bluuebunny/crossref_metadata_2025_split huggingface dataset:
Differential Regulation of Elafin in Normal and Tumor-Derived Mammary Epithelial Cells Is Mediated by CCAAT/Enhancer Binding Protein β
Authors: Yokota Tomoya , Bui Tuyen , Liu Yanna , Yi Min , Hunt Kelly K. , Keyomarsi Khandan 
Published: December 2007

Abstract
CCAAT/enhancer binding protein β (C/EBPβ) is a transcription factor implicated in the control of development, differentiation, and proliferation of mammary epithelial cells. However, it remains unclear how C/EBPβ is involved in tumor suppression through its interaction with specific downstream genes in breast cancer. Tumor cells overexpress serine proteases, which play crucial roles in tumor invasion and metastasis. Elafin is an endogenous serine protease inhibitor and is transcriptionally down-regulated in most tumor cell lines. In this study, we show that C/EBPβ is differentially expressed in normal versus tumor cell lines and normal adjacent versus tumor tissues obtained from breast cancer patients. We identified elafin as a downstream effector of C/EBPβ and show that elafin is also differentially regulated between normal and tumor cells. The mechanism by which C/EBPβ regulates elafin expression is through its direct interaction with the elafin promoter. There are three C/EBPβ binding sites involved in the elafin promoter activity, and the overexpression of C/EBPβ transactivates the elafin gene through these sites in tumor cells. RNA interference studies in normal cells further evidenced the requirement of the C/EBPβ for the elafin expression and negative feedback loop between C/EBPβ and elafin. We suggest that elafin is a novel substrate of C/EBPβ, and alterations in C/EBPβ isoforms result in their differential binding to the elafin promoter, leading to the altered expression of the elafin between normal and tumor cells. [Cancer Res 2007;67(23):11272–83]
Aurora-A Kinase Regulates Breast Cancer–Associated Gene 1 Inhibition of Centrosome-Dependent Microtubule Nucleation
Authors: Sankaran Satish , Crone Donna E. , Palazzo Robert E. , Parvin Jeffrey D. 
Published: December 2007

Abstract
Breast cancer–associated gene 1 (BRCA1) regulates the duplication and the function of centrosomes in breast cells. We have previously shown that BRCA1 ubiquitin ligase activity directly inhibits centrosome-dependent microtubule nucleation. However, there is a paradox because centrosome microtubule nucleation potential is highest during mitosis, a phase when BRCA1 is most abundant at the centrosome. In this study, we resolve this conundrum by testing whether centrosomes from cells in M phase are regulated differently by BRCA1 when compared with other phases of the cell cycle. We observed that BRCA1-dependent inhibition of centrosome microtubule nucleation was high in S phase but was significantly lower during M phase. The cell cycle–specific effects of BRCA1 on centrosome-dependent microtubule nucleation were detected in living cells and in cell-free experiments using centrosomes purified from cells at specific stages of the cell cycle. We show that Aurora-A kinase modulates the BRCA1 inhibition of centrosome function by decreasing the E3 ubiquitin ligase activity of BRCA1. In addition, dephosphorylation of BRCA1 by protein phosphatase 1α enhances the E3 ubiquitin ligase activity of BRCA1. These observations reveal that the inhibition of centrosome microtubule nucleation potential by the BRCA1 E3 ubiquitin ligase is controlled by Aurora-A kinase and protein phosphatase 1α–mediated phosphoregulation through the different phases of the cell cycle. [Cancer Res 2007;67(23):11186–94]
Differing Phenotypes between Intraepithelial and Stromal Lymphocytes in Early-Stage Tongue Cancer
Authors: Katou Fuminori , Ohtani Haruo , Watanabe Yoshiko , Nakayama Takashi , Yoshie Osamu , Hashimoto Kenji 
Published: December 2007

Abstract
The significance of tumor-infiltrating lymphocytes (TIL) has attracted much attention in relation to the prognosis of patients. We herein examined the activation status of the TILs in relation to the tumor microenvironment. By using frozen sections of human early-stage tongue cancers (n = 22), the TILs in the cancer nests and those in the cancer stroma were compared for the expression of PD-1, NKG2A, NKG2D, CD69, and Ki-67. The lymphocytes in oral lichen planus, an active immune response-mediated mucosal disease, were also analyzed for comparison purposes. All of the cancer specimens were abundantly infiltrated by CD8+ T cells and CD56+ natural killer (NK) cells in the stroma, as well as in the tumor nest. The tumor nest–infiltrating (intraepithelial) CD8+ T cells frequently expressed PD-1, an inhibitory receptor, in sharp contrast to those in the stroma or in the lichen planus. Conversely, the intraepithelial CD8+ T cells only infrequently expressed NKG2D, an activating receptor, in contrast to those in the stroma or in the lichen planus. No intraepithelial CD8+ T cells expressed Ki-67, a proliferation-associated marker, whereas those in the stroma frequently expressed it. Furthermore, the intraepithelial NK cells expressed NKG2A, an inhibitory receptor, more frequently than those in the stroma or the lichen planus. Collectively, the intraepithelial CD8+ T cells and NK cells are phenotypically inactivated, whereas stromal counterparts are phenotypically just as active as those in the lichen planus. These results suggest the first-step occurrence of an immune evasion mechanism in the tumor nest of oral squamous cell carcinoma. [Cancer Res 2007;67(23):11195–201]
Genetic Alterations in the Tyrosine Kinase Transcriptome of Human Cancer Cell Lines
Authors: Ruhe Jens E. , Streit Sylvia , Hart Stefan , Wong Chee-Hong , Specht Katja , Knyazev Pjotr , Knyazeva Tatjana , Tay Liang Seah , Loo Hooi Linn , Foo Priscilla , Wong Winnie , Pok Sharon , Lim Shu Jing , Ong Huimin , Luo Ming , Ho Han Kiat , Peng Kaitian , Lee Tze Chuen , Bezler Martin , Mann Christian , Gaertner Silvia , Hoefler Heinz , Iacobelli Stefano , Peter Stephan , Tay Alice , Brenner Sydney , Venkatesh Byrappa , Ullrich Axel 
Published: December 2007

AbstractProtein tyrosine kinases (PTKs) play a critical role in the manifestation of cancer cell properties, and respective signaling mechanisms have been studied extensively on immortalized tumor cells. To characterize and analyze commonly used cancer cell lines with regard to variations in the primary structure of all expressed PTKs, we conducted a cDNA-based sequence analysis of the entire tyrosine kinase transcriptome of 254 established tumor cell lines. The profiles of cell line intrinsic PTK transcript alterations and the evaluation of 155 identified polymorphisms and 234 somatic mutations are made available in a database designated “Tykiva” (tyrosine kinome variant). Tissue distribution analysis and/or the localization within defined protein domains indicate functional relevance of several genetic alterations. The cysteine replacement of the highly conserved Y367 residue in fibroblast growth factor receptor 4 or the Q26X nonsense mutation in the tumor-suppressor kinase CSK are examples, and may contribute to cell line–specific signaling characteristics and tumor progression. Moreover, known variants, such as epidermal growth factor receptor G719S, that were shown to mediate anticancer drug sensitivity could be detected in other than the previously reported tumor types. Our data therefore provide extensive system information for the design and interpretation of cell line–based cancer research, and may stimulate further investigations into broader clinical applications of current cancer therapeutics. [Cancer Res 2007;67(23):11368–76]
Choline Kinase Down-regulation Increases the Effect of 5-Fluorouracil in Breast Cancer Cells
Authors: Mori Noriko , Glunde Kristine , Takagi Tomoyo , Raman Venu , Bhujwalla Zaver M. 
Published: December 2007

Abstract
Identifying strategies to increase cancer cell kill while sparing normal tissue is critically important in cancer chemotherapy. Choline kinase (Chk), the enzyme that converts choline to phosphocholine (PC), is elevated in cancer cells and presents a novel target for increasing cell kill. Here, we have examined the effects of transiently down-regulating Chk by small interfering RNA against Chk (siRNA-chk) on PC and total choline-containing compound (tCho) levels and on the viability/proliferation of estrogen receptor–negative and estrogen receptor–positive breast cancer cell lines and a nonmalignant mammary epithelial cell line. We investigated the effects of combination treatment with transient siRNA-chk transfection and the anticancer drug 5-fluorouracil (5-FU) in those cell lines. Microarray analysis of the invasive estrogen receptor–negative MDA-MB-231 cell line was done to characterize molecular changes associated with Chk down-regulation. Chk down-regulation decreased PC and tCho levels in the malignant cell lines, whereas the cell viability/proliferation assays detected a decrease in proliferation in these cells. In contrast, Chk down-regulation had an almost negligible effect on PC and tCho levels as well as cell viability/proliferation in the nonmalignant cell line. A combination of siRNA-chk with 5-FU treatment resulted in a larger reduction of cell viability/proliferation in the breast cancer cell lines; this reduction was evident to a much lesser degree in the nonmalignant cells. Microarray analysis showed that Chk down-regulation affected 33 proliferation-related genes and 9 DNA repair–related genes. Chk down-regulation with siRNA-chk may provide a novel alternative to enhance the effect of anticancer drugs in malignant cells. [Cancer Res 2007;67(23):11284–90]
Down-regulation of Platelet-Derived Growth Factor-D Inhibits Cell Growth and Angiogenesis through Inactivation of Notch-1 and Nuclear Factor-κB Signaling
Authors: Wang Zhiwei , Kong Dejuan , Banerjee Sanjeev , Li Yiwei , Adsay N. Volkan , Abbruzzese James , Sarkar Fazlul H. 
Published: December 2007

Abstract
Platelet-derived growth factor-D (PDGF-D) signaling plays critical roles in the pathogenesis and progression of human malignancies; however, the precise mechanism by which PDGF-D causes tumor cell invasion and angiogenesis remain unclear. Because Notch-1, nuclear factor-κB (NF-κB), vascular endothelial growth factor (VEGF), and matrix metalloproteinases (MMP) are critically involved in the processes of tumor cell invasion and metastasis, we investigated whether PDGF-D down-regulation could be mechanistically associated with the down-regulation of Notch-1, NF-κB, VEGF, and MMP-9, resulting in the inhibition of tumor cell invasion and angiogenesis. Our data showed that down-regulation of PDGF-D leads to the inactivation of Notch-1 and NF-κB DNA-binding activity and, in turn, down regulates the expression of its target genes, such as VEGF and MMP-9. We also found that the down-regulation of PDGF-D by small interfering RNA (siRNA) decreased tumor cell invasion, whereas PDGF-D overexpression by cDNA transfection led to increased cell invasion. Consistent with these results, we also found that the down-regulation of PDGF-D not only decreased MMP-9 mRNA and its protein expression but also inhibited the processing of pro-MMP-9 protein to its active form. Moreover, conditioned medium from PDGF-D siRNA–transfected cells showed reduced levels of VEGF and, in turn, inhibited the tube formation of human umbilical vascular endothelial cells, suggesting that down-regulation of PDGF-D leads to the inhibition of angiogenesis. Taken together, we conclude that the down-regulation of PDGF-D by novel approaches could lead to the down-regulation of Notch-1 and, in turn, inactivate NF-κB and its target genes (i.e., MMP-9 and VEGF), resulting in the inhibition of invasion and angiogenesis. [Cancer Res 2007;67(23):11377–85]
The Cooked Meat Carcinogen 2-Amino-1-Methyl-6-Phenylimidazo[4,5-b]Pyridine Activates the Extracellular Signal–Regulated Kinase Mitogen-Activated Protein Kinase Pathway
Authors: Creton Stuart K. , Zhu Huijun , Gooderham Nigel J. 
Published: December 2007

Abstract
During the cooking of meat, mutagenic and carcinogenic heterocyclic amines are formed, the most abundant of which, 2-amino-1-methyl-6-phenylimidazo[4-5-b]pyridine (PhIP), induces tumors of the prostate, colon, and mammary gland in rats. Humans consuming cooked meat are exposed to PhIP on a daily basis, yet few studies have assessed the effects of PhIP at dietary relevant concentrations. In addition to its genotoxic properties, recent studies have shown that PhIP can activate estrogen receptor–mediated signaling pathways at doses that are similar to those that may be present in the body following consumption of a cooked meat meal. In the present study, we examined whether such doses of PhIP can affect estrogen receptor–independent signal transduction via the mitogen-activated protein kinase (MAPK) extracellular signal–related kinase (ERK) pathway to influence proliferation and migration in the human mammary epithelial cell line MCF10A and the prostate cancer cell line PC-3. At doses shown to have a proliferative effect on MCF10A cells (10−11–10−7 mol/L), PhIP induced a rapid, transient increase in phosphorylation of both MAPK/ERK kinase 1/2 and ERKs. Inhibition of this pathway significantly reduced the PhIP-induced proliferation of MCF10A cells and the migration of PC-3 cells. The data presented here show that levels of PhIP that approximate to human dietary exposure stimulate cellular signaling pathways and result in increased growth and migration, processes linked to the promotion and progression of neoplastic disease. These findings provide strong evidence that PhIP acts as a tumor initiator and promoter and that dietary exposure to this compound could contribute to carcinogenesis in humans. [Cancer Res 2007;67(23):11455–61]
3′-Deoxy-3′-[18F]Fluorothymidine Positron Emission Tomography Is a Sensitive Method for Imaging the Response of BRAF-Dependent Tumors to MEK Inhibition
Authors: Solit David B. , Santos Elmer , Pratilas Christine A. , Lobo Jose , Moroz Maxim , Cai Shangde , Blasberg Ronald , Sebolt-Leopold Judith , Larson Steven , Rosen Neal 
Published: December 2007

Abstract
Activating mutations of BRAF occur in ∼7% of all human tumors and in the majority of melanomas. These tumors are very sensitive to pharmacologic inhibition of mitogen-activated protein kinase/extracellular signal-regulated kinase kinase (MEK), which causes loss of D-cyclin expression, hypophosphorylation of Rb, and G1 arrest. Growth arrest is followed by differentiation or senescence and, in a subset of BRAF mutant tumors, by apoptosis. The former effects result in so-called “stable disease” and, in patients with cancer, can be difficult to distinguish from indolent tumor growth. The profound G1 arrest induced by MEK inhibition in BRAF mutant tumors is associated with a marked decline in thymidine uptake and is therefore potentially detectable in vivo by noninvasive 3′-deoxy-3′-[18F]fluorothymidine ([18F]FLT) positron emission tomography (PET) imaging. In SKMEL-28 tumor xenografts, MEK inhibition completely inhibited tumor growth and induced differentiation with only modest tumor regression. MEK inhibition also resulted in a rapid decline in the [18F]FLT signal in V600E BRAF mutant SKMEL-28 xenografts but not in BRAF wild-type BT-474 xenografts. The data suggest that [18F]FLT PET can effectively image induction of G1 arrest by MEK inhibitors in mutant BRAF tumors and may be a useful noninvasive method for assessing the early biological response to this class of drugs. [Cancer Res 2007;67(23):11463–9]
Plasma Cysteinylglycine Levels and Breast Cancer Risk in Women
Authors: Lin Jennifer , Manson JoAnn E. , Selhub Jacob , Buring Julie E. , Zhang Shumin M. 
Published: December 2007

Abstract
Cysteinylglycine, a prooxidant generated during the catabolism of glutathione, has been suggested to induce oxidative stress and lipid peroxidation, leading to the development of human cancers. Observational data relating cysteinylglycine status to breast cancer risk are lacking. We prospectively evaluated plasma cysteinylglycine levels and invasive breast cancer risk among 812 case-control pairs nested in the Women's Health Study, a completed randomized trial evaluating low-dose aspirin and vitamin E in middle-aged and older women. We additionally evaluated the effect modification by risk factors for oxidative stress, such as vitamin E assignment, alcohol consumption, obesity, and postmenopausal hormone use. Logistic regression controlling for matching factors, as well as other risk factors for breast cancer, was used to estimate relative risks (RR) and 95% confidence intervals (95% CI). All statistical tests were two sided. We observed no overall association between plasma cysteinylglycine and invasive breast cancer risk. However, higher cysteinylglycine levels were marginally associated with an increased risk of breast cancer in the high oxidative stress groups. Women in the highest quintile group of cysteinylglycine relative to the lowest group had multivariate RRs (95% CIs) of 1.64 (1.01–2.66; Ptrend = 0.04) in the vitamin E placebo group, 2.51 (1.01–6.24; Ptrend = 0.07) in the high alcohol intake group (≥9 g/day), and 1.66 (0.97–2.84; Ptrend = 0.03) in the overweight and obese group. Our findings suggest that women who are susceptible to experiencing oxidative stress may be at a greater risk for developing breast cancer. [Cancer Res 2007;67(23):11123–7]
Automated, Quantitative Screening Assay for Antiangiogenic Compounds Using Transgenic Zebrafish
Authors: Tran T. Cameron , Sneed Blossom , Haider Jamil , Blavo Delali , White Audrey , Aiyejorun Temitope , Baranowski Timothy C. , Rubinstein Amy L. , Doan Thanh N. , Dingledine Raymond , Sandberg Eric M. 
Published: December 2007

Abstract
Pathologic angiogenesis has emerged as an important therapeutic target in several major diseases. Zebrafish offer the potential for high-throughput drug discovery in a whole vertebrate system. We developed the first quantitative, automated assay for antiangiogenic compound identification using zebrafish embryos. This assay uses transgenic zebrafish with fluorescent blood vessels to facilitate image analysis. We developed methods for automated drugging and imaging of zebrafish in 384-well plates and developed a custom algorithm to quantify the number of angiogenic blood vessels in zebrafish. The assay was used to screen the LOPAC1280 compound library for antiangiogenic compounds. Two known antiangiogenic compounds, SU4312 and AG1478, were identified as hits. Additionally, one compound with no previously known antiangiogenic activity, indirubin-3′-monoxime (IRO), was identified. We showed that each of the hit compounds had dose-dependent antiangiogenic activity in zebrafish. The IC50 of SU4312, AG1478, and IRO in the zebrafish angiogenesis assay was 1.8, 8.5, and 0.31 μmol/L, respectively. IRO had the highest potency of the hit compounds. Moreover, IRO inhibited human umbilical vein endothelial cell tube formation and proliferation (IC50 of 6.5 and 0.36 μmol/L, respectively). It is therefore the first antiangiogenic compound discovered initially in a zebrafish assay that also has demonstrable activity in human endothelial cell-based angiogenesis assays. [Cancer Res 2007;67(23):11386–92]
Variants on 9p24 and 8q24 Are Associated with Risk of Colorectal Cancer: Results from the Colon Cancer Family Registry
Authors: Poynter Jenny N. , Figueiredo Jane C. , Conti David V. , Kennedy Kathleen , Gallinger Steven , Siegmund Kimberly D. , Casey Graham , Thibodeau Stephen N. , Jenkins Mark A. , Hopper John L. , Byrnes Graham B. , Baron John A. , Goode Ellen L. , Tiirikainen Maarit , Lindor Noralane , Grove John , Newcomb Polly , Jass Jeremy , Young Joanne , Potter John D. , Haile Robert W. , Duggan David J. , Le Marchand Loic ,   for the Colon CFR
Published: December 2007

Abstract
Recent publications have reported that common variants on 8q24 are associated with both prostate and colorectal cancers (CRC). In addition, one of these studies (the ARCTIC study) initially observed an association with a single nucleotide polymorphism (SNP) on 9p24 that was not confirmed in some of their validation data sets. In the research described here, we conducted a case-unaffected sibling analysis using population- and clinic-based discordant sibships (N = 1,567 sibships) from the Colon Cancer Family Registry (Colon CFR) to investigate the associations between common variants at 9p24 and 8q24 and risk of CRC. We also evaluated whether these associations differed by age, family history, and tumor characteristics, including microsatellite instability and tumor site. Associations were estimated using conditional logistic regression, treating sibship as the matching factor. Analyses were adjusted for age and sex, and stratified by ascertainment source (population versus clinic). We observed an association between a SNP on 9p24 (rs719725) and risk of CRC in the population-based series (AA versus CC: odds ratios, 1.46; 95% confidence interval, 1.06–2.02; AC versus CC: odds ratios, 1.50; 95% confidence interval, 1.14–1.98; P = 0.011 on 2 df). In the population-based series, we also detected statistically significant associations between two SNPs on 8q24, rs10505477 and rs6983267, and risk of CRC (P = 0.005 and P = 0.002, respectively). There was no evidence of statistically significant heterogeneity by age at diagnosis, family history of CRC, microsatellite instability, or tumor site at either locus and no evidence of interaction between SNPs on 8q24 and 9p24. These data suggest that common variants may play important roles in the risk of CRC. [Cancer Res 2007;67(23):11128–32]
Benefit of Complete Response in Multiple Myeloma Limited to High-Risk Subgroup Identified by Gene Expression Profiling
Authors: Haessler Jeffrey , Shaughnessy John D. , Zhan Fenghuang , Crowley John , Epstein Joshua , van Rhee Frits , Anaissie Elias , Pineda-Roman Mauricio , Zangari Maurizio , Hollmig Klaus , Mohiuddin Abid , Alsayed Yazan , Hoering Antje , Tricot Guido , Barlogie Bart 
Published: December 2007

Abstract
Experimental Design: To determine whether the clinical benefit of complete remission (CR) may depend on prognostic subgroups of patients with multiple myeloma.
Patients and Methods: Newly diagnosed patients with myeloma received a tandem autotransplant regimen. Using multivariate regression analyses, we examined the prognostic implications of time-dependent onset of CR on overall survival and event-free survival in the context of standard prognostic factors (SPF) and gene expression profiling–derived data available for 326 patients.
Results: CR benefited patients regardless of risk status when only SPFs were examined. With knowledge of gene array data, a survival (and event-free survival) benefit of CR only pertained to the small high-risk subgroup of 13% of patients (hazard ratio, 0.23; P = 0.001), whereas the majority of patients with low-risk disease had similar survival expectations whether or not CR was achieved (hazard ratio, 0.68; P = 0.128).
Conclusions: Access to gene expression information permitted the recognition of a small very high-risk subgroup of 13% of patients, in whom prolonged survival critically depended on achieving CR. Absence of such benefit in the remainder should lead to a reassessment of clinical trial designs that rely on this end point as a surrogate for long-term prognosis.