bluuebunny/crossref_metadata_2025_split huggingface dataset:
Impaired Skin and Mammary Gland Development and Increased γ-Irradiation–Induced Tumorigenesis in Mice Carrying a Mutation of S1152-ATM Phosphorylation Site in Brca1
Authors: Kim Sang Soo , Cao Liu , Baek Hye Jung , Lim Sung-Chul , Li Cuiling , Wang Rui-Hong , Xu Xiaoling , Cho Kwan Ho , Deng Chu-Xia 
Published: December 2009

Abstract
The tumor suppressor BRCA1 interacts with many proteins and undergoes multiple modifications on DNA damage. ATM, a key molecule of the DNA damage response, phosphorylates S1189 of BRCA1 after γ-irradiation. S1189 of BRCA1 is known as a unique ATM phosphorylation site in BRCA1 exon 11. To study the functions of ATM-dependent phosphorylation of BRCA1-S1189, we generated a mouse model carrying a mutation of S1152A (S1152 in mouse Brca1 corresponds to S1189 in human BRCA1) by gene targeting. Brca1S1152A/S1152A mice were born at the expected ratio, unlike that seen in previous studies of Brca1-null mice. However, 36% of Brca1S1152A/S1152A mice exhibited aging-like phenotypes including growth retardation, skin abnormalities, and delay of the mammary gland morphogenesis, with an increase in apoptosis. Mutant mice were hypersensitive to high doses of γ-irradiation, displaying shortened life span and reduction in intestinal villus size, associated with increased apoptosis. Aging-unaffected 18-month-old Brca1S1152A/S1152A female mice also showed mammary gland abnormalities with increased levels of cyclin D1 and phospho-ER-α, such as Brca1-Δ11 mutation. On low-dose γ-irradiation, they suffered a marked increase in tumor formation with an abnormal coat pattern. Furthermore, Brca1S1152A/S1152A embryonic fibroblasts failed to accumulate p53 on γ-irradiation with delayed phosphorylation of p53-S23. These observations indicate that ATM-mediated phosphorylation of S1189 is required for BRCA1 functions in the modulation of DNA damage response and in the suppression of tumor formation by regulating p53 and apoptosis. [Cancer Res 2009;69(24):9291–300]
ZBRK1 Acts as a Metastatic Suppressor by Directly Regulating MMP9 in Cervical Cancer
Authors: Lin Li-Fang , Chuang Chih-Hung , Li Chien-Feng , Liao Ching-Chun , Cheng Chun-Pei , Cheng Tian-Lu , Shen Meng-Ru , Tseng Joseph T. , Chang Wen-Chang , Lee Wen-Hwa , Wang Ju-Ming 
Published: December 2009

Abstract
The BRCA1-interacted transcriptional repressor ZBRK1 has been associated with antiangiogenesis, but direct evidence of a tumor suppressor role has been lacking. In this study, we provide evidence of such a role in cervical carcinoma. ZBRK1 levels in cervical tumor cells were significantly lower than in normal cervical epithelial cells. In HeLa cervical cancer cells, enforced expression inhibited malignant growth, invasion, and metastasis in a variety of in vitro and in vivo assays. Expression of the metalloproteinase MMP9, which is known to be an important driver of invasion and metastasis, was found to be inversely correlated with ZBRK1 in tumor tissues and a target for repression in tumor cells. Our findings suggest that ZBRK1 acts to inhibit metastasis of cervical carcinoma, perhaps by modulating MMP9 expression. Cancer Res; 70(1); 192–201
Mutant Metabolic Enzymes Are at the Origin of Gliomas
Authors: Yan Hai , Bigner Darell D. , Velculescu Victor , Parsons D. Williams 
Published: December 2009

Abstract
Mutations of the isocitrate dehydrogenase (IDH) metabolic enzymes IDH1 and IDH2 have been found to be frequent and early genetic alterations in astrocytomas and oligodendrogliomas. All mutations identified to date affect a single amino acid located within the isocitrate binding site (R132 of IDH1 and the analogous R172 residue of IDH2). IDH1 and IDH2 mutations define a specific subtype of gliomas and may have significant utility for the diagnosis, prognosis, and treatment of patients with these tumors. [Cancer Res 2009;69(24):9157–9]
Antigen Presentation by Dendritic Cells in Tumors Is Disrupted by Altered Metabolism that Involves Pyruvate Kinase M2 and Its Interaction with SOCS3
Authors: Zhang Zhuohan , Liu Qiaofei , Che Yongzhe , Yuan Xin , Dai Lingyun , Zeng Bin , Jiao Guohui , Zhang Yin , Wu Xue , Yu Yinyan , Zhang Yuan , Yang Rongcun 
Published: December 2009

AbstractDendritic cell (DC) function is negatively affected by tumors and tumor-derived factors, but little is known about the underlying mechanisms. Here, we show that intracellular SOCS3 in DCs binds to pyruvate kinase type M2 (M2-PK), which plays a critical role in ATP production through glycolysis. The interaction of SOCS3 with M2-PK reduced ATP production and impaired DC-based immunotherapy against tumors. Thus, SOCS3, which has been shown to be upregulated by tumor-derived factors, interacts with M2-PK to decrease ATP production, causing DC dysfunction. These dysfunctional DCs have a reduced ability to present antigens. Alteration of DC metabolism mediated by SOCS3 represents a novel mechanism for DC dysfunction in the tumor microenvironment. Cancer Res; 70(1); 89–98
The Aryl Hydrocarbon Receptor Functions as a Tumor Suppressor of Liver Carcinogenesis
Authors: Fan Yunxia , Boivin Gregory P. , Knudsen Erik S. , Nebert Daniel W. , Xia Ying , Puga Alvaro 
Published: December 2009

AbstractThe aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor that mediates the biological and toxic effects of its xenobiotic ligands. Previous cell culture studies have shown that, in addition to controlling the xenobiotic detoxification response, AHR activation leads to G0-G1 arrest, diminished capacity for DNA replication, and inhibition of cell proliferation. In fact, recent work from our own and from other laboratories suggests that AHR may function as a tumor suppressor gene that becomes silenced during the process of tumor formation. To test this hypothesis and determine whether the mouse Ahr gene acts as a tumor suppressor gene in vivo, we have examined the role of Ahr ablation in liver tumorigenesis induced by the genotoxic chemical diethylnitrosamine (DEN), a hepatic carcinogen that is not an AHR ligand. In mice given a single i.p. injection of DEN, AHR antagonized liver tumor formation and growth by regulating cell proliferation, inflammatory cytokine expression, and DNA damage, parameters which were significantly elevated in the livers of control and, more so, of DEN-exposed Ahr−/− mice. Ahr−/− hepatocytes also showed significantly higher numbers of 4N cells, increased expression of proliferative markers, and repression of tumor suppressor genes. These data support the concept that in its basal state in the absence of a xenobiotic ligand, the Ahr gene functions as a tumor suppressor gene, and that its silencing may be associated with cancer progression. Cancer Res; 70(1); 212–220
A Gold(III) Porphyrin Complex with Antitumor Properties Targets the Wnt/β-catenin Pathway
Authors: Chow Kim Hei-Man , Sun Raymond Wai-Yin , Lam Janice B.B. , Li Carrie Ka-Lei , Xu Aimin , Ma Dik-Lung , Abagyan Ruben , Wang Yu , Che Chi-Ming 
Published: December 2009

AbstractGold(III) complexes have shown promise as antitumor agents, but their clinical usefulness has been limited by their poor stability under physiological conditions. A novel gold(III) porphyrin complex [5-hydroxyphenyl-10,15,20-triphenylporphyrinato gold(III) chloride (gold-2a)] with improved aqueous stability showed 100-fold to 3,000-fold higher cytotoxicity than platinum-based cisplatin and IC50 values in the nanomolar range in a panel of human breast cancer cell lines. Intraductal injections of gold-2a significantly suppressed mammary tumor growth in nude mice. These effects are attributed, in part, to attenuation of Wnt/β-catenin signaling through inhibition of class I histone deacetylase (HDAC) activity. These data, in combination with computer modeling, suggest that gold-2a may represent a promising class of anticancer HDAC inhibitor preferentially targeting tumor cells with aberrant Wnt/β-catenin signaling. Cancer Res; 70(1); 329–37
14-3-3η Amplifies Androgen Receptor Actions in Prostate Cancer
Authors: Titus Mark A. , Tan Jiann-an , Gregory Christopher W. , Ford O. Harris , Subramanian Romesh R. , Fu Haian , Wilson Elizabeth M. , Mohler James L. , French Frank S. 
Published: December 2009

Abstract
Purpose: Androgen receptor abundance and androgen receptor–regulated gene expression in castration-recurrent prostate cancer are indicative of androgen receptor activation in the absence of testicular androgen. Androgen receptor transactivation of target genes in castration-recurrent prostate cancer occurs in part through mitogen signaling that amplifies the actions of androgen receptor and its coregulators. Herein we report on the role of 14-3-3η in androgen receptor action.
Experimental Design and Results: Androgen receptor and 14-3-3η colocalized in COS cell nuclei with and without androgen, and 14-3-3η promoted androgen receptor nuclear localization in the absence of androgen. 14-3-3η interacted with androgen receptor in cell-free binding and coimmunoprecipitation assays. In the recurrent human prostate cancer cell line, CWR-R1, native endogenous androgen receptor transcriptional activation was stimulated by 14-3-3η at low dihydrotestosterone concentrations and was increased by epidermal growth factor. Moreover, the dihydrotestosterone- and epidermal growth factor–dependent increase in androgen receptor transactivation was inhibited by a dominant negative 14-3-3η. In the CWR22 prostate cancer xenograft model, 14-3-3η expression was increased by androgen, suggesting a feed-forward mechanism that potentiates both 14-3-3η and androgen receptor actions. 14-3-3η mRNA and protein decreased following castration of tumor-bearing mice and increased in tumors of castrate mice after treatment with testosterone. CWR22 tumors that recurred 5 months after castration contained 14-3-3η levels similar to the androgen-stimulated tumors removed before castration. In a human prostate tissue microarray of clinical specimens, 14-3-3η localized with androgen receptor in nuclei, and the similar amounts expressed in castration-recurrent prostate cancer, androgen-stimulated prostate cancer, and benign prostatic hyperplasia were consistent with androgen receptor activation in recurrent prostate cancer.
Conclusion: 14-3-3η enhances androgen- and mitogen-induced androgen receptor transcriptional activity in castration-recurrent prostate cancer. (Clin Cancer Res 2009;15(24):7571–81)
Interactions between MDM2 and TP53 Genetic Alterations, and Their Impact on Response to MDM2 Inhibitors and Other Chemotherapeutic Drugs in Cancer Cells
Authors: Liu Wanqing , He Lijun , Ramírez Jacqueline , Ratain Mark J. 
Published: December 2009

Abstract
Purpose: MDM2 is a key negative regulator of the p53 signaling pathway. We aimed to evaluate the inter-relationships between MDM2 SNP309, mRNA expression, amplification, and TP53 mutations, as well as their correlations with responsiveness to MDM2 inhibitors and other commonly used cytotoxic drugs tested in the NCI-60 cancer cell panel.
Experimental Design: SNP309 was genotyped in the NCI-60 cancer cell lines. MDM2 mRNA levels and gene copy number were measured using real-time PCR. We assessed the inter-relationship between MDM2 genetic alterations, TP53 mutations, and the cytotoxicity of two MDM2 inhibitors (RITA and Nutlin-3) as well as 111 other drugs with known mechanisms of action.
Results: In the overall NCI-60 cell panel, MDM2 mRNA levels were not associated with SNP309 but with increased gene copy number. However, SNP309 strongly determined the MDM2 mRNA expression in cancer cells with wild-type TP53. Cancer cells with wild-type TP53 also had significantly higher MDM2 copies. In the overall panel, MDM2 copy number was independently correlated with increased sensitivity to commonly used alkylating agents and topoisomerase I and II inhibitors. SNP309 was significantly associated with increased sensitivity to alkylating agents and topoisomerase I inhibitors in the cells with wild-type TP53. In addition, TP53 mutations were the only factor significantly associated with cellular resistance to the MDM2 inhibitor RITA.
Conclusions: Our results suggest that MDM2 copy number and SNP309 may predict for response to alkylating agents and topoisomerase inhibitors. These markers should be tested further, particularly in combination with other putative predictive biomarkers. (Clin Cancer Res 2009;15(24):7602–7)
Predictive Potential of Angiogenic Growth Factors and Circulating Endothelial Cells in Breast Cancer Patients Receiving Metronomic Chemotherapy Plus Bevacizumab
Authors: Calleri Angelica , Bono Anna , Bagnardi Vincenzo , Quarna Jessica , Mancuso Patrizia , Rabascio Cristina , Dellapasqua Silvia , Campagnoli Elisabetta , Shaked Yuval , Goldhirsch Aron , Colleoni Marco , Bertolini Francesco 
Published: December 2009

Abstract
Purpose: The association of chemotherapy and antiangiogenic drugs has shown efficacy in clinical oncology. However, there is a need for biomarkers that allow selection of patients who are likely to benefit from such treatment and are useful for indicating best drug combination and schedule.
Experimental Design: We investigated the predictive potential of six angiogenic molecules/transcripts and nine subpopulations of circulating endothelial cells (CEC) and progenitors (CEP) in 46 patients with advanced breast cancer treated with metronomic cyclophosphamide and capecitabine plus bevacizumab.
Results: Median time to progression was 281 days. Baseline CECs higher than the first quartile were associated with an increased time to progression (P = 0.021). At progression, CECs were markedly reduced (P = 0.0002). In the cohort of 15 long-term responders, who progressed later than 1 year after beginning of therapy, circulating vascular endothelial growth factor (VEGF)-A levels measured after 2 months of therapy were significantly reduced, and there were significant trends toward lower levels of PDGF-BB, CEPs, and CECs. At the time of progression, angiogenic growth factors VEGF-A and basic fibroblast growth factor were significantly increased.
Conclusions: Baseline CECs (likely reflecting an active vascular turnover) predicted a prolonged clinical benefit. At the time of relapse, a pattern of decreased CECs and increased angiogenic growth factors suggested a switch toward a different type of cancer vascularization. VEGF-A and basic fibroblast growth factor levels after 2 months of therapy were also useful to identify patients whose disease was likely to progress. These biomarkers are likely to be useful for treatment selection and might be incorporated in design of future studies. (Clin Cancer Res 2009;15(24):7652–7)
Smoking-Related Gene Expression in Laser Capture–Microdissected Human Lung
Authors: Tan Xiang-Lin , Wang Tao , Xiong Shengli , Kumar Shalini V. , Han Weiguo , Spivack Simon D. 
Published: December 2009

AbstractPurpose: Interindividual differences in quantitative expression could underlie a propensity for lung cancer. To determine precise individual gene expression signatures on a lung compartment–specific basis, we investigated the expression of carcinogen metabolism genes encoding cytochromes P450 (CYP) 1B1, 2A13, GSTP1, and a tumor suppressor gene p16 in laser capture–microdissected samples of human alveolar compartment (AC) and bronchial epithelial compartment (BEC) lung tissue from 62 smokers and nonsmokers.Experimental Design: Tobacco exposure was determined by plasma nicotine, cotinine, and smoking history. Precise mRNA expression was determined using our RNA-specific qRT-PCR strategy, and correlated with detailed demographic and clinical characteristics.Results: Several correlations of mRNA expression included (a) CYP1B1 in AC (positively with plasma nicotine level, P = 0.008; plasma cotinine level, P = 0.001), (b) GSTP1 in AC (positively with plasma cotinine level, P = 0.003), and (c) GSTP1 in BEC (negatively with smoke dose, P = 0.043; occupational risk, P = 0.019). CYP2A13 was rarely expressed in AC and not expressed in BEC. p16 expression was not correlated with any measured factor. For each gene, subjects showed expression that was individually concordant between these compartments. No clear association of mRNA expression with lung cancer risk was observed in this pilot analysis.Conclusions: The association between lung mRNA expression and tobacco exposure implies that gene-tobacco interaction is a measurable quantitative trait, albeit with wide interindividual variation. Gene expression tends to be concordant for alveolar and bronchial compartments for these genes in an individual, controlling for proximate tobacco exposure. (Clin Cancer Res 2009;15(24):7562–70)
Characterizing the Clinical Relevance of an Embryonic Stem Cell Phenotype in Lung Adenocarcinoma
Authors: Stevenson Marvaretta , Mostertz William , Acharya Chaitanya , Kim William , Walters Kelli , Barry William , Higgins Kristin , Tuchman Sascha A. , Crawford Jeffrey , Vlahovic Gordana , Ready Neal , Onaitis Mark , Potti Anil 
Published: December 2009

Abstract
Purpose: Cancer cells possess traits reminiscent of those ascribed to normal stem cells. It is unclear whether these phenotypic similarities are the result of a common biological phenotype, such as regulatory pathways.
Experimental Design: Lung cancer cell lines with corresponding gene expression data and genes associated with an embryonic stem cell identity were used to develop a signature of embryonic stemness (ES) activity specific to lung adenocarcinoma. Biological characteristics were elucidated as a function of cancer biology/oncogenic pathway dysregulation. The ES signature was applied to three independent early-stage (I-IIIa) lung adenocarcinoma data sets with clinically annotated gene expression data. The relationship between the ES phenotype and cisplatin (current standard of care) sensitivity was evaluated.
Results: Pathway analysis identified specific regulatory networks [Ras (P = 0.0005), Myc (P = 0.0224), wound healing (P &lt; 0.0001), chromosomal instability (P &lt; 0.0001), and invasiveness (P &lt; 0.0001)] associated with the ES phenotype. The prognostic relevance of the ES signature, as related to patient survival, was characterized in three cohorts [CALGB 9761 (n = 82; P = 0.0001), National Cancer Institute Director's Challenge Consortium (n = 442; P = 0.0002), and Duke (n = 45; P = 0.06)]. The ES signature was not prognostic in prostate, breast, or ovarian adenocarcinomas. Lung tumors (n = 569) and adenocarcinoma cell lines (n = 31) expressing the ES phenotype were more likely to be resistant to cisplatin (P &lt; 0.0001 and P = 0.006, respectively).
Conclusions: Lung adenocarcinomas that share a common gene expression pattern with normal human embryonic stem cells were associated with decreased survival, increased biological complexity, and increased likelihood of resistance to cisplatin. This indicates the aggressiveness of these tumors. (Clin Cancer Res 2009;15(24):7553–61)
ABCC2, ABCC3, and ABCB1, but not CYP3A, Protect against Trabectedin-Mediated Hepatotoxicity
Authors: van Waterschoot Robert A.B. , Eman Rhandy M. , Wagenaar Els , van der Kruijssen Cornelia M.M. , Rosing Hilde , Beijnen Jos H. , Schinkel Alfred H. 
Published: December 2009

Abstract
Purpose: Trabectedin (Yondelis, ET-743) is a novel anticancer drug with potent activity against various tumors. However, dose-limiting hepatotoxicity was observed during clinical trials. Because recent reports have suggested that cytochrome P450 3A (CYP3A), as well as the drug transporters ABCB1, ABCC2, and ABCC3 might protect against trabectedin-mediated hepatotoxicity, we investigated the individual and combined roles of these detoxifying systems.
Experimental Design: Madin-Darby canine kidney cells expressing ABCC2 and ABCC3 were used to study in vitro trabectedin transport. We investigated the hepatotoxicity of trabectedin, and the plasma and liver levels of this drug and its metabolites in mice deficient for CYP3A, Abcb1a/1b, Abcc2, and/or Abcc3 after i.v. trabectedin administration.
Results: Trabectedin was transported by ABCC2 but only modestly by ABCC3. Contrary to our expectation, absence of CYP3A resulted in only a marginal increase in hepatotoxicity. Some hepatotoxicity was observed in Abcc2−/− mice, but very little in Abcb1a/1b−/− and Abcc3−/− mice. Strikingly, severe hepatotoxicity was found in Abcb1a/1b/Abcc2−/− and Abcc2/Abcc3−/− mice. However, hepatotoxicity was drastically decreased in Cyp3a/Abcb1a/1b/Abcc2−/− compared with Abcb1a/1b/Abcc2−/− mice. This suggests that the formation of CYP3A-specific metabolites is an important prerequisite for trabectedin-mediated hepatotoxicity. Further studies revealed that there is increased accumulation of metabolites of trabectedin, but not of trabectedin itself, in the livers of mice that lack Abcc2 but are CYP3A proficient.
Conclusions: Our data show that ABCB1, ABCC2, and ABCC3 have a profound and partially redundant function in protection from trabectedin-mediated hepatotoxicity, presumably by clearing the liver from hepatotoxic trabectedin metabolites that are primarily formed by CYP3A. (Clin Cancer Res 2009;15(24):7616–23)
Analysis of VHL Gene Alterations and their Relationship to Clinical Parameters in Sporadic Conventional Renal Cell Carcinoma
Authors: Young Alison C. , Craven Rachel A. , Cohen Dena , Taylor Claire , Booth Christopher , Harnden Patricia , Cairns David A. , Astuti Dewi , Gregory Walter , Maher Eamonn R. , Knowles Margaret A. , Joyce Adrian , Selby Peter J. , Banks Rosamonde E. 
Published: December 2009

Abstract
Purpose: This study aimed to carry out a comprehensive analysis of genetic and epigenetic changes of the von Hippel Lindau (VHL) gene in patients with conventional (clear cell) renal cell carcinoma and to determine their significance relative to clinicopathologic characteristics and outcome.
Experimental Design: The VHL status in 86 conventional renal cell carcinomas was determined by mutation detection, loss of heterozygosity (LOH), and promoter methylation analysis, extending our original cohort to a total of 177 patients. Data were analyzed to investigate potential relationships between VHL changes, clinical parameters, and outcome.
Results: LOH was found in 89.2%, mutation in 74.6%, and methylation in 31.3% of evaluable tumors; evidence of biallelic inactivation (LOH and mutation or methylation alone) was found in 86.0% whereas no involvement of VHL was found in only 3.4% of samples. Several associations were suggested, including those between LOH and grade, nodal status and necrosis, mutation and sex, and methylation and grade. Biallelic inactivation may be associated with better overall survival compared with patients with no VHL involvement, although small sample numbers in the latter group severely limit this analysis, which requires independent confirmation.
Conclusions: This study reports one of the highest proportions of conventional renal cell carcinoma with VHL changes, and suggests possible relationships between VHL status and clinical variables. The data suggest that VHL defects may define conventional renal cell carcinomas but the clinical significance of specific VHL alterations will only be clarified by the determination of their biological effect at the protein level rather than through genetic or epigenetic analysis alone. (Clin Cancer Res 2009;15(24):7582–92)