bluuebunny/crossref_metadata_2025_split huggingface dataset:
Repression of NHE1 Expression by PPARγ Activation Is a Potential New Approach for Specific Inhibition of the Growth of Tumor CellsIn vitroandIn vivo
Authors: Kumar Alan Prem , Quake Ai Li , Chang Michelle Ker Xing , Zhou Ting , Lim Kelly Swee Ying , Singh Rajeev , Hewitt Robert Edwin , Salto-Tellez Manuel , Pervaiz Shazib , Clément Marie-Véronique 
Published: November 2009

AbstractLigand-induced activation of peroxisome proliferator-activated receptor γ (PPARγ) inhibits proliferation in cancer cells in vitro and in vivo; however, the downstream targets remain undefined. We report the identification of a peroxisome proliferator response element in the promoter region of the Na+/H+ transporter gene NHE1, the overexpression of which has been associated with carcinogenesis. Exposure of breast cancer cells expressing high levels of PPARγ to its natural and synthetic agonists resulted in downregulation of NHE1 transcription as well as protein expression. Furthermore, the inhibitory effect of activated PPARγ on tumor colony-forming ability was abrogated on overexpression of NHE1, whereas small interfering RNA–mediated gene silencing of NHE1 significantly increased the sensitivity of cancer cells to growth-inhibitory stimuli. Finally, histopathologic analysis of breast cancer biopsies obtained from patients with type II diabetes treated with the synthetic agonist rosiglitazone showed significant repression of NHE1 in the tumor tissue. These data provide evidence for tumor-selective downregulation of NHE1 by activated PPARγ in vitro and in pathologic specimens from breast cancer patients and could have potential implications for the judicious use of low doses of PPARγ ligands in combination chemotherapy regimens for an effective therapeutic response. [Cancer Res 2009;69(22):8636–44]
Epigenetic Silencing of Interferon-κ in Human Papillomavirus Type 16–Positive Cells
Authors: Rincon-Orozco Bladimiro , Halec Gordana , Rosenberger Simone , Muschik Dorothea , Nindl Ingo , Bachmann Anastasia , Ritter Tina Maria , Dondog Bolormaa , Ly Regina , Bosch Franz X. , Zawatzky Rainer , Rösl Frank 
Published: November 2009

Abstract
We have investigated interferon-κ (IFN-κ) regulation in the context of human papillomavirus (HPV)–induced carcinogenesis using primary human foreskin keratinocytes (HFK), immortalized HFKs encoding individual oncoproteins of HPV16 (E6, E7, and E6/E7), and cervical carcinoma cells. Here, IFN-κ was suppressed in the presence of E6, whereas its expression was not affected in HFKs or E7-immortalized HFKs. Transcription could be reactivated after DNA demethylation but was decreased again upon drug removal. Partial reactivation could also be accomplished when E6 was knocked down, suggesting a contribution of E6 in IFN-κ de novo methylation. We identified a single CpG island near the transcriptional start site as being involved in selective IFN-κ expression. To prove the functional relevance of IFN-κ in building up an antiviral response, IFN-κ was ectopically expressed in cervical carcinoma cells where protection against vesicular stomatitis virus–mediated cytolysis could be achieved. Reconstitution of IFN-κ was accompanied by an increase of p53, MxA, and IFN-regulatory factors, which was reversed by knocking down either IFN-κ or p53 by small interfering RNA. This suggests the existence of a positive feedback loop between IFN-κ, p53, and components of IFN signaling pathway to maintain an antiviral state. Our in vitro findings were further corroborated in biopsy samples of cervical cancer patients, in which IFN-κ was also downregulated when compared with normal donor tissue. This is the first report showing an epigenetic silencing of type I IFN after HPV16 oncogene expression and revealing a novel strategy on how high-risk HPVs can abolish the innate immune response in their genuine host cells. [Cancer Res 2009;69(22):8718–25]
Wnt Signaling Stimulates Transcriptional Outcome of the Hedgehog Pathway by Stabilizing GLI1 mRNA
Authors: Noubissi Felicite K. , Goswami Srikanta , Sanek Nicholas A. , Kawakami Kazuyuki , Minamoto Toshinari , Moser Amy , Grinblat Yevgenya , Spiegelman Vladimir S. 
Published: November 2009

Abstract
Wnt and Hedgehog signaling pathways play central roles in embryogenesis, stem cell maintenance, and tumorigenesis. However, the mechanisms by which these two pathways interact are not well understood. Here, we identified a novel mechanism by which Wnt signaling pathway stimulates the transcriptional output of Hedgehog signaling. Wnt/β-catenin signaling induces expression of an RNA-binding protein, CRD-BP, which in turn binds and stabilizes GLI1 mRNA, causing an elevation of GLI1 expression and transcriptional activity. The newly described mode of regulation of GLI1 seems to be important to several functions of Wnt, including survival and proliferation of colorectal cancer cells. [Cancer Res 2009;69(22):8572–8]
β1-Integrin Circumvents the Antiproliferative Effects of Trastuzumab in Human Epidermal Growth Factor Receptor-2–Positive Breast Cancer
Authors: Lesniak David , Xu Yaoxian , Deschenes Jean , Lai Raymond , Thoms John , Murray David , Gosh Sunita , Mackey John R. , Sabri Siham , Abdulkarim Bassam 
Published: November 2009

Abstract
Resistance to trastuzumab, the monoclonal antibody targeting human epidermal growth factor receptor 2 (HER-2), is a major concern for HER-2–positive metastatic breast cancer (MBC) patients. To date, HER-2 status is the only available biomarker for selecting patients for trastuzumab-based therapy. β1-Integrin, an adhesion molecule involved in cell survival and drug resistance, shares common downstream signaling elements with HER-2, such as the phosphatidylinositol 3-kinase/Akt and extracellular signal-regulated kinase-1/2 (ERK1/2) pathways. The significance of β1-integrin expression in HER-2–positive breast cancer and its involvement in a patient's response to trastuzumab-based therapy are unknown. We show here that overexpression of β1-integrin is an independent negative prognostic factor for tumor progression of HER-2–positive MBC patients treated with trastuzumab-based chemotherapy. Enforced overexpression of β1-integrin, its small interfering RNA–induced knockdown or treatment with a β1-integrin–blocking antibody in HER-2–positive breast cancer cells, identified a strong inverse relationship between expression level of β1-integrin and in vitro sensitivity to trastuzumab. Notably, β1-integrin overexpression increased the phosphorylation of Akt-Ser473 and ERK1/2, thereby promoting survival and mitogenic signals to bypass the antiproliferative effects of trastuzumab. Our findings show that β1-integrin provides a novel independent prognostic biomarker of trastuzumab response in HER-2–positive MBC patients and suggest a new target to augment the antiproliferative effects of trastuzumab. [Cancer Res 2009;69(22):8620–8]
Inhibition of Lipocalin 2 Impairs Breast Tumorigenesis and Metastasis
Authors: Leng Xiaohong , Ding Tian , Lin Hui , Wang Yan , Hu Limei , Hu Jianhua , Feig Barry , Zhang Wei , Pusztai Lajos , Symmans W. Fraser , Wu Yun , Arlinghaus Ralph B. 
Published: November 2009

Abstract
Lipocalin 2 (LCN2; also known as NGAL) is a secreted glycoprotein and its elevated expression has been observed in breast cancers. However, the importance of LCN2 in breast tumorigenesis is unclear. Here, we employed a spontaneous mammary tumor mouse model showing that MMTV-ErbB2(V664E) mice lacking mouse LCN2 had significantly delayed mammary tumor formation and metastasis with reduced matrix metalloproteinase-9 activity in the blood. LCN2 expression is upregulated by HER2/phosphoinositide 3-kinase/AKT/NF-κB pathway. Decreasing LCN2 expression significantly reduced the invasion and migration ability of HER2+ breast cancer cells. Furthermore, injecting an anti-mouse LCN2 antibody into mice bearing established murine breast tumors resulted in significant blockage of lung metastasis. Our findings indicate that LCN2 is a critical factor in enhancing breast tumor formation and progression possibly in part by stabilizing matrix metalloproteinase-9. Our results suggest that inhibition of LCN2 function by an inhibitory monoclonal antibody has potential for breast cancer therapy, particularly by interfering with metastasis in aggressive types of breast cancer. [Cancer Res 2009;69(22):8579–84]
Paradoxical Dependencies of Tumor Dormancy and Progression on Basic Cell Kinetics
Authors: Enderling Heiko , Anderson Alexander R.A. , Chaplain Mark A.J. , Beheshti Afshin , Hlatky Lynn , Hahnfeldt Philip 
Published: November 2009

Abstract
Even after a tumor is established, it can early on enter a state of dormancy marked by balanced cell proliferation and cell death. Disturbances to this equilibrium may affect cancer risk, as they may cause the eventual lifetime clinical presentation of a tumor that might otherwise have remained asymptomatic. Previously, we showed that cell death, proliferation, and migration can play a role in shifting this dynamic, making the understanding of their combined influence on tumor development essential. We developed an individual cell-based computer model of the interaction of cancer stem cells and their nonstem progeny to study early tumor dynamics. Simulations of tumor growth show that three basic components of tumor growth—cell proliferation, migration, and death—combine in unexpected ways to control tumor progression and, thus, clinical cancer risk. We show that increased proliferation capacity in nonstem tumor cells and limited cell migration overall lead to space constraints that inhibit proliferation and tumor growth. By contrast, increasing the rate of cell death produces the expected tumor size reduction in the short term, but results ultimately in paradoxical accelerated long-term growth owing to the liberation of cancer stem cells and formation of self-metastases.[Cancer Res 2009;69(22):8814–21]
Motor Protein–Dependent Membrane Trafficking of KCl Cotransporter-4 Is Important for Cancer Cell Invasion
Authors: Chen Yih-Fung , Chou Cheng-Yang , Wilkins Robert J. , Ellory J. Clive , Mount David B. , Shen Meng-Ru 
Published: November 2009

Abstract
The KCl cotransporter (KCC) is a major determinant of osmotic homeostasis and plays an emerging role in tumor biology. This study stresses the important role of KCC4 in tumor malignant behavior. Real-time reverse transcription-PCR on samples collected by laser microdissection and immunofluorescent stainings with different KCC isoform antibodies indicate that KCC4 is abundant in metastatic cervical and ovarian cancer tissues. Insulin-like growth factor I (IGF-I) and epidermal growth factor (EGF) stimulate KCC4 recruitment from a presumably inactive cytoplasmic pool of endoplasmic reticulum and Golgi to plasma membrane along actin cytoskeleton that is significantly inhibited by LY294002 and wortmannin. Throughout the trafficking process, KCC4 is incorporated into lipid rafts that function as a platform for the association between KCC4 and myosin Va, an actin-dependent motor protein. KCC4 and ezrin, a membrane cytoskeleton linker, colocalize at lamellipodia of migratory cancer cells. Interference with KCC activity by either an inhibitor or a dominant-negative loss-of-function mutant profoundly suppressed the IGF-I–induced membrane trafficking of KCC4 and the structural interaction between KCC4 and ezrin near the cell surface. Endogenous cancer cell invasiveness was significantly attenuated by small interfering RNA targeting KCC4, and the residual invasiveness was much less sensitive to IGF-I or EGF stimulation. In the metastatic cancer tissues, KCC4 colocalizes with IGF-I or EGF, indicating a likely in vivo stimulation of KCC4 function by growth factors. Thus, blockade of KCC4 trafficking and surface expression may provide a potential target for the prevention of IGF-I– or EGF-dependent cancer spread. [Cancer Res 2009;69(22):8585–93]
Titanium Dioxide Nanoparticles Induce DNA Damage and Genetic Instability In vivo in Mice
Authors: Trouiller Benedicte , Reliene Ramune , Westbrook Aya , Solaimani Parrisa , Schiestl Robert H. 
Published: November 2009

Abstract
Titanium dioxide (TiO2) nanoparticles are manufactured worldwide in large quantities for use in a wide range of applications including pigment and cosmetic manufacturing. Although TiO2 is chemically inert, TiO2 nanoparticles can cause negative health effects, such as respiratory tract cancer in rats. However, the mechanisms involved in TiO2-induced genotoxicity and carcinogenicity have not been clearly defined and are poorly studied in vivo. The present study investigates TiO2 nanoparticles–induced genotoxicity, oxidative DNA damage, and inflammation in a mice model. We treated wild-type mice with TiO2 nanoparticles in drinking water and determined the extent of DNA damage using the comet assay, the micronuclei assay, and the γ-H2AX immunostaining assay and by measuring 8-hydroxy-2′-deoxyguanosine levels and, as a genetic instability endpoint, DNA deletions. We also determined mRNA levels of inflammatory cytokines in the peripheral blood. Our results show that TiO2 nanoparticles induced 8-hydroxy-2′-deoxyguanosine, γ-H2AX foci, micronuclei, and DNA deletions. The formation of γ-H2AX foci, indicative of DNA double-strand breaks, was the most sensitive parameter. Inflammation was also present as characterized by a moderate inflammatory response. Together, these results describe the first comprehensive study of TiO2 nanoparticles–induced genotoxicity in vivo in mice possibly caused by a secondary genotoxic mechanism associated with inflammation and/or oxidative stress. Given the growing use of TiO2 nanoparticles, these findings raise concern about potential health hazards associated with TiO2 nanoparticles exposure. [Cancer Res 2009;69(22):8784–9]
NPM-ALK Oncogenic Tyrosine Kinase Controls T-Cell Identity by Transcriptional Regulation and Epigenetic Silencing in Lymphoma Cells
Authors: Ambrogio Chiara , Martinengo Cinzia , Voena Claudia , Tondat Fabrizio , Riera Ludovica , di Celle Paola Francia , Inghirami Giorgio , Chiarle Roberto 
Published: November 2009

Abstract
Transformed cells in lymphomas usually maintain the phenotype of the postulated normal lymphocyte from which they arise. By contrast, anaplastic large cell lymphoma (ALCL) is a T-cell lymphoma with aberrant phenotype because of the defective expression of the T-cell receptor and other T-cell–specific molecules for still undetermined mechanisms. The majority of ALCL carries the translocation t(2;5) that encodes for the oncogenic tyrosine kinase NPM-ALK, fundamental for survival, proliferation, and migration of transformed T cells. Here, we show that loss of T-cell–specific molecules in ALCL cases is broader than reported previously and involves most T-cell receptor–related signaling molecules, including CD3ϵ, ZAP70, LAT, and SLP76. We further show that NPM-ALK, but not the kinase-dead NPM-ALKK210R, downregulated the expression of these molecules by a STAT3-mediated gene transcription regulation and/or epigenetic silencing because this downregulation was reverted by treating ALCL cells with 5-aza-2-deoxycytidine or by knocking down STAT3 through short hairpin RNA. Finally, NPM-ALK increased the methylation of ZAP70 intron 1-exon 2 boundary region, and both NPM-ALK and STAT3 regulated the expression levels of DNA methyltransferase 1 in transformed T cells. Thus, our data reveal that oncogene-deregulated tyrosine kinase activity controls the expression of molecules that determine T-cell identity and signaling. [Cancer Res 2009;69(22):8611–9]
Microarray-Based Determination of Estrogen Receptor, Progesterone Receptor, and HER2 Receptor Status in Breast Cancer
Authors: Roepman Paul , Horlings Hugo M. , Krijgsman Oscar , Kok Marleen , Bueno-de-Mesquita Jolien M. , Bender Richard , Linn Sabine C. , Glas Annuska M. , van de Vijver Marc J. 
Published: November 2009

Abstract
Purpose: The level of estrogen receptor (ER), progesterone receptor (PR), and HER2 aids in the determination of prognosis and treatment of breast cancer. Immunohistochemistry is currently the predominant method for assessment, but differences in methods and interpretation can substantially affect the accuracy, resulting in misclassification. Here, we investigated the association of microarray-based mRNA expression levels compared with immunohistochemistry.
Experimental Design: Microarray mRNA quantification of ER, PR, and HER2 was done by the developed TargetPrint test and compared with immunohistochemical assessment for breast tumors from 636 patients. Immunohistochemistry was done in a central laboratory and in an independent reference laboratory according to American Society of Clinical Oncology/College of American Pathologists guidelines for 100 cases. For HER2 immunohistochemistry 2+ cases, additional chromogenic in situ hybridization (CISH) was used to determine the final status.
Results: ER concordance between microarray and central immunohistochemistry was 93 [95 confidence interval (95 CI), 91-95]. Only 4 of immunohistochemistry-positive samples were classified negative using microarray, whereas 18 of immunohistochemistry-negative samples showed a positive microarray ER status. Concordance for PR was 83 (95 CI, 80-86) and 96 of all samples showed an identical classification of HER2 status by microarray and immunohistochemistry/CISH (95 CI, 94-98). Nine percent of immunohistochemistry HER2-positive samples showed a negative microarray classification. Detailed review of 11 cases with discordant classifications by American Society of Clinical Oncology/College of American Pathologists and central immunohistochemistry indicated that microarray assessment was likely to add additional information in 5 cases.
Conclusion: Microarray-based readout of ER, PR, and HER2 shows a high concordance with immunohistochemistry/CISH and provides an additional, objective, and quantitative assessment of tumor receptor status in breast cancer. (Clin Cancer Res 2009;15(22):700311)
Activation of Host Wound Responses in Breast Cancer Microenvironment
Authors: Troester Melissa A. , Lee Myung Hee , Carter Matthew , Fan Cheng , Cowan David W. , Perez Erick Roman , Pirone Jason R. , Perou Charles M. , Jerry D. Joseph , Schneider Sallie Smith 
Published: November 2009

Abstract
Purpose: Cancer progression is mediated by processes that are also important in wound repair. As a result, cancers have been conceptualized as overhealing wounds or wounds that do not heal, and gene expression signatures reflective of wound repair have shown value as predictors of breast cancer survival. Despite the widespread acknowledgment of commonalities between host responses to wounds and host responses to cancer, the gene expression responses of normal tissue adjacent to cancers have not been well characterized.
Experimental Design: Using RNA extracted from histologically normal breast tissue from 107 patients, including 60 reduction mammoplasty patients and 47 cancer patients, we measured whole genome expression profiles and identified a gene expression signature that is induced in response to breast cancer.
Results: This signature represents an in vivo wound response signature that is differentially expressed in the normal tissue of breast cancer patients compared with those without disease and is highly accurate (at least 92 sensitivity and 98 specificity) in distinguishing diseased and nondiseased. The in vivo wound response signature is highly prognostic of breast cancer survival, and there is a strong association between the groups identified by this signature and those identified using serum-treated fibroblasts and other microenvironment-derived or microenvironment-related signatures.
Conclusions: The prevalence of the wound response signature in histologically normal tissue adjacent to breast cancer suggests that microenvironment response is an important variable in breast cancer progression and may be an important target for clinical interventions. (Clin Cancer Res 2009;15(22):70208)
Lysine 63 Polyubiquitination in Immunotherapy and in Cancer-promoting Inflammation
Authors: Martinez-Forero Ivan , Rouzaut Ana , Palazon Asis , Dubrot Juan , Melero Ignacio 
Published: November 2009

Abstract
Covalent and reversible post-translational modifications of proteins are a common theme in signaling. Ubiquitin conjugation was originally described to target proteins to proteasomal degradation by ubiquitin polymerization involving lysine (K) 48 residues. Differently linked polymers of polyubiquitin have been found that modify proteins without targeting to proteasomal degradation. Instead this pathway creates docking sites for signaling scaffolds that are key to control the nuclear factor-B (NF-B) pathway. Indeed TRAF-2, TRAF-6, and TRAF-3 are E3 ubiquitin ligases that form K63-linked ubiquitin polymers. Therefore signaling via TNF family receptors, IL1R, IL-18R, T-cell receptor (TCR), and Toll-like receptors (TLR) use this type of post-translational modification. Specific enzymes exist (DUBs) that deactivate this system, degrading K63 polyubiquitin chains. Interestingly, mice deficient in these deubiquitinases develop autoimmunity and inflammation. In carcinogenesis, the K63 polyubiquitin pathway is possibly critical for inflammation-driven tumor promotion. The pathway is also critically involved in costimulation of tumor immunity/immunotherapy as well as in the biology of malignant cells themselves. The elements of this new signaling paradigm offer the opportunity for therapeutic exploitation and drug discovery. (Clin Cancer Res 2009;15(22):67517)
Combined Inhibition of Janus Kinase 1/2 for the Treatment of JAK2V617F-Driven Neoplasms: Selective Effects on Mutant Cells and Improvements in Measures of Disease Severity
Authors: Liu Phillip C.C. , Caulder Eian , Li Jun , Waeltz Paul , Margulis Alex , Wynn Richard , Becker-Pasha Mary , Li Yanlong , Crowgey Erin , Hollis Gregory , Haley Patrick , Sparks Richard B. , Combs Andrew P. , Rodgers James D. , Burn Timothy C. , Vaddi Kris , Fridman Jordan S. 
Published: November 2009

Abstract
Purpose: Deregulation of the Janus kinase-signal transducers and activators of transcription (JAK-STAT) pathway is a hallmark for the Philadelphia chromosomenegative myeloproliferative diseases polycythemia vera, essential thrombocythemia, and primary myelofibrosis. We tested the efficacy of a selective JAK1/2 inhibitor in cellular and in vivo models of JAK2-driven malignancy.
Experimental Design: A novel inhibitor of JAK1/2 was characterized using kinase assays. Cellular effects of this compound were measured in cell lines bearing the JAK2V617F or JAK1V658F mutation, and its antiproliferative activity against primary polycythemiavera patient cells was determined using clonogenic assays. Antineoplastic activity in vivo was determined using a JAK2V617F-driven xenograft model, and effects of the compound on survival, organomegaly, body weight, and disease-associated inflammatory markers were measured.
Results: INCB16562 potently inhibited proliferation of cell lines and primary cells from PV patients carrying the JAK2V617F or JAK1V658F mutation by blocking JAK-STAT signaling and inducing apoptosis. In vivo, INCB16562 reduced malignant cell burden, reversed splenomegaly and normalized splenic architecture, improved body weight gains, and extended survival in a model of JAK2V617F-driven hematologic malignancy. Moreover, these mice suffered from markedly elevated levels of inflammatory cytokines, similar to advanced myeloproliferative disease patients, which was reversed upon treatment.
Conclusions: These data showed that administration of the dual JAK1/2 inhibitor INCB16562 reduces malignant cell burden, normalizes spleen size and architecture, suppresses inflammatory cytokines, improves weight gain, and extends survival in a rodent model of JAK2V617F-driven hematologic malignancy. Thus, selective inhibitors of JAK1 and JAK2 represent a novel therapy for the patients with myeloproliferative diseases and other neoplasms associated with JAK dysregulation. (Clin Cancer Res 2009;15(22):6891900)