through VEGFR1 and induces expression of Bcl-2 and the proangiogenic chemokines CXCL1 and CXCL8 in HNSCC cells. Notably, inhibition of Bcl-2 expression in neovascular endothelial cells with RNA interference down-regulates expression of Bcl-2, CXCL8, and CXCL1 in HNSCC cells, and is sufficient to inhibit growth and decrease the microvessel density of xenografted HNSCC in immunodeficient mice. Together, these results show that Bcl-2 is the orchestrator of a cross-talk between neovascular endothelial cells and tumor cells, which has a direct effect on tumor growth. This work identifies a new function for Bcl-2 in cancer biology that is beyond its classic role in cell survival. [Cancer Res 2007;67(20):9685–93]
Transforming Growth Factor-β Promotes Survival of Mammary Carcinoma Cells through Induction of Antiapoptotic Transcription Factor DEC1
Authors: Ehata Shogo , Hanyu Aki , Hayashi Makoto , Aburatani Hiroyuki , Kato Yukio , Fujime Makoto , Saitoh Masao , Miyazawa Keiji , Imamura Takeshi , Miyazono Kohei 
Published: October 2007

Abstract
Transforming growth factor-β (TGF-β) signaling facilitates tumor growth and metastasis in advanced cancer. In the present study, we identified differentially expressed in chondrocytes 1 (DEC1, also known as SHARP2 and Stra13) as a downstream target of TGF-β signaling, which promotes the survival of breast cancer cells. In the mouse mammary carcinoma cell lines JygMC(A) and 4T1, the TGF-β type I receptor kinase inhibitors A-44-03 and SB431542 induced apoptosis of cells under serum-free conditions. Oligonucleotide microarray and real-time reverse transcription-PCR analyses revealed that TGF-β induced DEC1 in these cells, and the increase of DEC1 was suppressed by the TGF-β type I receptor kinase inhibitors as well as by expression of dominant-negative TGF-β type II receptor. Overexpression of DEC1 prevented the apoptosis of JygMC(A) cells induced by A-44-03, and knockdown of endogenous DEC1 abrogated TGF-β–promoted cell survival. Moreover, a dominant-negative mutant of DEC1 prevented lung and liver metastasis of JygMC(A) cells in vivo. Our observations thus provide new insights into the molecular mechanisms governing TGF-β–mediated cell survival and metastasis of cancer. [Cancer Res 2007;67(20):9694–703]