bluuebunny/crossref_metadata_2025_split huggingface dataset:
Progression-Specific Genes Identified by Expression Profiling of Matched Ductal Carcinomas In situ and Invasive Breast Tumors, Combining Laser Capture Microdissection and Oligonucleotide Microarray Analysis
Authors: Schuetz Christina S. , Bonin Michael , Clare Susan E. , Nieselt Kay , Sotlar Karl , Walter Michael , Fehm Tanja , Solomayer Erich , Riess Olaf , Wallwiener Diethelm , Kurek Raffael , Neubauer Hans J. 
Published: May 2006

Abstract
Becoming invasive is a crucial step in breast cancer oncogenesis. At this point, a lesion carries the potential for spreading and metastasis—a process, whose molecular characteristics still remain poorly understood. In this article, we describe a matched-pair analysis of ductal carcinoma in situ (DCIS) and invasive ductal carcinoma (IDC) of nine breast ductal carcinomas to identify novel molecular markers characterizing the transition from DCIS to IDC. The purpose of this study was to better understand the molecular biology of this transition and to identify candidate genes whose products might serve as prognostic markers and/or as molecular targets for treatment. To obtain cellular-based gene expression profiles from epithelial tumor cells, we combined laser capture microdissection with a T7-based two-round RNA amplification and Affymetrix oligonucleotide microarray analysis. Altogether, a set of 24 tumor samples was analyzed, comprised of nine matched DCIS/IDC and replicate DCIS/IDC preparations from three of the nine tumors. Cluster analysis on expression data shows the robustness and reproducibility of the techniques we established. Using multiple statistical methods, 546 significantly differentially expressed probe sets were identified. Eighteen candidate genes were evaluated by RT-PCR. Examples of genes already known to be associated with breast cancer invasion are BPAG1, LRRC15, MMP11, and PLAU. The expression of BPAG1, DACT1, GREM1, MEF2C, SART2, and TNFAIP6 was localized to epithelial tumor cells by in situ hybridization and/or immunohistochemistry, confirming the accuracy of laser capture microdissection sampling and microarray analysis. (Cancer Res 2006; 66(10): 5278-86)
A Prospective Study on Habitual Duration of Sleep and Incidence of Breast Cancer in a Large Cohort of Women
Authors: Pinheiro Simone P. , Schernhammer Eva S. , Tworoger Shelley S. , Michels Karin B. 
Published: May 2006

Abstract
Mounting evidence suggests habitual sleep duration is associated with various health outcomes; both short and long sleep duration have been implicated in increased risk of cardiovascular disease, diabetes, and all-cause mortality. However, data on the relation between sleep duration and cancer risk are sparse and inconclusive. A link between low levels of melatonin, a hormone closely related to sleep, and increased risk of breast cancer has recently been suggested but it is unclear whether duration of sleep may affect breast cancer risk. We explored the association between habitual sleep duration reported in 1986 and subsequent risk of breast cancer in the Nurses' Health Study using Cox proportional hazards models. During 16 years of follow-up, 4,223 incident cases of breast cancer occurred among 77,418 women in this cohort. Compared with women sleeping 7 hours, covariate-adjusted hazard ratios and 95% confidence intervals for those sleeping ≤5, 6, 8, and ≥9 hours were 0.93 (0.79-1.09), 0.98 (0.91-1.06), 1.05 (0.97-1.13), and 0.95 (0.82-1.11), respectively. A moderate trend in risk increase towards longer sleep duration was observed when analyses were restricted to participants who reported same sleep duration in 1986 and 2000 (Ptrend = 0.05). In this prospective study, we found no convincing evidence for an association between sleep duration and the incidence of breast cancer. (Cancer Res 2006; 66(10): 5521-25)
Regulatory T Cells and Toll-Like Receptors in Cancer Therapy
Authors: Wang Rong-Fu 
Published: May 2006

Abstract
T regulatory (Treg) cells that suppress immune responses may limit the efficiency of cancer immunotherapy. Recent findings indicate that Toll-like receptors (TLR) directly regulate the suppressive activity of Treg cells. Linking TLR signaling to the functional control of Treg cells may offer new opportunities to improve the outcome of cancer immunotherapy by coadminstration of certain TLR ligands. (Cancer Res 2006; 66(10): 4987-90)
Quantitative In situ Analysis of β-Catenin Expression in Breast Cancer Shows Decreased Expression Is Associated with Poor Outcome
Authors: Dolled-Filhart Marisa , McCabe Anthony , Giltnane Jennifer , Cregger Melissa , Camp Robert L. , Rimm David L. 
Published: May 2006

Abstract
The role of β-catenin in breast cancer and its prognostic value is controversial. The prognostic value had been assessed previously in a series of nonquantitative immunohistochemical studies with conflicting results. In efforts to clarify the relationship between β-catenin protein expression and breast cancer prognosis, we have assessed a retrospective 600 case cohort of breast cancer tumors from the Yale Pathology archives on tissue microarrays. They were assessed using automated quantitative analysis (AQUA) with a series of array-embedded cell lines for which the β-catenin concentration was standardized by an ELISA assay. The expression levels of the standard clinical markers HER2, estrogen receptor (ER), progesterone receptor (PR), and Ki-67 were also assessed on the same cohort. X-tile software was used to select optimal protein concentration cutpoints and to evaluate the outcome using a training set and a validation set. We found that low-level expression of membranous β-catenin is associated with significantly worse outcome (38% versus 76%, 10-year survival, validation set log-rank P = 0.0016). Multivariate analysis of this marker, assessed in a proportional hazards model with tumor size, age, node status, nuclear grade, ER, PR, HER2, and Ki-67, is still highly significant with a hazard ratio of 6.8 (P &lt; 0.0001, 95% confidence interval, 3.1-15.1). These results suggest that loss of β-catenin expression at the membrane, as assessed by objective quantitative analysis methods, may be useful as a prognostic marker or may be part of a useful algorithm for prognosis in breast cancer. (Cancer Res 2006; 66(10): 5487-94)
MDM2 SNP309 Accelerates Tumor Formation in a Gender-Specific and Hormone-Dependent Manner
Authors: Bond Gareth L. , Hirshfield Kim M. , Kirchhoff Tomas , Alexe Gabriella , Bond Elisabeth E. , Robins Harlan , Bartel Frank , Taubert Helge , Wuerl Peter , Hait William , Toppmeyer Deborah , Offit Kenneth , Levine Arnold J. 
Published: May 2006

Abstract
The importance of the p53 stress response pathway in the suppression of tumor formation is well documented. In a previous report, a single nucleotide polymorphism (SNP309 T/G) was found in the promoter of the MDM2 gene resulting in higher levels of MDM2 RNA and protein and, consequently, in the attenuation of the p53 pathway both in vitro and in vivo. As the SNP309 locus is found in a region of the MDM2 promoter, which is regulated by hormonal signaling pathways, and the G-allele of SNP309 increases the affinity of a well-described cotranscriptional activator of nuclear hormone receptors (i.e., Sp1), the hypothesis that the SNP309 locus could alter the effects of hormones on tumorigenesis was tested in vivo in humans. Data obtained from patients with three different sporadic cancers, from four independent case studies, support this hypothesis, providing an example for the genetic basis of gender differences in cancer and showing that the genotype at a specific locus can affect how hormones, like estrogen, affect tumorigenesis in humans. (Cancer Res 2006; 66(10): 5104-10)
(−)-Epigallocatechin-3-Gallate Prevents Photocarcinogenesis in Mice through Interleukin-12–Dependent DNA Repair
Authors: Meeran Syed M. , Mantena Sudheer K. , Elmets Craig A. , Katiyar Santosh K. 
Published: May 2006

AbstractWe have shown previously that topical application of (−)-epigallocatechin-3-gallate (EGCG), the major polyphenol of green tea, prevents photocarcinogenesis in mice. EGCG prevents UVB-induced immunosuppression by inducing interleukin-12 (IL-12). As immunosuppression is a risk factor for photocarcinogenesis, we investigated the possibility that EGCG also prevents UVB-induced photocarcinogenesis through an IL-12–dependent DNA repair mechanism. To investigate this possibility, we determined the effects of EGCG on photocarcinogenesis in IL-12 knockout (KO) mice using the formation of cyclobutane pyrimidine dimers (CPD) as an indicator of the extent of UVB-induced DNA damage. Topical application of EGCG (1 mg/cm2 skin) prevented photocarcinogenesis in wild-type (C3H/HeN) mice in terms of tumor incidence and tumor multiplicity but did not prevent photocarcinogenesis in IL-12 KO mice. UVB-induced DNA damage, as determined by the formation of CPDs and the number of sunburn cells, was resolved more rapidly in the skin of wild-type mice treated with EGCG than untreated control mice. In contrast, the extent of UVB-induced DNA damage and the numbers of sunburn cells were not significantly different in the EGCG-treated IL-12 KO mice and untreated control mice. In addition, treatment of XPA-proficient human fibroblast cells with EGCG promoted repair of UVB-induced CPDs in a dose-dependent manner but not in an XPA-deficient cells, indicating that the nucleotide excision repair mechanism is involved in EGCG-mediated DNA repair. Taken together, these results indicate for the first time that EGCG can prevent photocarcinogenesis through an EGCG-induced IL-12–dependent DNA repair mechanism. (Cancer Res 2006; 66(10): 5512-20)
c-Jun NH2-Terminal Kinase Signaling Axis Regulates Diallyl Trisulfide–Induced Generation of Reactive Oxygen Species and Cell Cycle Arrest in Human Prostate Cancer Cells
Authors: Antosiewicz Jedrzej , Herman-Antosiewicz Anna , Marynowski Stanley W. , Singh Shivendra V. 
Published: May 2006

Abstract
We have shown previously that generation of reactive oxygen species (ROS) is a critical event in G2-M phase cell cycle arrest caused by diallyl trisulfide (DATS), which is a highly promising anticancer constituent of processed garlic. Using DU145 and PC-3 human prostate cancer cells as a model, we now report a novel mechanism involving c-Jun NH2-terminal kinase (JNK) signaling axis, which is known for its role in regulation of cell survival and apoptosis, in DATS-induced ROS production. The DATS-induced ROS generation, G2-M phase cell cycle arrest and degradation, and hyperphosphorylation of Cdc25C were significantly attenuated in the presence of EUK134, a combined mimetic of superoxide dismutase and catalase. Interestingly, the DATS-induced ROS generation and G2-M phase cell cycle arrest were also inhibited significantly in the presence of desferrioxamine, an iron chelator, but this protection was not observed with iron-saturated desferrioxamine. DATS treatment caused a marked increase in the level of labile iron that was accompanied by degradation of light chain of iron storage protein ferritin. Interestingly, DATS-mediated degradation of ferritin, increase in labile iron pool, ROS generation, and/or cell cycle arrest were significantly attenuated by ectopic expression of a catalytically inactive mutant of JNK kinase 2 and RNA interference of stress-activated protein kinase/extracellular signal-regulated kinase 1 (SEK1), upstream kinases in JNK signal transduction pathway. In conclusion, the present study provides experimental evidence to indicate existence of a novel pathway involving JNK signaling axis in regulation of DATS-induced ROS generation. (Cancer Res 2006; 66(10): 5379-86)
Therapeutic Efficacy of Antigen-Specific Vaccination and Toll-Like Receptor Stimulation against Established Transplanted and Autochthonous Melanoma in Mice
Authors: Tormo Damia , Ferrer Aleix , Bosch Pilar , Gaffal Evelyn , Basner-Tschakarjan Etiena , Wenzel Jörg , Tüting Thomas 
Published: May 2006

Abstract
Malignant melanoma is an attractive model disease for the development of antigen-specific immunotherapy because many antigens recognized by tumor-specific T cells have been identified. In C57BL/6 mice, genetic immunization with recombinant adenovirus encoding xenogeneic human tyrosinase-related protein 2 (Ad-hTRP2) induces protective but not therapeutic cellular immunity against growth of transplanted B16 melanoma cells. Here, we additionally applied CpG DNA and synthetic double-stranded RNA, which activate the innate immune system via Toll-like receptors (TLR). Both adenoviral vaccination and peritumoral injections of TLR ligands were required for rejection of established B16 melanoma in the skin. To more closely mimic the clinical situation in patients with melanoma, we evaluated this combined immunotherapeutic strategy in genetically modified mice, which overexpress hepatocyte growth factor (HGF) and carry an oncogenic mutation in the cyclin-dependent kinase 4 (CDK4)R24C. HGF × CDK4R24C mice rapidly develop multiple invasive melanomas in the skin following neonatal carcinogen treatment, which spontaneously metastasize to lymph nodes and lungs. Vaccination with Ad-hTRP2 followed by injections of TLR ligands resulted in delayed growth of autochthonous primary melanomas in the skin and reduction in the number of spontaneous lung metastases but did not induce tumor regression. Carcinogen-treated HGF × CDK4R24C mice bearing multiple autochthonous melanomas did not reject transplanted B16 melanoma despite treatment with Ad-hTRP2 and TLR ligands, suggesting the development of tumor immunotolerance. Further investigations in our novel genetic melanoma model may help to better understand the role of the immune system in the pathogenesis and treatment of this life-threatening disease. (Cancer Res 2006; 66(10): 5427-35)
CpG Island M`ethylation Status in Gastric Carcinoma with and without Infection of Epstein-Barr Virus
Authors: Chang Moon-Sung , Uozaki Hiroshi , Chong Ja-Mun , Ushiku Tetsuo , Sakuma Kazuya , Ishikawa Shunpei , Hino Rumi , Barua Rita Rani , Iwasaki Yoshiaki , Arai Kuniyoshi , Fujii Hideki , Nagai Hideo , Fukayama Masashi 
Published: May 2006

AbstractPurpose: EBV-associated gastric carcinoma shows global CpG island methylation of the promoter region of various cancer-related genes. To further clarify the significance of CpG island methylator phenotype (CIMP) status in gastric carcinoma, we investigated methylation profile and clinicopathologic features including overall survival in four subgroups defined by EBV infection and CIMP status: EBV-associated gastric carcinoma and EBV-negative/CIMP-high (H), EBV-intermediate (I), and EBV-negative (N) gastric carcinoma.Experimental Design: Methylation-specific PCR was applied to 106 gastric carcinoma cases. CIMP-N, CIMP-I, and CIMP-H status was determined by the number (0, 1-3, and 4-5, respectively) of methylated marker genes (LOX, HRASLS, FLNc, HAND1, and TM), that were newly identified as highly methylated in gastric cancer cell lines. The methylation status of 10 other cancer-related genes (p14, p15, p16, p73, TIMP-3, E-cadherin, DAPK, GSTP1, hMLH1, and MGMT) was also evaluated.Results: Nearly all (14 of 15) of EBV-associated gastric carcinoma exhibited CIMP-H, constituting a homogenous group (14%). EBV-negative gastric carcinoma consisted of CIMP-H (24%), CIMP-I (38%), and CIMP-N (24%). EBV-associated gastric carcinoma showed significantly higher frequencies of methylation of cancer-related genes (mean number ± SD = 6.9 ± 1.5) even if compared with EBV-negative/CIMP-H gastric carcinoma (3.5 ± 1.8). Among EBV-negative gastric carcinoma subgroups, CIMP-H gastric carcinoma showed comparatively higher frequency of methylation than CIMP-I or CIMP-N, especially of p16 and hMLH1. CIMP-N gastric carcinoma predominantly consisted of advanced carcinoma with significantly higher frequency of lymph node metastasis. The prognosis of the patients of CIMP-N was significantly worse compared with other groups overall by univariate analysis (P = 0.0313).Conclusion: The methylation profile of five representative genes is useful to stratify gastric carcinomas into biologically different subgroups. EBV-associated gastric carcinoma showed global CpG island methylation, comprising a pathogenetically distinct subgroup in CIMP-H gastric carcinoma.
Prognostic Significance of Activated AKT Expression in Soft-Tissue Sarcoma
Authors: Tomita Yasuhiko , Morooka Takaya , Hoshida Yoshihiko , Zhang Binglin , Qiu Ying , Nakamichi Itsuko , Hamada Ken-ichiro , Ueda Takafumi , Naka Norifumi , Kudawara Ikuo , Aozasa Katsuyuki 
Published: May 2006

Abstract
Purpose: AKT is a serine/threonine kinase which is important in tumorigenesis. Several molecules involved in AKT pathway are dysregulated in various kinds of human cancers.
Patients and Methods: Ninety-three patients (53 males and 40 females), ages ranging from 19 to 77 years (median, 57 years), with localized soft-tissue sarcomas arising in the trunk and extremities, were analyzed. Immunoperoxidase procedure (avidin-biotin complex method) was done on paraffin-embedded sections with anti–phosphorylated AKT (Thr308), anti–phosphorylated p44/42 extracellular signal–regulated kinase 1 and 2 (ERK1/2) (Thr202/Tyr204), anti–phosphorylated forkhead in rhabdomyosarcoma (FKHR) (Ser256), and anti-Ki 67 antibodies. Expression levels of phosphorylated AKT (p-AKT), phosphorylated ERK1/2 (p-ERK1/2), and phosphorylated FKHR (p-FKHR) were categorized as either weaker (level 1) or equal to or stronger (level 2) compared with those in the endothelial cells of the same specimens. Percentage of cells showing intranuclear staining with Ki-67 was shown as the Ki-67 labeling index (LI). Cases were divided into two groups: level 1, Ki-67 LI &lt; 20%; level 2, Ki-67 LI ≥ 20%.
Results: Twenty-six (28.0%), 6 (6.5%), and 46 (44.1%) of the tumors showed level 2 expression for p-AKT, p-ERK1/2, and Ki-67 LI, respectively. Tumors with level 2 p-AKT expression showed a higher ratio of level 2 p-FKHR expression (P &lt; 0.01). Multivariate analysis revealed p-AKT expression and Ki-67 LI to be independent prognosticators for overall survival, and p-AKT expression for disease-free survival.
Conclusion: p-AKT expression level is a significant prognosticator in soft-tissue sarcoma.
Clinical Significance ofTROP2Expression in Colorectal Cancer
Authors: Ohmachi Takahiro , Tanaka Fumiaki , Mimori Koshi , Inoue Hiroshi , Yanaga Katsuhiko , Mori Masaki 
Published: May 2006

AbstractPurpose and Experimental Design: To identify cancer-related genes, the expression profiles of colorectal cancer cells and normal epithelial cells were examined and compared using laser microdissection and cDNA microarray analysis. From these combined techniques, several cancer-related genes, including TROP2, were identified. TROP2 is known as a calcium signal transducer and is highly expressed in several types of tumors. However, no studies have investigated the significance of TROP2 expression in colorectal cancer. Thus, the expression status of TROP2 was investigated in 74 colorectal cancer samples by quantitative real-time reverse transcription-PCR and immunohistochemical studies.Results: Laser microdissection and cDNA microarray analysis showed that there were 84 overexpressed genes in cancer cells. One of the highly overexpressed genes was TROP2. Quantitative real-time reverse transcription-PCR showed that TROP2 expression in cancer samples was significantly higher than in normal samples (P &lt; 0.001). The samples were divided into high (n = 26) and low (n = 48) TROP2 expression groups. The cases with high TROP2 expression showed a higher frequency of liver metastasis (P = 0.005) and more cancer-related death (P = 0.046). Those cases also had an inclination of deeper depth of invasion (P = 0.064) and more lymph node metastasis (P = 0.125). Interestingly, the patients with high TROP2 expression tumors had poorer prognosis (P = 0.0036). Multivariate analysis showed that TROP2 expression status was an independent prognostic factor (relative risk, 2.38; 95% confidence interval, 1.29-4.74; P &lt; 0.01).Conclusion: TROP2 is one of the cancer-related genes that correlates with biological aggressiveness and poor prognosis of colorectal cancer. Thus, TROP2 is a possible candidate gene for diagnosis and molecular target therapy of colorectal cancer.
17β-Estradiol Induces Down-Regulation of Cap43/NDRG1/Drg-1, a Putative Differentiation-Related and Metastasis Suppressor Gene, in Human Breast Cancer Cells
Authors: Fotovati Abbas , Fujii Teruhiko , Yamaguchi Miki , Kage Masayoshi , Shirouzu Kazuo , Oie Shinji , Basaki Yuji , Ono Mayumi , Yamana Hideaki , Kuwano Michihiko 
Published: May 2006

Abstract
Purpose: Cap43 is known as a nickel- and calcium-inducible gene. In the present study, we examined whether 17β-estradiol (E2) could affect the expression of Cap43 in breast cancer.
Experimental Design: Real-time PCR, immunoblotting, and immunocytochemistry were used to examine the expression of Cap43 and estrogen receptor-α (ER-α) in breast cancer cell lines. MDA-MB-231 and SK-BR-3 cell lines were transfected with ER-α cDNA to establish cells overexpressing ER-α. Immunohistochemistry was used to evaluate the expression of the Cap43 protein in breast cancer patients (n = 96), and the relationship between Cap43 expression and clinicopathologic findings was examined.
Results: Of the eight cell lines, four expressed higher levels of Cap43 with very low levels of ER-α, whereas the other four expressed lower levels of Cap43 with high ER-α levels. Treatment with E2 decreased the expression of Cap43 dose-dependently in ER-α-positive cell lines but not in ER-α-negative lines. Administration of antiestrogens, tamoxifen and ICI 182780, abrogated the E2-induced down-regulation of Cap43. Overexpression of ER-α in both ER-α-negative cell lines, SK-BR-3 and MDA-MB-231, resulted in down-regulation of Cap43. Immunostaining studies showed a significant correlation between Cap43 expression and the histologic grade of tumors (P = 0.0387). Furthermore, Cap43 expression was inversely correlated with the expression of ER-α (P = 0.0374).
Conclusions: E2-induced down-regulation of Cap43 seems to be mediated through ER-α-dependent pathways in breast cancer cells both in culture and in patients. Cap43 has potential as a molecular marker to determine the therapeutic efficacy of antiestrogenic anticancer agents in breast cancer.