bluuebunny/crossref_metadata_2025_split huggingface dataset:
X-Linked Ectodermal Dysplasia Receptor Is Downregulated in Breast Cancer via Promoter Methylation
Authors: Punj Vasu , Matta Hittu , Chaudhary Preet M. 
Published: February 2010

Abstract
Purpose: The X-linked ectodermal dysplasia receptor (XEDAR) is a novel receptor of the tumor necrosis factor receptor family that binds to ectodysplasin-A2 (EDA-A2) and induces cell death. The purpose of this study was to determine the tumor-suppressive potential of XEDAR in the development of breast cancer.
Experimental Design: We analyzed the expression of XEDAR in breast cancer cell lines and tumor samples using quantitative real-time PCR analysis and immunoblotting. We analyzed the human XEDAR gene promoter for the presence of any CpG island and examined its methylation status using methylation-specific real-time PCR. We examined the effect of 5-aza-2′-deoxycytidine on the expression of XEDAR and sensitivity to EDA-A2–induced apoptosis in breast cancer cell lines.
Results: Expression of XEDAR, but not EDA-A2, was downregulated in most tumorigenic breast cancer cell lines and tumor samples. Loss of XEDAR expression correlated with the hypermethylation of its promoter. Ectopic expression of XEDAR in MDA-MB-231 cells resulted in significant induction of apoptosis and reduction in colony formation. Treatment with 5-aza-2′-deoxycytidine restored XEDAR expression in breast cancer cell lines with methylated XEDAR promoter and sensitized them to EDA-A2–induced cell death.
Conclusions: Our results suggest that XEDAR expression is downregulated in most breast cancers via promoter methylation, which may contribute to accelerated tumor development by blocking EDA-A2–induced cell death. XEDAR may represent a novel breast tumor suppressor gene, and restoration of its expression by treatment with DNA demethylating agents may represent an attractive approach for the treatment of breast cancer. Clin Cancer Res; 16(4); 1140–8
Frequent Downregulation of miR-34 Family in Human Ovarian Cancers
Authors: Corney David C. , Hwang Chang-Il , Matoso Andres , Vogt Markus , Flesken-Nikitin Andrea , Godwin Andrew K. , Kamat Aparna A. , Sood Anil K. , Ellenson Lora H. , Hermeking Heiko , Nikitin Alexander Yu. 
Published: February 2010

Abstract
Purpose: The miR-34 family is directly transactivated by tumor suppressor p53, which is frequently mutated in human epithelial ovarian cancer (EOC). We hypothesized that miR-34 expression would be decreased in EOC and that reconstituted miR-34 expression might reduce cell proliferation and invasion of EOC cells.
Experimental Designs: miR-34 expression was determined by quantitative reverse transcription-PCR and in situ hybridization in a panel of 83 human EOC samples. Functional characterization of miR-34 was accomplished by reconstitution of miR-34 expression in EOC cells with synthetic pre-miR molecules followed by determining changes in proliferation, apoptosis, and invasion.
Results: miR-34a expression is decreased in 100%, and miR-34b*/c in 72%, of EOC with p53 mutation, whereas miR-34a is also downregulated in 93% of tumors with wild-type p53. Furthermore, expression of miR-34b*/c is significantly reduced in stage IV tumors compared with stage III (P = 0.0171 and P = 0.0029, respectively). Additionally, we observed promoter methylation and copy number variations at mir-34. In situ hybridization showed that miR-34a expression is inversely correlated with MET immunohistochemical staining, consistent with translational inhibition by miR-34a. Finally, miR-34 reconstitution experiments in p53 mutant EOC cells resulted in reduced proliferation, motility, and invasion, the latter of which was dependent on MET expression.
Conclusions: Our work suggests that miR-34 family plays an important role in EOC pathogenesis and reduced expression of miR-34b*/c may be particularly important for progression to the most advanced stages. Part of miR-34 effects on motility and invasion may be explained by regulation of MET, which is frequently overexpressed in EOC. Clin Cancer Res; 16(4); 1119–28
A 3′-Untranslated Region Polymorphism in IGF1 Predicts Survival of Non–Small Cell Lung Cancer in a Chinese Population
Authors: Zhang Mingfeng , Hu Zhibin , Huang Jinlin , Shu Yongqian , Dai Juncheng , Jin Guangfu , Tang Rong , Dong Jing , Chen Yijiang , Xu Lin , Huang Xinen , Shen Hongbing 
Published: February 2010

Abstract
Purpose: Disruption of the balance of insulin-like growth factor I (IGF-I) and IGF-binding protein 3 (IGFBP3) has been implicated in the etiology and progression of lung and other cancers. Single nucleotide polymorphisms (SNP) in IGF1 and IGFBP3 have been reported to be associated with the expression of the IGF-I/IGFBP3 axis. Therefore, we hypothesized that SNPs in these two genes were associated with lung cancer survival.
Experimental Design: We selected and genotyped 21 tagging and potentially functional SNPs in IGF1 and IGFBP3 by using Illumina Goldengate Genotyping Chip in a case cohort of 568 patients diagnosed with non–small cell lung cancer (NSCLC) in a Chinese population. Log-rank test and Cox proportional hazard models were used for the survival analyses.
Results: We found that rs5742714C/G in the 3′-untranslated region of IGF1 was associated significantly with NSCLC survival after adjustment for demographic and clinicopathologic factors, showing an improved median survival time in patients carrying variant CG/GG genotypes [median survival time, 28.5 months for CG/GG and 23.0 for CC; crude hazard ratio (HR), 0.74; 95% confidence interval (95% CI), 0.57-0.95, and adjusted HR, 0.77; 95% CI, 0.60-0.99]. This protective effect was more predominant for patients receiving surgical operation (HR, 0.58; 95% CI, 0.40-0.85; P for heterogeneity test = 0.045), along with a significant multiplicative interaction between variant genotypes and operation status (P = 0.028).
Conclusions: Our findings suggest that rs5742714 in IGF1 may be a genetic modifier for NSCLC prognosis in this Chinese population, especially among patients with surgical operation. Clin Cancer Res; 16(4); 1236–44
Finding the Right Dose for Cancer Therapeutics—Can We Do Better?
Authors: Rubin Eric H. , Anderson Keaven M. 
Published: February 2010

Abstract
Unlike other diseases, dose-selection for cancer therapeutics is often based on the maximum-tolerated dose in phase 1 studies involving relatively few patients. In this issue of Clinical Cancer Research, Jain and colleagues provide evidence that lower doses may be as effective as maximum-tolerated doses in the treatment of cancer patients. Clin Cancer Res; 16(4); 1085–7
The Mismatch Repair System Modulates Curcumin Sensitivity through Induction of DNA Strand Breaks and Activation of G2-M Checkpoint
Authors: Jiang Zhihua , Jin ShunQian , Yalowich Jack C. , Brown Kevin D. , Rajasekaran Baskaran 
Published: February 2010

AbstractThe highly conserved mismatch (MMR) repair system corrects postreplicative errors and modulates cellular responses to genotoxic agents. Here, we show that the MMR system strongly influences cellular sensitivity to curcumin. Compared with MMR-proficient cells, isogenically matched MMR-deficient cells displayed enhanced sensitivity to curcumin. Similarly, cells suppressed for MLH1 or MSH2 expression by RNA interference displayed increased curcumin sensitivity. Curcumin treatment generated comparable levels of reactive oxygen species and the mutagenic adduct 8-oxo-guanine in MMR-proficient and MMR-deficient cells; however, accumulation of γH2AX foci, a marker for DNA double-strand breaks (DSB), occurred only in MMR-positive cells in response to curcumin treatment. Additionally, MMR-positive cells showed activation of Chk1 and induction of G2-M cell cycle checkpoint following curcumin treatment and inhibition of Chk1 by UCN-01 abrogated Chk1 activation and heightened apoptosis in MMR-proficient cells. These results indicate that curcumin triggers the accumulation of DNA DSB and induction of a checkpoint response through a MMR-dependent mechanism. Conversely, in MMR-compromised cells, curcumin-induced DSB is significantly blunted, and as a result, cells fail to undergo cell cycle arrest, enter mitosis, and die through mitotic catastrophe. The results have potential therapeutic value, especially in the treatment of tumors with compromised MMR function. Mol Cancer Ther; 9(3); 558–68
Urinary-Type Plasminogen Activator Receptor/α3β1 Integrin Signaling, Altered Gene Expression, and Oral Tumor Progression
Authors: Ghosh Supurna , Koblinski Jennifer , Johnson Jeffrey , Liu Yueying , Ericsson Aaron , Davis J. Wade , Shi Zonggao , Ravosa Matthew J. , Crawford Susan , Frazier Shellaine , Stack M. Sharon 
Published: February 2010

AbstractOral squamous cell carcinoma (OSCC) has 50% 5-year survival rate, highlighting our limited understanding of the molecular events that contribute to disease progression. Microarray analyses of primary oral tumors have identified urinary-type plasminogen activator (uPA) and its receptor (uPAR) as key genes associated with human OSCC progression. The uPAR functions as both a proteinase receptor and an integrin ligand, modifying proteolysis, migration, integrin signaling, and cellular transcription. In the current study, uPAR expression levels were modified in OSCC cells followed by analysis of tumor growth in an in vivo orthotopic xenograft model and by transcriptional profiling. Overexpression of uPAR resulted in more infiltrative and less differentiated tumors, with ill-defined borders, cytologic atypia, and enhanced vascularity. Analysis of serial sections of both murine experimental tumors and microarrayed human OSCC showed a statistically significant association between uPAR and α3 integrin colocalization in areas exhibiting extracellular signal-regulated kinase phosphorylation, suggesting that uPAR/α3 integrin interaction potentiates extracellular signal-regulated kinase signaling in vivo. This is supported by cDNA microarray analysis, which showed differential expression of 148 genes (113 upregulated and 35 downregulated). Validation of gene expression changes in human OSCC using immunohistochemistry and quantitative real-time PCR showed increased growth factors, proteinases/inhibitors, and matrix components in uPAR-overexpressing tumors. Together, these results support a model wherein increased uPAR expression promotes α3β1 integrin association, resulting in increased mitogen-activated protein kinase signaling and transcriptional activation, leading to the formation of more aggressive tongue tumors. This combined approach has efficacy to identify additional biomarkers and/or prognostic indicators associated with aggressive human OSCC. Mol Cancer Res; 8(2); 145–58
FEN1 Functions in Long Patch Base Excision Repair Under Conditions of Oxidative Stress in Vertebrate Cells
Authors: Asagoshi Kenjiro , Tano Keizo , Chastain Paul D. , Adachi Noritaka , Sonoda Eiichiro , Kikuchi Koji , Koyama Hideki , Nagata Kenji , Kaufman David G. , Takeda Shunichi , Wilson Samuel H. , Watanabe Masami , Swenberg James A. , Nakamura Jun 
Published: February 2010

Abstract
From in vitro studies, flap endonuclease 1 (FEN1) has been proposed to play a role in the long patch (LP) base excision repair (BER) subpathway. Yet the role of FEN1 in BER in the context of the living vertebrate cell has not been thoroughly explored. In the present study, we cloned a DT40 chicken cell line with a deletion in the FEN1 gene and found that these FEN1-deficient cells exhibited hypersensitivity to H2O2. This oxidant produces genotoxic lesions that are repaired by BER, suggesting that the cells have a deficiency in BER affecting survival. In experiments with extracts from the isogenic FEN1 null and wild-type cell lines, the LP-BER activity of FEN1 null cells was deficient, whereas repair by the single-nucleotide BER subpathway was normal. Other consequences of the FEN1 deficiency were also evaluated. These results illustrate that FEN1 plays a role in LP-BER in higher eukaryotes, presumably by processing the flap-containing intermediates of BER. Mol Cancer Res; 8(2); 204–15
Phosphorylation of p53 Serine 18 Upregulates Apoptosis to Suppress Myc-Induced Tumorigenesis
Authors: Sluss Hayla K. , Gannon Hugh , Coles Andrew H. , Shen Qichang , Eischen Christine M. , Jones Stephen N. 
Published: February 2010

Abstract
ATM and p53 are critical regulators of the cellular DNA damage response and function as potent tumor suppressors. In cells undergoing ionizing radiation, ATM is activated by double-strand DNA breaks and phosphorylates the NH2 terminus of p53 at serine residue 18. We have previously generated mice bearing an amino acid substitution at this position (p53S18A) and documented a role for p53 phosphorylation in DNA damage–induced apoptosis. In this present study, we have crossed Eμmyc transgenic mice with our p53S18A mice to explore a role for ATM-p53 signaling in response to oncogene-induced tumorigenesis. Similar to DNA damage induced by ionizing radiation, expression of c-Myc in pre–B cells induces p53 serine18 phosphorylation and Puma expression to promote apoptosis. Eμmyc transgenic mice develop B-cell lymphoma more rapidly when heterozygous or homozygous for p53S18A alleles. However, Eμmyc-induced tumorigenesis in p53S18A mice is slower than that observed in Eμmyc mice deficient for either p53 or ATM, indicating that both p53-induced apoptosis and p53-induced growth arrest contribute to the suppression of B-cell lymphoma formation in Eμmyc mice. These findings further reveal that oncogene expression and DNA damage activate the same ATM-p53 signaling cascade in vivo to regulate apoptosis and tumorigenesis. Mol Cancer Res; 8(2); 216–22
Bcl-2 Overexpression Induces a Partial Epithelial to Mesenchymal Transition and Promotes Squamous Carcinoma Cell Invasion and Metastasis
Authors: Zuo Jianhong , Ishikawa Tohru , Boutros Shadi , Xiao Zhiqiang , Humtsoe Joseph O. , Kramer Randall H. 
Published: February 2010

Abstract
Evidence shows that Bcl-2 family members play a direct role in the development of some human malignancies. However, the mechanism by which Bcl-2 may influence tumor cell invasion and metastasis remains unclear. Ectopic overexpression of Bcl-2 in the human squamous carcinoma cell line HSC-3 enhanced tumorigenicity and experimental pulmonary metastasis. Interestingly, Bcl-2–expressing cells showed morphologic changes that resembled that of cells with an epithelial-mesenchymal transition phenotype. Analysis revealed increased N-cadherin and vimentin expression in parallel with attenuated E-cadherin level, along with enhanced migration and invasive behavior. Zymography studies confirmed elevated levels of matrix metalloproteinase-9 (MMP-9) in media of Bcl-2–expressing cells. siRNA-mediated suppression of N-cadherin expression not only prevented the enhanced invasion but also blocked the increased MMP-9 expression induced by elevated Bcl-2 expression. Accordingly, pharmacologic inhibition of MMP-9 abrogated the increased tumor cell invasion. Furthermore, the Bcl-2–mediated increase in MMP-9 expression and tumor cell invasion was dependent on fibroblast growth factor receptor-1 or extracellular signal–regulated kinase signaling. Collectively, the data establish that Bcl-2 overexpression in squamous carcinoma cells induces a partial epithelial to mesenchymal transition that promotes not only survival but also invasion and metastasis through the N-cadherin/fibroblast growth factor receptor/extracellular signal–regulated kinase pathway. Mol Cancer Res; 8(2); 170–82
Cyclooxygenase-2 Is a Novel Transcriptional Target of the Nuclear EGFR-STAT3 and EGFRvIII-STAT3 Signaling Axes
Authors: Lo Hui-Wen , Cao Xinyu , Zhu Hu , Ali-Osman Francis 
Published: February 2010

Abstract
Emerging evidence indicates a novel mode of epidermal growth factor receptor (EGFR) signaling, notably, one involves EGFR nuclear translocalization and subsequent gene activation. To date, however, the significance of the nuclear EGFR pathway in glioblastoma (GBM) is unknown. Here, we report that EGFR and its constitutively activated variant EGFRvIII undergo nuclear translocalization in GBM cells, in which the former event requires EGF stimulation and the latter is constitutive. To gain insights into the effect of nuclear EGFR on gene expression in GBM, we created isogenic GBM cell lines, namely, U87MG-vector, U87MG-EGFR, and U87MG-EGFRdNLS that, respectively, express the control vector, EGFR, and nuclear entry–defective EGFR with a deletion of the nuclear localization signal (NLS). Microarray analysis shows that 19 genes, including cyclooxygenase-2 (COX-2), to be activated in U87MG-EGFR cells but not in U87MG-EGFRdNLS and U87MG-vector cells. Subsequent validation studies indicate that COX-2 gene is expressed at higher levels in cells with EGFR and EGFRvIII than those with EGFRdNLS and EGFRvIIIdNLS. Nuclear EGFR and its transcriptional cofactor signal transducer and activator of transcription 3 (STAT3) associate with the COX-2 promoter. Increased expression of EGFR/EGFRvIII and activated STAT3 leads to the synergistic activation of the COX-2 promoter. Promoter mutational analysis identified a proximal STAT3-binding site that is required for EGFR/EGFRvIII-STAT3–mediated COX-2 gene activation. In GBM tumors, an association exists between levels of COX-2, EGFR/EGFRvIII, and activated STAT3. Together, these findings indicate the existence of the nuclear EGFR/EGFRvIII signaling pathway in GBM and its functional interaction with STAT3 to activate COX-2 gene expression, thus linking EGFR-STAT3 and EGFRvIII-STAT3 signaling axes to proinflammatory COX-2 mediated pathway. Mol Cancer Res; 8(2); 232–45
Elevated Phosphate Activates N-ras and Promotes Cell Transformation and Skin Tumorigenesis
Authors: Camalier Corinne E. , Young Matthew R. , Bobe Gerd , Perella Christine M. , Colburn Nancy H. , Beck George R. 
Published: February 2010

AbstractRecent results suggest a paradigm shift from viewing inorganic phosphate as a passive requirement for basic cell functions to an active regulator of cell behavior. We have previously shown that elevated concentrations of phosphate increased cell proliferation and expression of protumorigenic genes such as Fra-1 and osteopontin in a preosteoblast cell line. Therefore, we hypothesized that elevated phosphate concentrations would promote cell transformation in vitro and tumorigenesis in vivo. Supplementation of medium with phosphate increased anchorage-independent transformation and proliferation of BALB/c mouse JB6 epidermal cells, activation of N-ras, ERK1/2, and activator protein-1, and increased gene expression of Fra-1, COX-2, and osteopontin in a dose-dependent manner. These in vitro results led to the hypothesis that varying the levels of dietary inorganic phosphate would alter tumorigenesis in the mouse model of skin carcinogenesis. Female FVB/N mice were treated with 7,12-dimethylbenz(a)anthracene/12-O-tetradecanoylphorbol-13-acetate and fed high- or low-phosphate diets (1.2% versus 0.2% of the diet) for 19 weeks. The high-phosphate diet increased skin papilloma number by ∼50% without changing feed intake and body weights. High dietary phosphate increased serum concentrations of phosphate, parathyroid hormone, and osteopontin and decreased serum concentrations of calcium. Thus, we conclude that elevated phosphate promotes cell transformation and skin tumorigenesis partly by increasing the availability of phosphate for activation of N-ras and its downstream targets, which defines reducing dietary phosphate as a novel target for chemoprevention. Cancer Prev Res; 3(3); 359–70
Parity-Induced Decrease in Systemic Growth Hormone Alters Mammary Gland Signaling: A Potential Role in Pregnancy Protection from Breast Cancer
Authors: Dearth Robert K. , Delgado David A. , Hiney Jill K. , Pathiraja Thushangi , Oesterreich Steffi , Medina Dan , Dees W. Les , Lee Adrian V. 
Published: February 2010

AbstractEarly full-term pregnancy is an effective natural protection against breast cancer in both humans and experimental rodents. The protective effect of an early pregnancy is, in part, linked to changes in circulating hormones that are involved in both normal breast development and breast cancer. For example, a reduction in circulating growth hormone (GH) has been shown to protect rats from carcinogen-induced mammary tumors. We examined the ability of a full-term pregnancy to alter the endocrine GH/insulin-like growth factor-I (IGF-I) axis and how this change affected normal mammary gland function in two commonly used rat models (Sprague-Dawley and Wistar Furth). Circulating GH and IGF-I were measured in blood drawn every 30 minutes from parous and age-matched virgin female rats. Mean serum GH levels were significantly decreased (P &lt; 0.01) in parous compared with age-matched virgin rats for both strains. Changes in GH levels were independent of estrous cycle, indicated by a significant (P &lt; 0.05) reduction in circulating levels of GH during estrus and diestrus in both parous strains. Despite the decrease in circulating GH, pituitary GH mRNA levels were unaltered in parous rats. Circulating IGF-I and hepatic IGF-I mRNA were also unaltered by parity in either rat strain. Immunoblot analysis of mammary glands showed decreases in phosphorylation of signal transducer and activator of transcription 5A and Janus-activated kinase 2, suggesting reduced action of GH in the mammary gland. Therefore, although the parity reduction in circulating GH does not affect circulating IGF-I levels, it is possible that reduced GH acts directly at the mammary gland and may play a role in pregnancy protection from breast cancer. Cancer Prev Res; 3(3); 312–21
Null Activity of Selenium and Vitamin E as Cancer Chemopreventive Agents in the Rat Prostate
Authors: McCormick David L. , Rao K.V.N. , Johnson William D. , Bosland Maarten C. , Lubet Ronald A. , Steele Vernon E. 
Published: February 2010

Abstract
To evaluate the potential efficacy of selenium and vitamin E as inhibitors of prostate carcinogenesis, four chemoprevention studies using a common protocol were done in a rat model of androgen-dependent prostate cancer. After stimulation of prostate epithelial cell proliferation by a sequential regimen of cyproterone acetate followed by testosterone propionate, male Wistar-Unilever rats received a single i.v. injection of N-methyl-N-nitrosourea (MNU) followed by chronic androgen stimulation via subcutaneous implantation of testosterone pellets. At 1 week post-MNU, groups of carcinogen-treated rats (39-44/group) were fed either a basal diet or a basal diet supplemented with l-selenomethionine (3 or 1.5 mg/kg diet; study 1), dl-α-tocopherol (vitamin E, 4,000 or 2,000 mg/kg diet; study 2), l-selenomethionine + vitamin E (3 + 2,000 mg/kg diet or 3 + 500 mg/kg diet; study 3), or selenized yeast (target selenium levels of 9 or 3 mg/kg diet; study 4). Each chemoprevention study was terminated at 13 months post-MNU, and prostate cancer incidence was determined by histopathologic evaluation. No statistically significant reductions in prostate cancer incidence were identified in any group receiving dietary supplementation with selenium and/or vitamin E. These data do not support the hypotheses that selenium and vitamin E are potent cancer chemopreventive agents in the prostate, and when considered with the recent clinical data reported in the Selenium and Vitamin E Cancer Prevention Trial (SELECT), show the predictive nature of this animal model for human prostate cancer chemoprevention. Cancer Prev Res; 3(3); 381–92