bluuebunny/crossref_metadata_2025_split huggingface dataset:
TOB1 Is Regulated by EGF-Dependent HER2 and EGFR Signaling, Is Highly Phosphorylated, and Indicates Poor Prognosis in Node-Negative Breast Cancer
Authors: Helms Mike W. , Kemming Dirk , Contag Christopher H. , Pospisil Heike , Bartkowiak Kai , Wang Alice , Chang Sheng-Yung , Buerger Horst , Brandt Burkhard H. 
Published: June 2009

AbstractClinical and animal studies have shown that coexpression of the receptor tyrosine kinases HER2 and epidermal growth factor (EGF) receptor (EGFR) indicates a highly metastatic phenotype of breast cancer. In a cellular model of this phenotype using differential gene expression analysis, we identified TOB1 to be up-regulated depending on EGF stimulation and transduction through phosphorylation of HER2 tyrosine 1248. mRNA expression analysis of breast cancers from a cohort of node-negative patients showed significantly shortened distant metastasis-free survival for patients with high TOB1 expression. In subsequent tissue microarray studies of 725 clinical samples, high HER2 and EGF protein levels were significantly correlated with TOB1 expression in breast cancer, whereas EGFR and EGF levels correlated with TOB1 phosphorylation. We did not observe a correlation between TOB1 expression and cyclin D1, which was previously suggested to mediate the antiproliferative effect of unphosphorylated TOB1. A positive correlation of TOB1 phosphorylation status with proliferation marker Ki67 suggests that elevated TOB1 phosphorylation might abrogate the antiproliferative effect of TOB1 in breast cancer. This suggests a new regulatory role for TOB1 in cancer progression with particular significance in HER2- and/or EGFR-positive breast cancers. [Cancer Res 2009;69(12):5049–56]
Effects of Vandetanib on Lung Adenocarcinoma Cells Harboring Epidermal Growth Factor Receptor T790M Mutation In vivo
Authors: Ichihara Eiki , Ohashi Kadoaki , Takigawa Nagio , Osawa Masahiro , Ogino Atsuko , Tanimoto Mitsune , Kiura Katsuyuki 
Published: June 2009

Abstract
Vandetanib is a novel multitarget tyrosine kinase inhibitor (TKI) that inhibits vascular endothelial growth factor receptor-2 (VEGFR-2), with additional inhibition of epidermal growth factor receptor (EGFR) and rearranged during transfection receptor signaling, which has shown promising results in clinical trials for advanced non–small cell lung cancer. However, the mechanisms of acquired resistance to vandetanib remain unclear. Therefore, we established in vitro vandetanib-resistant PC-9/VanR cells from PC-9, a vandetanib-sensitive lung adenocarcinoma cell line, by chronic exposure to this agent. PC-9/VanR cells were 50-fold more resistant to vandetanib than PC-9 cells in vitro. Compared with PC-9 cells, PC-9/VanR cells showed emergence of an EGFR T790M mutation, moderately elevated MET amplification, and similar VEGFR-2 inhibition by vandetanib. Note that phospho-MET in PC-9/VanR was suppressed following EGFR inhibition by an irreversible EGFR-TKI, indicating that MET signaling of PC-9/VanR was dependent on EGFR signaling and that MET amplification was not the primary mechanism of resistance to vandetanib. In contrast to the in vitro experiment, vandetanib effectively inhibited the growth of PC-9/VanR tumors in an in vivo xenograft model through the antiangiogenesis effects of VEGFR-2 inhibition. In conclusion, the multitarget TKI vandetanib induced or selected for the EGFR T790M mutation as observed previously with highly selective EGFR-TKIs. However, vandetanib retained significant efficacy in vivo against xenografts harboring the T790M mutation, providing a strong scientific rationale for investigating vandetanib in clinical settings where acquired resistance through emergence of EGFR T790M mutations limits the effectiveness of highly selective EGFR-TKIs. [Cancer Res 2009;69(12):5091–8]
The mRNA-Destabilizing Protein Tristetraprolin Is Suppressed in Many Cancers, Altering Tumorigenic Phenotypes and Patient Prognosis
Authors: Brennan Sarah E. , Kuwano Yuki , Alkharouf Nadim , Blackshear Perry J. , Gorospe Myriam , Wilson Gerald M. 
Published: June 2009

Abstract
AU-rich element-binding proteins (ARE-BP) regulate the stability and/or translational efficiency of mRNAs containing cognate binding sites. Many targeted transcripts encode factors that control processes such as cell division, apoptosis, and angiogenesis, suggesting that dysregulated ARE-BP expression could dramatically influence oncogenic phenotypes. Using several approaches, we evaluated the expression of four well-characterized ARE-BPs across a variety of human neoplastic syndromes. AUF1, TIA-1, and HuR mRNAs were not systematically dysregulated in cancers; however, tristetraprolin mRNA levels were significantly decreased across many tumor types, including advanced cancers of the breast and prostate. Restoring tristetraprolin expression in an aggressive tumor cell line suppressed three key tumorgenic phenotypes: cell proliferation, resistance to proapoptotic stimuli, and expression of vascular endothelial growth factor mRNA. However, the cellular consequences of tristetraprolin expression varied across different cell models. Analyses of gene array data sets revealed that suppression of tristetraprolin expression is a negative prognostic indicator in breast cancer, because patients with low tumor tristetraprolin mRNA levels were more likely to present increased pathologic tumor grade, vascular endothelial growth factor expression, and mortality from recurrent disease. Collectively, these data establish that tristetraprolin expression is frequently suppressed in human cancers, which in turn can alter tumorigenic phenotypes that influence patient outcomes. [Cancer Res 2009;69(12):5168–76]
Akt1 and Akt2 Play Distinct Roles in the Initiation and Metastatic Phases of Mammary Tumor Progression
Authors: Dillon Rachelle L. , Marcotte Richard , Hennessy Bryan T. , Woodgett James R. , Mills Gordon B. , Muller William J. 
Published: June 2009

AbstractThe phosphatidylinositol 3-kinase (PI3K)/Akt survival pathway is often dysregulated in cancer. Our previous studies have shown that coexpression of activated Akt1 with activated ErbB2 or polyoma virus middle T antigen uncoupled from the PI3K pathway (PyVmT Y315/322F) accelerates mammary tumor development but cannot rescue the metastatic phenotype associated with these models. Here, we report the generation of transgenic mice expressing activated Akt2 in the mammary epithelium. Like the mouse mammary tumor virus-Akt1 strain, mammary-specific expression of Akt2 delayed mammary gland involution. However, in contrast to Akt1, coexpression of Akt2 with activated ErbB2 or PyVmT Y315/322F in the mammary glands of transgenic mice did not affect the latency of tumor development. Strikingly, Akt2 coexpresssion markedly increased the incidence of pulmonary metastases in both tumor models, demonstrating a unique role in tumor progression. Together, these observations argue that these highly conserved kinases have distinct biological and biochemical outputs that play opposing roles in mammary tumor induction and metastasis. [Cancer Res 2009;69(12):5057–64]
HOXA13 Promotes Cancer Cell Growth and Predicts Poor Survival of Patients with Esophageal Squamous Cell Carcinoma
Authors: Gu Zhen-Dong , Shen Lu-Yan , Wang Hua , Chen Xiao-Mei , Li Yong , Ning Tao , Chen Ke-Neng 
Published: June 2009

AbstractHomeobox genes are known to be classic examples of the intimate relationship between embryogenesis and tumorigenesis. Here, we investigated whether inhibition of HOXA13, a member of the homeobox genes, was sufficient to affect the proliferation of esophageal cancer cells in vitro and in vivo, and studied the association between HOXA13 expression and survival of patients with esophageal squamous cell carcinoma (ESCC). HOXA13 expression was permanently knocked down using an RNA interference technique, and cell strain with stable knockdown of HOXA13 protein was established. Colony formation assay showed that the number of colonies in HOXA13 protein–deficient cells was significantly less than that of control cells (P &lt; 0.01). Tumor growth in nude mice showed that the weight and volume of tumors from the HOXA13 knockdown cells was significantly less than that from the control cells (P &lt; 0.01). Then, HOXA13 expression in ESCC specimens and paired noncancerous mucosa was detected by immunohistochemistry, and overexpression of HOXA13 was found to be more pronounced in ESCCs than paired noncancerous mucosa (P &lt; 0.05). Furthermore, the association of HOXA13 expression and disease-free survival time was analyzed in 155 ESCC cases. The median survival time of patients expressing HOXA13 was significantly shorter than HOXA13-negative patients (P = 0.0006). Multivariate analysis indicated that tumor-node-metastasis (TNM) stage and HOXA13 expression were independent predictors of disease-free survival time of patients with ESCC. Our results showed that HOXA13 expression enhanced tumor growth in vitro and in vivo, and was a negative independent predictor of disease-free survival of patients with ESCC. [Cancer Res 2009;69(12):4969–73]
Genetic Variants on Chromosome 15q25 Associated with Lung Cancer Risk in Chinese Populations
Authors: Wu Chen , Hu Zhibin , Yu Dianke , Huang Liming , Jin Guangfu , Liang Jie , Guo Huan , Tan Wen , Zhang Mingfeng , Qian Ji , Lu Daru , Wu Tangchun , Lin Dongxin , Shen Hongbing 
Published: June 2009

Abstract
Recent three genome-wide association studies have mapped a lung cancer susceptibility locus to chromosome 15q25 in Caucasians. However, the reported risk single nucleotide polymorphisms (SNPs) are extremely rare in Asians, arguing against any of these being causative variants. This study sought to identify other variants on 15q25 associated with lung cancer susceptibility in Chinese. Two-stage case-control studies were conducted in subjects derived from both Northern and Southern China. The first-stage, consisting of 576 cases and 576 controls, was to discover novel risk variants using a haplotype-tagging SNP approach, and these variants were then replicated in the second-stage, consisting of 2,989 cases and 2,880 controls. Associations were estimated by logistic regression models, and function of the variants was examined by biochemical assays. We found that the three risk SNPs reported in Caucasians were not associated with lung cancer risk in Chinese. However, we identified four novel SNPs (rs2036534C&gt;T, rs667282C&gt;T, rs12910984G&gt;A, and rs6495309T&gt;C) that were associated with significantly increased lung cancer risk and smoking behavior, which were all confirmed in the replication analyses [odds ratios (95% confidence intervals) in the dominant model: 1.39 (1.23–1.57; P = 2.3 × 10−7), 1.52 (1.35–1.71; P = 2.0 × 10−12), 1.44 (1.28–1.63; P = 2.7 × 10−9), and 1.43 (1.27–1.61; P = 2.6 × 10−9), respectively]. We characterized the rs6495309T&gt;C change in the CHRNA3 promoter as a functional variant because it affected the Oct-1 binding ability, resulting in increased CHRNA3 expression. These results support 15q25 as a susceptibility region for lung cancer in Chinese but underscore the difference in genetic markers among different ethnic populations. [Cancer Res 2009;69(12):5065–72]
A Novel Type of p53 Pathway Dysfunction in Chronic Lymphocytic Leukemia Resulting from Two Interacting Single Nucleotide Polymorphisms within the p21 Gene
Authors: Johnson Gillian G. , Sherrington Paul D. , Carter Anthony , Lin Ke , Liloglou Triantafillos , Field John K. , Pettitt Andrew R. 
Published: June 2009

Abstract
The ATM-p53 pathway plays an important role in the biology of chronic lymphocytic leukemia (CLL). Its functional integrity can be probed by exposing CLL cells to ionizing radiation (IR) and measuring levels of p53 protein and one of its transcriptional targets, the cyclin-dependent kinase inhibitor p21. We have previously identified two abnormal p53/p21 response patterns associated with inactivating mutations of TP53 and ATM, respectively. Here, we describe a third abnormal response pattern characterized by failure of p21 protein accumulation despite a normal p53 protein response. This so-called "type C" response was detected in 10.6% of unselected patients and was associated with resistance of CLL cells to p53-dependent killing by IR, with the clinically more aggressive variant of CLL characterized by unmutated immunoglobulin heavy-chain genes and with a single nucleotide polymorphism at codon 31 of the p21 gene in which Ser is replaced by Arg. CLL samples with this allelic variant displayed impaired IR-induced up-regulation of total p21 mRNA and did not express the Arg-encoding transcript, except in those cases harboring an additional single nucleotide polymorphism (T instead of C) in the 3′-untranslated region of the same p21 allele. Our data provide new insight into the importance of p21 in CLL biology. [Cancer Res 2009;69(12):5210–17]
The Tumor Suppressor Gene Hypermethylated in Cancer 1 Is Transcriptionally Regulated by E2F1
Authors: Jenal Mathias , Trinh Emmanuelle , Britschgi Christian , Britschgi Adrian , Roh Vincent , Vorburger Stephan A. , Tobler Andreas , Leprince Dominique , Fey Martin F. , Helin Kristian , Tschan Mario P. 
Published: June 2009

Abstract
The Hypermethylated in Cancer 1 (HIC1) gene encodes a zinc finger transcriptional repressor that cooperates with p53 to suppress cancer development. We and others recently showed that HIC1 is a transcriptional target of p53. To identify additional transcriptional regulators of HIC1, we screened a set of transcription factors for regulation of a human HIC1 promoter reporter. We found that E2F1 strongly activates the full-length HIC1 promoter reporter. Promoter deletions and mutations identified two E2F responsive elements in the HIC1 core promoter region. Moreover, in vivo binding of E2F1 to the HIC1 promoter was shown by chromatin immunoprecipitation assays in human TIG3 fibroblasts expressing tamoxifen-activated E2F1. In agreement, activation of E2F1 in TIG3-E2F1 cells markedly increased HIC1 expression. Interestingly, expression of E2F1 in the p53−/− hepatocellular carcinoma cell line Hep3B led to an increase of endogenous HIC1 mRNA, although bisulfite genomic sequencing of the HIC1 promoter revealed that the region bearing the two E2F1 binding sites is hypermethylated. In addition, endogenous E2F1 induced by etoposide treatment bound to the HIC1 promoter. Moreover, inhibition of E2F1 strongly reduced the expression of etoposide-induced HIC1. In conclusion, we identified HIC1 as novel E2F1 transcriptional target in DNA damage responses. (Mol Cancer Res 2009;7(6):916–22)
Src Promotes Survival and Invasion of Lung Cancers with Epidermal Growth Factor Receptor Abnormalities and Is a Potential Candidate for Molecular-Targeted Therapy
Authors: Leung Elaine Lai-Han , Tam Issan Yee-San , Tin Vicky Pui-Chi , Chua Daniel Tsin-Tien , Sihoe Alan Dart-Loon , Cheng Lik-Cheung , Ho James Chung-Man , Chung Lap-Ping , Wong Maria Pik 
Published: June 2009

Abstract
Molecular-targeted therapy using tyrosine kinase inhibitors against epidermal growth factor receptor (EGFR) is an effective therapy for non–small cell lung cancer that harbor EGFR mutations. This study aimed to investigate the role of Src, a close EGFR associator, as a drug target in NSCLC cells with different EGFR genomic statuses. Src inhibition was achieved using 4-(4′-Phenoxyanilino)-6,7-dimethoxyquinazolinee (SKI-1) and the specificity of action was verified by RNA interference. The results showed that SKI-1 induced significant apoptosis in a dose-dependent manner in cancer cells with high basal Src activation. Activation of FAK and p130Cas was involved in Src-mediated invasion in SKI-1–sensitive cells. SKI-1 inhibited phosphorylation of EGFR as well as EGFR downstream effectors, such as signal transducers and activators of transcription 3/5, extracellular signal-regulated kinase 1/2 and AKT in the mutant cells but not the wild-type cells. This inhibition profile of EGFR implicates that induction of apoptosis and sensitivity of mutant cells to SKI treatment is mediated by EGFR and EGFR downstream pathways. Cotreatment with SKI-1 and gefitinib enhanced apoptosis in cancer cells that contained EGFR mutation and/or amplification. SKI-1 treatment alone induced significant apoptosis in H1975 cells known to be resistant to gefitinib. Src phosphorylation was shown by immunohistochemistry in around 30% of primary lung carcinomas. In 152 adenocarcinomas studied, p-Src was associated with EGFR mutations (P = 0.029). Overall, the findings indicated that Src could be a useful target for treatment of non–small cell lung cancer. Besides EGFR genomic mutations, other forms of EGFR and related family member abnormalities such as EGFR amplification might enhance SKI sensitivity. (Mol Cancer Res 2009;7(6):923–32)
Modulation by Phenethyl Isothiocyanate and Budesonide of Molecular and Histopathologic Alterations Induced by Environmental Cigarette Smoke in Mice
Authors: D'Agostini Francesco , Mastracci Luca , Izzotti Alberto , Balansky Roumen , Pennisi Tanya M. , Steele Vernon E. , De Flora Silvio 
Published: June 2009

Abstract
Our discovery that the perinatal period involves nucleotide modifications and gene overexpression in mouse lung prompted us to evaluate whether mice may become more susceptible to cigarette smoke when exposure starts immediately after birth. We previously showed that mainstream cigarette smoke is a quite potent carcinogen in neonatal mice. Further on, we showed that exposure of mice to environmental cigarette smoke (ECS), starting at birth, results in alterations of a variety of intermediate biomarkers. However, after 4 months of exposure to ECS followed by 7 months of recovery in filtered air, the lung tumor yield was rather low. In the present study, we evaluated the protective effects of the glucocorticoid budesonide and of the dietary agent phenethyl isothiocyanate in mice exposed to ECS for 9 months followed by 2 months of recovery. After weanling, the mice exposed to ECS since birth underwent a variety of alterations of molecular and cytogenetical end points, and 11 months after birth, they exhibited significant histopathologic changes, such as pulmonary anthracosis, emphysema, hemorrhagic areas, alveolar bronchiolarization, bronchial hyperplasia, and tumors, both benign and malignant. The carcinogenic response was less evident in dams exposed to ECS under identical conditions. Both phenethyl isothiocyanate and budesonide, administered daily with the diet after weanling, attenuated several alterations of ECS-related biomarkers and moderately protected the lungs from histopathologic alterations, including tumors. Thus, although not as efficiently as the bioassay in mainstream cigarette smoke–exposed mice, the model in neonatal mice is suitable to evaluate both ECS carcinogenicity and its modulation by chemopreventive agents.
Molecular Profiles of Finasteride Effects on Prostate Carcinogenesis
Authors: Li Jin , Kim Jeri 
Published: June 2009

AbstractOur inability to distinguish between low-grade prostate cancers that pose no threat and those that can kill compels newly diagnosed early prostate cancer patients to make decisions that may negatively affect their lives needlessly for years afterward. To reliably stratify patients into different risk categories and apply appropriate treatment, we need a better molecular understanding of prostate cancer progression. Androgen ablation therapy and 5-α reductase inhibitors reduce dihydrotestosterone levels and increase apoptosis. Because of the differing biological potentials of tumor cells, however, these treatments may, in some cases, worsen outcome by selecting for or inducing adaptation of stronger androgen receptor signaling pathways. Reduced dihydrotestosterone also may be associated with altered survival pathways. Complicating treatment effects further, molecular adaptation may be accelerated by interactions between epithelial and stromal cells. The hypothesis that early prostate cancer cells with differing biological potential may respond differently to finasteride treatment is worth testing. Ongoing studies using a systems biology approach in a preoperative prostate cancer setting are testing this hypothesis toward developing more-rational clinical interventions.
The Role of Convective Moistening in the Madden–Julian Oscillation
Authors: Thayer-Calder Katherine , Randall David A. 
Published: June 2009

Abstract
This study compares two models that differ primarily in their cloud parameterizations and produce extremely different simulations of the Madden–Julian oscillation (MJO). The Community Atmosphere Model (CAM) version 3.0 from NCAR uses the Zhang–McFarlane scheme for deep convection and does not produce an MJO. The “superparameterized” version of the CAM (SP-CAM) replaces the cloud parameterizations with a two-dimensional cloud-resolving model (CRM) in each grid column and produces an extremely vigorous MJO.
This analysis shows that the CAM is unable to produce high-humidity regions in the mid- to lower troposphere because of a lack of coupling between parameterized convection and environmental relative humidity. The SP-CAM produces an overly moist column due in part to excessive near-surface winds and evaporation during strong convective events. In the real tropics and the SP-CAM, convection within a high-humidity environment produces intense latent heating, which excites the large-scale circulation that is the signature of the MJO. The authors suggest that a model must realistically represent convective processes that moisten the entire tropical troposphere in order to produce a simulation of the MJO.
Topographic Influence on the MJO in the Maritime Continent
Authors: Wu Cheng-Han , Hsu Huang-Hsiung 
Published: June 2009

Abstract
This study demonstrates that during the passage of the MJO through the Maritime Continent in the boreal winter, the corresponding deep convection and near-surface wind anomalies tend to skirt around mountainous islands. Flow bifurcation around elongated mountainous islands, such as New Guinea, is clearly seen. Topographic blocking generates distinctive vorticity and convergence distributions in this specific domain. Mountain-wave-like structures are also observed throughout the Maritime Continent, with a clear spatial relationship with the high terrains in Sumatra, Sulawesi, and New Guinea. The existence of topography seems to create extra lifting and sinking within the large-scale circulation and thus the convective system exhibits quasi-stationary features near the major topography during the MJO passage through the Maritime Continent. It is suggested that resolving the detailed topographic effects may play a key role in simulating realistic characteristics of the MJO in the Maritime Continent.