bluuebunny/crossref_metadata_2025_split huggingface dataset:
Down-regulation of Polo-like Kinase 1 Elevates Drug Sensitivity of Breast Cancer CellsIn vitroandIn vivo
Authors: Spänkuch Birgit , Heim Sandra , Kurunci-Csacsko Elisabeth , Lindenau Christine , Yuan Juping , Kaufmann Manfred , Strebhardt Klaus 
Published: June 2006

AbstractHuman polo-like kinase 1 (Plk1) is a key player in different stages of mitosis and modulates the spindle checkpoint at the metaphase-anaphase transition. Overexpression of Plk1 is observed in various human tumors and it is a negative prognostic factor in patients suffering from diverse cancers. We used phosphorothioate antisense oligonucleotides (ASO) targeted against Plk1, together with paclitaxel, carboplatin, and Herceptin, for the treatment of breast cancer cells to identify conditions for enhanced drug sensitivity. After transfection of the breast cancer cell lines BT-474, MCF-7, and MDA-MB-435 with Plk1-specific ASOs, paclitaxel, carboplatin, or Herceptin was added and cell proliferation, cell cycle distribution, and apoptosis were measured. Whereas the dual treatment of breast cancer cells with Plk1-specific ASOs with carboplatin or Herceptin caused only a limited antiproliferative effect in breast cancer cells, we observed synergistic effects after combination of low doses of Plk1-specific ASOs with paclitaxel, which is used in a variety of clinical anticancer regimens. Plk1-specific ASOs also acted synergistically with paclitaxel in the arrest of the cell cycle at the G2-M phase and in the induction of apoptosis. Interestingly, in a human xenograft experiment using MDA-MB-435 cells, the combination of Plk1 ASOs with paclitaxel led to synergistic reduction of tumor growth after 3 weeks of treatment compared with either agent alone. This study suggests that antisense inhibitors against Plk1 at well-tolerated doses may be considered as highly efficient promoters for the antineoplastic potential of taxanes, such as paclitaxel, causing synergistic effects in breast cancer cells. (Cancer Res 2006; 66(11): 5836-46)
AKT Activation in Human Glioblastomas Enhances Proliferation via TSC2 and S6 Kinase Signaling
Authors: Riemenschneider Markus J. , Betensky Rebecca A. , Pasedag Saskia M. , Louis David N. 
Published: June 2006

Abstract
Aberrant AKT (protein kinase B) signaling is common in many cancers, including glioblastoma. Current models suggest that AKT acts directly, or indirectly via the TSC complex, to activate the mammalian target of rapamycin (mTOR) as the main downstream mediator of AKT signaling. mTOR activation results in subsequent activation of S6K and STAT3, as well as suppression (i.e., phosphorylation) of 4E-BP1, leading to cell cycle progression and inhibition of apoptosis. Most studies of this pathway have used in vitro systems or tumor lysate–based approaches. We aimed to delineate these pathways in a primarily in situ manner using immunohistochemistry in a panel of 29 glioblastomas, emphasizing the histologic distribution of molecular changes. Within individual tumors, increased expression levels of p-TSC2, p-mTOR, p-4E-BP1, p-S6K, p-S6, and p-STAT3 were found in regions defined by elevated AKT activation. However, only TSC2, S6K, and S6 activation levels correlated significantly with AKT activation and clustered together in multidimensional scaling analyses. Ki-67 proliferation indices were significantly elevated in p-AKT-overexpressing regions, whereas expression of the apoptosis marker cleaved caspase 3 was generally low and not significantly different between the regions. These findings provide the first in vivo evidence for a close correlation between AKT and TSC2 phosphorylation levels in glioblastoma. Moreover, they suggest that downstream p-AKT effects are primarily mediated by S6 kinase signaling, thus enhancing proliferation rather than inhibiting apoptosis. (Cancer Res 2006; 66(11): 5618-23)
A Systems Approach to Model Metastatic Progression
Authors: Taylor Barry S. , Varambally Sooryanarayana , Chinnaiyan Arul M. 
Published: June 2006

Abstract
Proteomic profiling of human disease has seen much early activity with the accessibility of the newest generation of high-throughput platforms and technologies. Nevertheless, the nature of the dynamic physiologic milieu and high dimensionality of the data has complicated major diagnostic and prognostic breakthroughs. Our recent article in Cancer Cell delineates an integrative model for culling a molecular signature of metastatic progression in prostate cancer from proteomic and transcriptomic analyses and shows its facility as a predictor of prognosis. The study leveraged direct proteomic analysis of tumor tissue extracts, differential feature selection characterizing the proteomic alterations of prostate cancer subclasses, and integration with public and study-derived genomic data to construct a multiplex gene signature representing progression of indolent cancer to aggressive disease. This further predicted clinical outcome in a variety of solid tumors. This review describes the context of the work, the framework for the analysis itself, and a look forward to the promise of this systems approach to human disease. (Cancer Res 2006; 66(11): 5537-9)
Human Papillomavirus Type 16 E7 Up-regulates AKT Activity through the Retinoblastoma Protein
Authors: Menges Craig W. , Baglia Laurel A. , Lapoint Randi , McCance Dennis J. 
Published: June 2006

Abstract
Human papillomaviruses (HPV) are small DNA tumor viruses causally associated with cervical cancer. The early gene product E7 from high-risk HPV is considered the major transforming protein expressed by the virus. Although many functions have been described for E7 in disrupting normal cellular processes, we describe in this study a new cellular target in primary human foreskin keratinocytes (HFK), the serine/threonine kinase AKT. Expression of HPV type 16 E7 in HFK caused inhibition of differentiation, hyperproliferation, and up-regulation of AKT activity in organotypic raft cultures. The ability of E7 to up-regulate AKT activity is dependent on its ability to bind to and inactivate the retinoblastoma (Rb) gene product family of proteins. Furthermore, we show that knocking down Rb alone, with short hairpin RNAs, was sufficient to up-regulate AKT activity in differentiated keratinocytes. Up-regulation of AKT activity and loss of Rb was also observed in HPV-positive cervical high-grade squamous intraepithelial lesions when compared with normal cervical tissue. Together, these data provide evidence linking inactivation of Rb by E7 in the up-regulation of AKT activity during cervical cancer progression. (Cancer Res 2006; 66(11): 5555-9)
A Modular Analysis of Breast Cancer Reveals a Novel Low-Grade Molecular Signature in Estrogen Receptor–Positive Tumors
Authors: Yu Kun , Ganesan Kumaresan , Miller Lance D. , Tan Patrick 
Published: June 2006

Abstract
Purpose: Previous reports using genome-wide gene expression data to classify breast tumors have typically used standard unsupervised or supervised techniques, both of which have known limitations. We hypothesized that novel clinically relevant information could be revealed in these data sets by an alternative analytic approach. Using a recently described algorithm, signature analysis (SA), we identified “modules,” comprising groups of tightly coexpressed genes that are conditionally linked to particular tumors, in a series of breast tumor gene expression profiles.
Experimental Design and Results: The SA successfully identified multiple breast cancer modules specifically linked to distinct biological functions. We identified a novel module, TuM1, whose presence was not readily discernible by conventional clustering techniques. The TuM1 module is expressed in a subset of estrogen receptor (ER)–positive tumors and is significantly enriched with genes involved in apoptosis and cell death. Clinically, TuM1-expressing tumors are associated with low histopathologic grade, and this association is independent of the inherent ER status of a tumor. We confirmed the robustness and general applicability of TuM1 module by demonstrating its association with low tumor grade in multiple independent breast cancer data sets generated using different array technologies. In vitro, the TuM1 module is down-regulated in ER+ MCF7 cells upon treatment with tamoxifen, suggesting that TuM1 expression may be dependent on active signaling by ER. Initial data is also suggestive that TuM1 expression may be clinically associated with a patient's response to antihormonal therapy.
Conclusion: Our results suggest that modular-based approaches toward gene expression data can prove useful in identifying novel, robust, and biologically relevant signatures even from data sets that have been the subject of substantial prior analysis.
Overexpression of Focal Adhesion Kinase in Head and Neck Squamous Cell Carcinoma Is Independent of fak Gene Copy Number
Authors: Canel Marta , Secades Pablo , Rodrigo Juan-Pablo , Cabanillas Rubén , Herrero Agustín , Suarez Carlos , Chiara María-Dolores 
Published: June 2006

Abstract
The development of human malignancies can involve the aberrant regulation of intracellular signal transduction pathways that regulate cell-extracellular matrix interactions.
Purpose: In the current study, we aimed to evaluate focal adhesion kinase (FAK) at both genetic and protein expression levels in head and neck squamous cell carcinomas (HNSCC) and to explore the prognostic significance of FAK.
Experimental Design: A total of 211 tissue specimens, including 147 primary tumors, 56 lymph node metastases, 3 benign hyperplasias, and 5 dysplasias, were analyzed using immunohistochemistry. The fak gene dosage was determined in 33 tumors. Correlations among DNA, protein, and clinicopathologic variables were analyzed.
Results: FAK protein was overexpressed in HNSCCs compared with corresponding normal mucosa. High expression levels were found in 62% of the samples. Positive immunostaining was also detected in benign hyperplasias and preinvasive dysplastic lesions. All lymph node metastases examined showed FAK overexpression, with significant correlation with the expression in matched primary tumor. DNA copy number ratios for fak were higher in 39% of the tumors compared with normal mucosa. However, elevated FAK expression did not correlate with gains on DNA level, and not all cases with an amplification of the fak gene displayed protein overexpression. Similar data were obtained in five HNSCC-derived cell lines, in which FAK mRNA levels were precisely correlated with FAK protein levels. FAK protein overexpression in tumors correlated with nodal metastases.
Conclusions: These findings suggest an involvement of FAK in the onset and progression of HNSCC and provide an insight into a mechanism of FAK activation alternative to gene amplification.
The Coincidence of Chromosome 15 Aberrations and β2-Microglobulin Gene Mutations Is Causative for the Total Loss of Human Leukocyte Antigen Class I Expression in Melanoma
Authors: Paschen Annette , Arens Norbert , Sucker Antje , Greulich-Bode Karin M. , Fonsatti Ester , Gloghini Annunziata , Striegel Sandra , Schwinn Nicole , Carbone Antonino , Hildenbrand Ralf , Cerwenka Adelheid , Maio Michele , Schadendorf Dirk 
Published: June 2006

AbstractPurpose: Total loss of surface presentation of human leukocyte antigen (HLA) class I molecules, protecting tumor cells from the recognition by cytotoxic host CD8+ T cells, is known to be caused by mutations in the β2-microglobulin (β2m) gene. We asked whether abnormalities of chromosome 15, harboring the β2m gene on 15q21, in addition to β2m gene mutations, are causative for the HLA class I–negative phenotype of melanoma cells.Experimental Design: To answer this, we established primary cell lines from the β2m-negative metastatic melanoma tissues of four different patients and analyzed them for β2m gene mutations and chromosome 15 aberrations, the latter by loss of heterozygosity analysis, fluorescence in situ hybridization (FISH), and multicolor FISH.Results: Mutations at the β2m gene level were detected in all cell lines. The loss of heterozygosity analysis of microsatellite markers located on chromosome 15 in three of the four cell lines pointed to an extensive loss of chromosome 15 material. Subsequent molecular cytogenetic analysis revealed the coexistence of apparently normal and rearranged versions of chromosome 15 in three cell lines whereas the fourth cell line solely showed rearranged versions. Two of the four cell lines exhibited a special type of intrachromosomal rearrangement characterized by FISH signals specific for the subtelomeric region of 15q at both ends of the chromosome and one centromeric signal in between.Conclusions: Our data indicate that the complete loss of HLA class I expression in melanoma cells is due to the coincidence of the following mutational events: (a) chromosome 15 instability associated with an extensive loss of genetic material and (b) β2m gene mutations.
Loss of β4 Integrin Subunit Reduces the Tumorigenicity of MCF7 Mammary Cells and Causes Apoptosis upon Hormone Deprivation
Authors: Bon Giulia , Folgiero Valentina , Bossi Gianluca , Felicioni Laura , Marchetti Antonio , Sacchi Ada , Falcioni Rita 
Published: June 2006

Abstract
Purpose: The α6β4 integrin, a laminin receptor, has been implicated from many studies in tumor progression and invasion. We showed that the β4 integrin subunit associates with the ErbB-2 tyrosine kinase in human mammary carcinoma cell lines and that its overexpression in NIH3T3/ErbB-2–transformed cells causes a constitutive activation of phosphatidylinositol 3-kinase (PI3K), inducing a strong increase of their invasive capacity. In this study, we investigated the biological consequences of interference with the endogenous β4 integrin subunit expression.
Experimental Design: In vitro and in vivo tumor growth and the biochemical consequences of β4 integrin inactivation were studied in mammary tumor cells by using short hairpin RNA approach.
Results: Our data show that tumor growth of mammary tumor cells strictly depends on β4 expression, confirming the relevance of β4 protein in these cells. Moreover, interference with β4 expression significantly reduces endogenous PI3K activity and AKT and mammalian target of rapamycin phosphorylation. Accordingly, with these results and considering that PI3K activity in mammary tumor plays a relevant role in hormone resistance, we asked whether β4 expression might be relevant for hormone responsiveness in these cells. Data reported indicate that the interference with endogenous β4 expression, upon hormone deprivation, induces caspase-9 and cytochrome c–mediated apoptosis, which is enhanced upon tamoxifen treatment. On the other hand, the expression of myr-AKT in MCF7 β4–short hairpin RNA cells rescues the cells from apoptosis in the absence of hormones and upon tamoxifen treatment.
Conclusions: Overall, these results confirm the relevance of β4 expression in mammary tumors and indicate this integrin as a relevant target for tumor therapy.
Constructing Molecular Classifiers for the Accurate Prognosis of Lung Adenocarcinoma
Authors: Guo Lan , Ma Yan , Ward Rebecca , Castranova Vince , Shi Xianglin , Qian Yong 
Published: June 2006

AbstractPurpose: Individualized therapy of lung adenocarcinoma depends on the accurate classification of patients into subgroups of poor and good prognosis, which reflects a different probability of disease recurrence and survival following therapy. However, it is currently impossible to reliably identify specific high-risk patients. Here, we propose a computational model system which accurately predicts the clinical outcome of individual patients based on their gene expression profiles.Experimental Design: Gene signatures were selected using feature selection algorithms random forests, correlation-based feature selection, and gain ratio attribute selection. Prediction models were built using random committee and Bayesian belief networks. The prognostic power of the survival predictors was also evaluated using hierarchical cluster analysis and Kaplan-Meier analysis.Results: The predictive accuracy of an identified 37-gene survival signature is 0.96 as measured by the area under the time-dependent receiver operating curves. The cluster analysis, using the 37-gene signature, aggregates the patient samples into three groups with distinct prognoses (Kaplan-Meier analysis, P &lt; 0.0005, log-rank test). All patients in cluster 1 were in stage I, with N0 lymph node status (no metastasis) and smaller tumor size (T1 or T2). Additionally, a 12-gene signature correctly predicts the stage of 94.2% of patients.Conclusions: Our results show that the prediction models based on the expression levels of a small number of marker genes could accurately predict patient outcome for individualized therapy of lung adenocarcinoma. Such an individualized treatment may significantly increase survival due to the optimization of treatment procedures and improve lung cancer survival every year through the 5-year checkpoint.
Tumor-Infiltrating Cytotoxic T Cells but not Regulatory T Cells Predict Outcome in Anal Squamous Cell Carcinoma
Authors: Grabenbauer Gerhard G. , Lahmer Godehard , Distel Luitpold , Niedobitek Gerald 
Published: June 2006

AbstractPurpose: Tumor-infiltrating lymphocytes (TIL) are a possible prognostic factor in solid tumors. Cytotoxic TILs are generally considered as prognostically favorable, whereas regulatory T cells (Treg) may have adverse effects by virtue of their ability to inhibit effector cells. We have evaluated the effect of T-cell subsets on survival in patients with anal squamous cell carcinoma following radiochemotherapy.Methods: Biopsy specimens from 38 patients with anal carcinomas were evaluated using tissue microarrays and immunohistochemistry for the presence of tumor-infiltrating immune cells using CD3, CD4, CD8, and CD68 antibodies. Treg were identified using an antibody directed against the transcription factor FoxP3, and granzyme B served as a marker for cytotoxic cells. Intratumoral immune cells were enumerated using a semiautomatic image analysis program. Prognostic effect of TIL subsets was evaluated by the log-rank test comparing no evidence of disease survival for groups with high and low numbers using median values as cutoff.Results: CD3+ and CD4+ TILs influenced no evidence of disease survival: 3-year rates for patients with low numbers were 89% and 95%, respectively, and 54% (P = 0.02) and 48%, (P = 0.01), respectively, in cases with high numbers. Large numbers of tumor-infiltrating granzyme B+ cytotoxic cells had a significant negative prognostic effect (P = 0.008), whereas no effect was observed for Treg.Conclusions: TILs were identified as negative prognostic indicators in anal squamous cell carcinomas with granzyme B+ cytotoxic cells showing highest effect on outcome. This is possibly explained by the selection of therapy-resistant tumor cell clones. No prognostic influence of Treg was found. Knowledge of local immune responses is important for the development of immunotherapeutic strategies.
Germ Line Mutations of Mismatch Repair Genes in Hereditary Nonpolyposis Colorectal Cancer Patients with Small Bowel Cancer: International Society for Gastrointestinal Hereditary Tumours Collaborative Study
Authors: Park Jae-Gahb , Kim Duck-Woo , Hong Chang Won , Nam Byung-Ho , Shin Young-Kyoung , Hong Sung-Hye , Kim Il-Jin , Lim Seok-Byung , Aronson Melyssa , Bisgaard Marie Luise , Brown Gregor J. , Burn John , Chow Elizabeth , Conrad Peggy , Douglas Fiona , Dunlop Malcolm , Ford James , Greenblatt Marc S. , Heikki Jarvinen , Heinimann Karl , Lynch Elly L. , Macrae Finlay , McKinnon Wendy C. , Möeslein Gabriela , Rossi Benedito Mauro , Rozen Paul , Schofield Lyn , Vaccaro Carlos , Vasen Hans , Velthuizen Mary , Viel Alessandra , Wijnen Juul 
Published: June 2006

Abstract
Purpose: The aim of study was to determine the clinical characteristics and mutational profiles of the mismatch repair genes in hereditary nonpolyposis colorectal cancer (HNPCC) patients with small bowel cancer (SBC).
Experimental Design: A questionnaire was mailed to 55 members of the International Society for Gastrointestinal Hereditary Tumours, requesting information regarding patients with HNPCC-associated SBC and germ line mismatch repair gene mutations.
Results: The study population consisted of 85 HNPCC patients with identified mismatch repair gene mutations and SBCs. SBC was the first HNPCC-associated malignancy in 14 of 41 (34.1%) patients for whom a personal history of HNPCC-associated cancers was available. The study population harbored 69 different germ line mismatch repair gene mutations, including 31 mutations in MLH1, 34 in MSH2, 3 in MSH6, and 1 in PMS2. We compared the distribution of the mismatch repair mutations in our study population with that in a control group, including all pathogenic mismatch repair mutations of the International Society for Gastrointestinal Hereditary Tumours database (excluding those in our study population). In patients with MSH2 mutations, patients with HNPCC-associated SBCs had fewer mutations in the MutL homologue interaction domain (2.9% versus 19.9%, P = 0.019) but an increased frequency of mutations in codons 626 to 733, a domain that has not previously been associated with a known function, versus the control group (26.5% versus 2.8%, P &lt; 0.001).
Conclusions: In HNPCC patients, SBC can be the first and only cancer and may develop as soon as the early teens. The distribution of MSH2 mutations found in patients with HNPCC-associated SBCs significantly differed from that found in the control group (P &lt; 0.001).