bluuebunny/crossref_metadata_2025_split huggingface dataset:
Fibronectin Expression Modulates Mammary Epithelial Cell Proliferation during Acinar Differentiation
Authors: Williams Courtney M. , Engler Adam J. , Slone R. Daniel , Galante Leontine L. , Schwarzbauer Jean E. 
Published: May 2008

Abstract
The mammary gland consists of a polarized epithelium surrounded by a basement membrane matrix that forms a series of branching ducts ending in hollow, sphere-like acini. Essential roles for the epithelial basement membrane during acinar differentiation, in particular laminin and its integrin receptors, have been identified using mammary epithelial cells cultured on a reconstituted basement membrane. Contributions from fibronectin, which is abundant in the mammary gland during development and tumorigenesis, have not been fully examined. Here, we show that fibronectin expression by mammary epithelial cells is dynamically regulated during the morphogenic process. Experiments with synthetic polyacrylamide gel substrates implicate both specific extracellular matrix components, including fibronectin itself, and matrix rigidity in this regulation. Alterations in fibronectin levels perturbed acinar organization. During acinar development, increased fibronectin levels resulted in overproliferation of mammary epithelial cells and increased acinar size. Addition of fibronectin to differentiated acini stimulated proliferation and reversed growth arrest of mammary epithelial cells negatively affecting maintenance of proper acinar morphology. These results show that expression of fibronectin creates a permissive environment for cell growth that antagonizes the differentiation signals from the basement membrane. These effects suggest a link between fibronectin expression and epithelial cell growth during development and oncogenesis in the mammary gland. [Cancer Res 2008;68(9):3185–92]
MDM2 Regulates Dihydrofolate Reductase Activity through Monoubiquitination
Authors: Maguire Maria , Nield Paul C. , Devling Timothy , Jenkins Rosalind E. , Park B. Kevin , Polański Radosław , Vlatković Nikolina , Boyd Mark T. 
Published: May 2008

Abstract
MDM2 is a ubiquitin ligase that is best known for its essential function in the negative regulation of p53. In addition, MDM2 expression is associated with tumor progression in a number of common cancers, and in some cases, this has been shown to be independent of p53 status. MDM2 has been shown to promote the degradation of a number of other proteins involved in the regulation of normal cell growth and proliferation, including MDM4 and RB1. Here, we describe the identification of a novel substrate for the MDM2 ubiquitin ligase: dihydrofolate reductase (DHFR). MDM2 binds directly to DHFR and catalyses its monoubiquitination and not its polyubiquitination. In addition, MDM2 expression reduces DHFR activity in a p53-independent manner, but has no effect upon the steady-state level of expression of DHFR. We show that changes in MDM2 expression alter folate metabolism in cells as evidenced by MDM2-dependent alteration in the sensitivity of cells to the antifolate drug methotrexate. Furthermore, we show that the ability of MDM2 to inhibit DHFR activity depends upon an intact MDM2 RING finger. Our studies provide for the first time a link between MDM2, an oncogene with a critical ubiquitin ligase activity and a vital one-carbon donor pathway involved in epigenetic regulation, and DNA metabolism, which has wide ranging implications for both cell biology and tumor development. [Cancer Res 2008;68(9):3232–41]
Inhibition of Telomerase Activity Enhances Hyperthermia-Mediated Radiosensitization
Authors: Agarwal Manjula , Pandita Shruti , Hunt Clayton R. , Gupta Arun , Yue Xuan , Khan Saira , Pandita Raj K. , Pratt David , Shay Jerry W. , Taylor John-Stephen A. , Pandita Tej K. 
Published: May 2008

Abstract
Hyperthermia is a potent sensitizer of cell killing by ionizing radiation (IR); however, hyperthermia also induces heat shock protein 70 (HSP70) synthesis and HSP70 expression is associated with radioresistance. Because HSP70 interacts with the telomerase complex and expression of the telomerase catalytic unit (hTERT) extends the life span of the human cells, we determined if heat shock influences telomerase activity and whether telomerase inhibition enhances heat-mediated IR-induced cell killing. In the present study, we show that moderate hyperthermia (43°C) enhances telomerase activity. Inhibition of telomerase activity with human telomerase RNA–targeted antisense agents, and in particular GRN163L, results in enhanced hyperthermia-mediated IR-induced cell killing, and ectopic expression of catalytic unit of telomerase (TERT) decreased hyperthermia-mediated IR-induced cell killing. The increased cell killing by heat and IR exposure in telomerase-inhibited cells correlates with delayed appearance and disappearance of γ-H2AX foci as well as decreased chromosome repair. These results suggest that inactivation of telomerase before combined hyperthermia and radiotherapy could improve tumor killing. [Cancer Res 2008;68(9):3370–9]
Oncogene Addiction versus Oncogene Amnesia: Perhaps More than Just a Bad Habit?
Authors: Felsher Dean W. 
Published: May 2008

AbstractCancer is a multistep process whereby genetic events that result in the activation of proto-oncogenes or the inactivation of tumor suppressor genes usurp physiologic programs mandating relentless proliferation and growth. Experimental evidence surprisingly illustrates that the inactivation of even a single oncogene can be sufficient to induce sustained tumor regression. These observations suggest the hypothesis that tumors become irrevocably addicted to the oncogenes that initiated tumorigenesis. The proposed explanation for this phenomenon is that activated oncogenes result in a signaling state in which the sudden abatement of oncogene activity balances towards proliferative arrest and apoptosis. Indeed, substantial evidence supports this hypothesis. Here, we propose an alternative, although not necessarily mutually exclusive, explanation for how oncogenes initiate and sustain tumorigenesis. We suggest that oncogene activation initiates tumorigenesis precisely because it directly overrides physiologic programs inducing a state of cellular amnesia, not only inducing relentless cellular proliferation, but also bypassing checkpoint mechanisms that are essential for cellular mortality, self-renewal, and genomic integrity. Because no single oncogenic lesion is sufficient to overcome all of these physiologic barriers, oncogenes are restrained from inducing tumorigenesis. Correspondingly, in a tumor that has acquired the complete complement of oncogenic lesions required to overcome all of these safety mechanisms, the inactivation of a single oncogene can restore some of these pathways resulting in proliferative arrest, differentiation, cellular senescence, and/or apoptosis. Thus, oncogenes induce cancer because they induce a cellular state of enforced oncogenic amnesia in which, only upon oncogene inactivation, the tumor becomes aware of its transgression. [Cancer Res 2008;68(9):3081–6]
mda-9/Syntenin: More than Just a Simple Adapter Protein When It Comes to Cancer Metastasis
Authors: Sarkar Devanand , Boukerche Habib , Su Zao-zhong , Fisher Paul B. 
Published: May 2008

Abstract
Cancer is a progressive disease that, in many instances, if untreated, can culminate in metastatic spread of primary tumor cells to distant sites in the body. Metastasis frequently confers virulence and therapy resistance to cancer cells, and defining the molecular events that control metastasis will be mandatory to develop rational, targeted therapies for effective intervention, prevention of recurrence, and the “holy grail” of engendering a cure. Adapter proteins are physiologically pertinent molecules that, through interactions with key regulatory proteins via specific conserved domains, control important cellular events. Melanoma differentiation associated gene-9 (mda-9), also known as syntenin, is a PDZ domain–containing adapter protein that is involved in organization of protein complexes in the plasma membranes, regulation of B-cell development, intracellular trafficking and cell-surface targeting, synaptic transmission, and axonal outgrowth. Recent studies now define a seminal role for mda-9/sytenin in cancer metastasis. The present review provides a current perspective of our understanding of this important aspect of mda-9/sytenin, suggesting that this gene and its encoded protein and interacting protein partners may provide viable targets for intervening in the final and invariably the most lethal stage of cancer progression, namely, cancer metastasis. [Cancer Res 2008;68(9):3087–93]
Amplification of Telomerase Reverse Transcriptase Gene in Human Mammary Epithelial Cells with Limiting Telomerase RNA Expression Levels
Authors: Cao Ying , Huschtscha Lily I. , Nouwens Amanda S. , Pickett Hilda A. , Neumann Axel A. , Chang Andy C-M. , Toouli Christian D. , Bryan Tracy M. , Reddel Roger R. 
Published: May 2008

Abstract
Activation of telomerase is a crucial step during cellular immortalization, and in some tumors this results from amplification of the human telomerase reverse transcriptase (hTERT) gene. Immortalization of normal human cells has been achieved by transduction with hTERT cDNA under the control of a strong heterologous enhancer/promoter, but this is sometimes an inefficient process, with periods of poor growth or even crisis occurring before immortalization. Here, we showed that normal human mammary epithelial cells expressing exogenous hTERT amplified the transgene extensively and expressed high levels of hTERT mRNA and protein. Paradoxically, the cells had low levels of telomerase activity and very short telomeres, indicating that telomerase activity did not correlate with hTERT expression. These cells contained only ∼20 human telomerase RNA (hTR) molecules/cell (compared with ∼120 hTR molecules per 293 cell). Expression of exogenous hTR caused increased telomerase activity and telomere lengthening. These data indicate that some hTERT-transduced normal cells may express high levels of the transgene but fail to up-regulate endogenous hTR expression sufficiently to enable expression of robust levels of telomerase activity. [Cancer Res 2008;68(9):3115–23]
Genetic Variants Contributing to Daunorubicin-Induced Cytotoxicity
Authors: Huang R. Stephanie , Duan Shiwei , Kistner Emily O. , Bleibel Wasim K. , Delaney Shannon M. , Fackenthal Donna L. , Das Soma , Dolan M. Eileen 
Published: May 2008

Abstract
Identifying heritable genetic variants responsible for chemotherapeutic toxicities has been challenging due in part to its multigenic nature. To date, there is a paucity of data on genetic variants associated with patients experiencing severe myelosuppression or cardiac toxicity following treatment with daunorubicin. We present a genome-wide model using International HapMap cell lines that integrate genotype and gene expression to identify genetic variants that contribute to daunorubicin-induced cytotoxicity. A cell growth inhibition assay was used to measure variations in the cytotoxicity of daunorubicin. Gene expression was determined using the Affymetrix GeneChip Human Exon 1.0ST Array. Using sequential analysis, we evaluated the associations between genotype and cytotoxicity, those significant genotypes with gene expression and correlated gene expression of the identified candidates with cytotoxicity. A total of 26, 9, and 18 genetic variants were identified to contribute to daunorubicin-induced cytotoxicity through their effect on 16, 9, and 36 gene expressions in the combined, Centre d' Etude du Polymorphisme Humain (CEPH), and Yoruban populations, respectively. Using 50 non-HapMap CEPH cell lines, single nucleotide polymorphisms generated through our model predicted 29% of the overall variation in daunorubicin sensitivity and the expression of CYP1B1 was significantly correlated with sensitivity to daunorubicin. In the CEPH validation set, rs120525235 and rs3750518 were significant predictors of transformed daunorubicin IC50 (P = 0.005 and P = 0.0008, respectively), and rs1551315 trends toward significance (P = 0.089). This unbiased method can be used to elucidate genetic variants contributing to a wide range of cellular phenotypes. [Cancer Res 2008;68(9):3161–8]
Microphthalmia-Associated Transcription Factor Is a Critical Transcriptional Regulator of Melanoma Inhibitor of Apoptosis in Melanomas
Authors: Dynek Jasmin N. , Chan Sara M. , Liu Jinfeng , Zha Jiping , Fairbrother Wayne J. , Vucic Domagoj 
Published: May 2008

Abstract
Melanoma inhibitor of apoptosis (ML-IAP) is a potent inhibitor of apoptosis, which is highly expressed in melanomas and likely contributes to their resistance to chemotherapeutic treatments. Herein, we show that the lineage survival oncogene microphthalmia-associated transcription factor (MITF) is a critical regulator of ML-IAP transcription in melanoma cells. The ML-IAP promoter contains two MITF consensus sites, and analysis of MITF and ML-IAP mRNA levels revealed a high correlation in melanoma tumor samples and cell lines. In reporter assays, MITF promoted a strong stimulation of transcriptional activity from the ML-IAP promoter, and MITF bound the endogenous ML-IAP promoter in melanoma cells by chromatin immunoprecipitation and electrophoretic mobility shift assay. Strikingly, small interfering RNA (siRNA)–mediated knockdown of MITF in melanoma cells led to a dramatic decrease in ML-IAP mRNA and protein levels, establishing that ML-IAP expression in melanoma cells is MITF dependent. Additionally, cyclic AMP–mediated induction of MITF expression in melanocytes resulted in increased ML-IAP expression, suggesting that melanocytes can express ML-IAP when MITF levels are heightened. Disruption of MITF by siRNA led to a decrease in melanoma cell viability, which could be rescued by ectopic expression of ML-IAP. Collectively, these findings implicate MITF as a major transcriptional regulator of ML-IAP expression in melanomas, and suggest that ML-IAP contributes to the prosurvival activity of MITF in melanoma progression. [Cancer Res 2008;68(9):3124–32]
Protein Kinase A Effects of an Expressed PRKAR1A Mutation Associated with Aggressive Tumors
Authors: Meoli Elise , Bossis Ioannis , Cazabat Laure , Mavrakis Manos , Horvath Anelia , Stergiopoulos Sotiris , Shiferaw Miriam L. , Fumey Glawdys , Perlemoine Karine , Muchow Michael , Robinson-White Audrey , Weinberg Frank , Nesterova Maria , Patronas Yianna , Groussin Lionel , Bertherat Jérôme , Stratakis Constantine A. 
Published: May 2008

Abstract
Most PRKAR1A tumorigenic mutations lead to nonsense mRNA that is decayed; tumor formation has been associated with an increase in type II protein kinase A (PKA) subunits. The IVS6+1G&gt;T PRKAR1A mutation leads to a protein lacking exon 6 sequences [R1αΔ184-236 (R1αΔ6)]. We compared in vitro R1αΔ6 with wild-type (wt) R1α. We assessed PKA activity and subunit expression, phosphorylation of target molecules, and properties of wt-R1α and mutant (mt) R1α; we observed by confocal microscopy R1α tagged with green fluorescent protein and its interactions with Cerulean-tagged catalytic subunit (Cα). Introduction of the R1αΔ6 led to aberrant cellular morphology and higher PKA activity but no increase in type II PKA subunits. There was diffuse, cytoplasmic localization of R1α protein in wt-R1α– and R1αΔ6-transfected cells but the former also exhibited discrete aggregates of R1α that bound Cα; these were absent in R1αΔ6-transfected cells and did not bind Cα at baseline or in response to cyclic AMP. Other changes induced by R1αΔ6 included decreased nuclear Cα. We conclude that R1αΔ6 leads to increased PKA activity through the mt-R1α decreased binding to Cα and does not involve changes in other PKA subunits, suggesting that a switch to type II PKA activity is not necessary for increased kinase activity or tumorigenesis. [Cancer Res 2008;68(9):3133–41]
A Phase 2 Clinical Trial of Deforolimus (AP23573, MK-8669), a Novel Mammalian Target of Rapamycin Inhibitor, in Patients with Relapsed or Refractory Hematologic Malignancies
Authors: Rizzieri David A. , Feldman Eric , DiPersio John F. , Gabrail Nashat , Stock Wendy , Strair Roger , Rivera Victor M. , Albitar Maher , Bedrosian Camille L. , Giles Francis J. 
Published: May 2008

Abstract
Purpose: Deforolimus (AP23573), a novel non-prodrug rapamycin analogue, inhibits the mammalian target of rapamycin, a downstream effector of the phosphatidylinositol 3-kinase/Akt and nutrient-sensing pathways. A phase 2 trial was conducted to determine the efficacy and safety of single-agent deforolimus in patients with relapsed or refractory hematologic malignancies.
Experimental Design: Eligible patients were assigned to one of five disease-specific, parallel cohorts and given 12.5 mg deforolimus as a 30-minute infusion once daily for 5 days every 2 weeks. A Simon two-stage design was used for each cohort. Safety, pharmacokinetics, pharmacodynamics, and antitumor response were assessed.
Results: Fifty-five patients received deforolimus as follows: cohort 1 23 acute myelogenous leukemia, two myelodysplastic syndrome and one chronic myelogenous leukemia in nonlymphoid blast phase; cohort 2, one acute lymphocytic leukemia; cohort 3, nine agnogenic myeloid metaplasia; cohort 4, eight chronic lymphocytic leukemia; cohort 5, nine mantle cell lymphoma and two T-cell leukemia/lymphoma. Most patients were heavily pretreated. Of the 52 evaluable patients, partial responses were noted in five (10%), two of seven agnogenic myeloid metaplasia and three of nine mantle cell lymphoma. Hematologic improvement/stable disease was observed in 21 (40%). Common treatment-related adverse events, which were generally mild and reversible, were mouth sores, fatigue, nausea, and thrombocytopenia. Decreased levels of phosphorylated 4E-BP1 in 9 of 11 acute myelogenous leukemia/myelodysplastic syndrome patients after therapy showed mammalian target of rapamycin inhibition by deforolimus.
Conclusions: Deforolimus was well-tolerated in patients with heavily pretreated hematologic malignancies, and antitumor activity was observed. Further investigation of deforolimus alone and in combination with other therapeutic agents is warranted in patients with selected hematologic malignancies.
MicroRNA Expression Profiles in Serous Ovarian Carcinoma
Authors: Nam Eun Ji , Yoon Heejei , Kim Sang Wun , Kim Hoguen , Kim Young Tae , Kim Jae Hoon , Kim Jae Wook , Kim Sunghoon 
Published: May 2008

Abstract
Purpose: Although microRNAs have recently been recognized as riboregulators of gene expression, little is known about microRNA expression profiles in serous ovarian carcinoma. We assessed the expression of microRNA and the association between microRNA expression and the prognosis of serous ovarian carcinoma.
Experimental Design: Twenty patients diagnosed with serous ovarian carcinoma and eight patients treated for benign uterine disease between December 2000 and September 2003 were enrolled in this study. The microRNA expression profiles were examined using DNA microarray and Northern blot analyses.
Results: Several microRNAs were differentially expressed in serous ovarian carcinoma compared with normal ovarian tissues, including miR-21, miR-125a, miR-125b, miR-100, miR-145, miR-16, and miR-99a, which were each differentially expressed in &gt;16 patients. In addition, the expression levels of some microRNAs were correlated with the survival in patients with serous ovarian carcinoma. Higher expression of miR-200, miR-141, miR-18a, miR-93, and miR-429, and lower expression of let-7b, and miR-199a were significantly correlated with a poor prognosis (P &lt; 0.05).
Conclusion: Our results indicate that dysregulation of microRNAs is involved in ovarian carcinogenesis and associated with the prognosis of serous ovarian carcinoma.
Tagging Single Nucleotide Polymorphisms in Phosphoinositide-3-Kinase–Related Protein Kinase Genes Involved in DNA Damage “Checkpoints” and Lung Cancer Susceptibility
Authors: Hu Zhibin , Liu Hongliang , Wang Haifeng , Miao Ruifen , Sun Weiwei , Jin Guangfu , Wang Ying , Ma Hongxia , Jin Li , Wei Qingyi , Lu Daru , Huang Wei , Shen Hongbing 
Published: May 2008

Abstract
Purpose: DNA damage checkpoints are initiated by its sensor proteins of the phosphoinositide-3-kinase–related protein kinase family, including ataxia-telangiectasia mutated, ataxia-telangiectasia and Rad3-related, and DNA-dependent protein kinase catalytic subunit (DNA-PKcs). We hypothesized that polymorphisms in these genes may alter the regulation of DNA repair and the risk of lung cancer.
Experimental Design: We genotyped 12 tagging single nucleotide polymorphisms (tSNP) in these three phosphoinositide-3-kinase–related protein kinase genes in 500 incident lung cancer cases and 517 controls in a Chinese population by using the Illumina SNP genotyping BeadLab platform.
Results: Single locus analyses revealed that some of the heterozygotes or variant homozygotes of DNA-PKcs tSNPs were associated with decreased risks of lung cancer compared with their wild-type homozygotes. In the combined analyses of two tSNPs (rs8178085 and rs12334811) with approaching dose-dependent effect on lung cancer predisposition, subjects carrying two to four risk genotypes were associated with a 43% decreased lung cancer risk compared with subjects carrying zero to one risk genotypes (adjusted odds ratio, 0.53; 95% confidence interval, 0.35-0.80). Moreover, the decreased risk associated with the combined genotypes of rs8178085 and rs12334811 was slightly more pronounced in nonsmokers and in carriers with ataxia-telangiectasia mutated rs228591 variant allele or ataxia-telangiectasia and Rad3-related rs6782400 wild-type homozygous genotype.
Conclusion: These results indicate, for the first time, that tSNPs in DNA-PKcs may play a protective role in lung cancer development.
The Acidic Tumor Microenvironment Promotes the Reconversion of Nitrite into Nitric Oxide: Towards a New and Safe Radiosensitizing Strategy
Authors: Frérart Françoise , Sonveaux Pierre , Rath Géraldine , Smoos Alexandra , Meqor Ahlam , Charlier Nicolas , Jordan Bénédicte F. , Saliez Julie , Noël Agnès , Dessy Chantal , Gallez Bernard , Feron Olivier 
Published: May 2008

AbstractPurpose: The biological status of nitrite recently evolved from an inactive end product of nitric oxide catabolism to the largest intravascular and tissue storage of nitric oxide (NO). Although low partial O2 pressure favors enzymatic reconversion of nitrite into NO, low pH supports a nonenzymatic pathway. Because hypoxia and acidity are characteristics of the tumor microenvironment, we examined whether nitrite injection could preferentially lead to NO production in tumors and influence response to treatments.Experimental Design: The effects of nitrite were evaluated on arteriole vasorelaxation, tumor cell respiration and tumor blood flow, oxygenation, and response to radiotherapy.Results: We first showed that a small drop in pH (−0.6 pH unit) favored the production of bioactive NO from nitrite by documenting a higher cyclic guanosine 3′,5′-monophosphate–dependent arteriole vasorelaxation. We then documented that an i.v. bolus injection of nitrite to tumor-bearing mice led to a transient increase in partial O2 pressure in tumor but not in healthy tissues. Blood flow measurements failed to reveal an effect of nitrite on tumor perfusion, but we found that O2 consumption by nitrite-exposed tumor cells was decreased at acidic pH. Finally, we showed that low dose of nitrite could sensitize tumors to radiotherapy, leading to a significant growth delay and an increase in mouse survival (versus irradiation alone).Conclusions: This study identified low pH condition (encountered in many tumors) as an exquisite environment that favors tumor-selective production of NO in response to nitrite systemic injection. This work opens new perspectives for the use of nitrite as a safe and clinically applicable radiosensitizing modality.