bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 494: Proteolysis of pseudokinase PTK7 controls cancer cell invasion
Authors: Golubkov Vladislav , Strongin Alex 
Published: August 2012

Abstract
Deregulated cell motility promotes cancer progression and metastasis, a major cause of cancer patient death. Understanding the molecular mechanisms regulating cell motility in malignancy will facilitate an identification of novel anti-metastatic therapies. Recently, we identified a new mechanism, the proteolytic control of directional cell motility and invasion. The membrane protein tyrosine kinase 7 (PTK7) controls the orientation of cells in a tissue plane (planar cell polarity, PCP) and inhibits cancer cell invasion. The pro-invasive membrane type-1 matrix metalloprotease (MT1-MMP/MMP-14) directly cleaves PTK7 at the cell surface and reverses the inhibitory anti-invasive signal of the full-length PTK7. Thus, PTK7 proteolysis by MT1-MMP turns on cell motility and invasion. This ubiquitous mechanism is conserved in processes as diverse as embryo development and cancer cell invasion. Because both the pro-invasive MT1-MMP and the polarity regulating PTK7 are linked to cancer, the precise understanding of the role of PTK7 proteolysis in cancer progression is important to discover novel therapies.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 494. doi:1538-7445.AM2012-494
Abstract 4940: Activated signaling mechanism of glioblastoma recurrence derived from genetics, epigenetics, and genomics abnormalities
Authors: Jin Guangxu , Gao Junfeng , Wong Stephen T.C. 
Published: August 2012

Abstract
Recurrence or progession happens to certain glioblastoma (GBM) patients after given surgeries and complex treatment regimens. This implies that the pathways related to cell growth or apoptosis resistance have been activated. However, it lacks an efficient model to identify the activated pathways from a variety of data generated by the platforms on genetics, epigenetics, and genomics. Here, we develop a new computational model, called as CSB-MOO (Cancer Signaling Bridges - Multiple Objective Optimization), to address signaling mechanism associated with the recurrence or progression of GBM. We used a pathway-driven method to address the activated pathways. In the model of CSB-MOO, a new type of network elements, Cancer Signaling Bridge (CSB), was used to expand the known signaling pathways to the cancer genes (with genetic disorders) of GBM. Facilitated by CSBs, more than 60 known signaling pathways are found to be connected with the cancer genes for GBM. Then, a well-established mathematical method, Multi-Objective Optimization (MOO), was applied to identify activated pathways from multiple-type data. We used Pareto optimal to solve this MOO problem. We applied the CSB-MOO to the multiple-type data of GBM in TCGA (n=595). 15 proteins are activated in the 7 common pathways for both of the patients with and without recurrence/progression. These proteins include EGFR and JAK proteins. The patients without recurrence or progression activate another 11 activated proteins related to metabolic of amino acids (Tryptophan and Phenylalanine). Specifically, the patients with recurrence or progression activate another seventeen proteins, e.g., PIK3R1, and 2 protein complexes, i.e., [PLCG2/PLCG1] and [ITPR3/ITPR2/ITPR1], in which the SH2 domain of PIK3R1 acts an adaptor between the kinases [PLCG2/PLCG1] and the targeted proteins. In addition, these proteins facilitate the signal transduction from EGFR to downstream proteins through mediating phosphorylation. This is consistent with the fact that the recurrence/progression patients can activate the progession of GMB. The identified activated pathways classify the GBM patients with and without recurrence/progression in an accuracy of 80.89% (P &lt; 10−4, Fisher exact test). Survival analysis indicates that the activated pathways with genetics, epigenetics, and genomics patterns accurately predict the patients’ lifespan (P = 0.0007, Chi-squared test). Acknowledgements: This work was supported by NIH grant U54CA149196 to STCW.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4940. doi:1538-7445.AM2012-4940
Abstract 495: Overexpression of TIS21/BTG2/PC3 inhibits formation of invadopodia in the highly metastatic breast cancer cells MDA-MB-231
Authors: Choi Jung A , Lim In Kyoung 
Published: August 2012

Abstract
Invasion of cancer cells depends on the proteolytic degradation of extracellular matrix and it is initiated by the actin-driven membrane protrusions, called invadopodia. However, the mechanisms underlying invadopodia formation remain largely unknown. In this study, we report that TIS21/BTG2/PC3, tumor suppressor gene, suppress invadopodia formation in the highly invasive breast cancer cells, MDA-MB-231. To understand downstream mechanisms regulating invadopodia formation by TIS21, generation of ROS (reactive oxygen species) by NADPH oxidase (Nox) was examined and observed that adenoviral transduction of TIS21 markedly attenuated generation of ROS. The transduction of TIS21 significantly inhibited mRNA expression of Nox1 and Nox4, but not p22phox. In contrast, formation of invadopodia was much higher in the TIS21KO-mouse embryo fibroblasts (TIS21−/- MEF) along with elevated expression of Nox1 and Nox4, compared with those of the wild type MEF. The data strongly suggest that TIS21 contributes inhibition of invadopodia formation through the regulation of Nox expression. Noticeably, transduction of TIS21 regulated reorganization of actin-assoicated protein and cytockelectal proteins such as F-actin and vimentin. Similarly, inhibition of Nox-derived ROS by using DPI reversed reorganization of the proteins. The above data clearly indicate that generation of Nox-derived ROS play a critical role in the distribution of actin-assoicated protein and cytockelectal proteins. Taken together, present report demonstrates, for the first time, that the TIS21/BTG2-ROS-linked cascades is required for formation of invadopodia in the highly invasive breast cancer cells and may provide insight into mechanisms of metastatic signaling in breast cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 495. doi:1538-7445.AM2012-495
Abstract 4950: Discovery of the pro-apoptotic genes induced by tumor suppressor p53
Authors: DASHZEVEG Nurmaa , TAIRA Naoe , MIKI Yoshio , YOSHIDA Kiyotsugu 
Published: August 2012

Abstract
The tumor suppressor p53 regulates apoptosis in response to DNA damage. Promoter selectivity of p53 depends mainly on its phosphorylation. Notably, the phosphorylation at serine-46 (Ser46) of p53 is indispensable to promote pro-apoptotic genes. However, little is known about the pro-apoptotic genes induced by Ser46 phosphorylation of p53. In our study, we aimed to investigate pro-apoptotic genes induced by p53 using microarray analysis and ChIP sequencing assay. Although microarray analysis became common tool in molecular biology, novelty of our research is combining microarray analysis with ChIP sequencing assay to discover direct target of p53 in Ser46 specific manner. Analyze of microarray showed specific up-regulation of 2723 genes in wild type p53 (wt-p53). Alternatively, 1338 genes were interacted directly with only wt-p53 but not with mutant p53 (Ser46 is substituted with alanine, p53S46A) in ChIP sequencing assay. The comparison of two assays, microarray analysis and ChIP sequencing assay, investigated thirty genes in relation with Ser46 phosphorylation of tumor suppressor p53. Those thirty genes were clarified by real time RT-PCR and the genes strongly elicited were chosen further study. The research will be continued with more clarification and apoptotic function of candidate genes in response to DNA damage will be investigated. We hope that the discovery of pro-apoptotic genes induced by p53 will convey the important role in cancer research and therapy. Acknowledgement: This project is partly supported by Global Center of Excellence (GCOE) program at TMDU.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4950. doi:1538-7445.AM2012-4950
Abstract 4952: Persistent expression of Nqo1 by p62-mediated Nrf2 activation facilitates p53-dependent mitotic catastrophe
Authors: Bui Chi Bao 
Published: August 2012

Abstract
Prolonged mitosis due to aberrant chromosome segregation permits cells to enter the G1 phase without cytokinesis and subsequently triggers the p53-dependent cell death program, known as mitotic catastrophe. Cells which fail to go through mitotic catastrophe create aneuploidy, posing a risk of oncogenesis. In the present report, we show that p62-mediated non-canonical activation of Nrf2 leads to the persistent expression of Nqo1, which plays a critical role for p53 stabilization during mitotic catastrophe. With prolonged exposure to nocodazole, a microtubule-depolymerizing agent, p62-deficient HCT116 cells exhibited an accumulation of a polyploid population with a limited appearance of apoptoic cells, which was attributable to the attenuated stabilization of p53. Combinatorial gene manipulation analysis verified that the regulatory cascade with a hierarchy of p62-Keap1-Nrf2-Nqo1 is required for p53 stabilization for mitotic catastrophe. This is consistent with the role of Nqo1 as a gatekeeper for proteasomal degradation of p53. Thus, we demonstrate for the first time the functional connection between the non-canonical Nrf2 pathway and p53-dependent cell death program upon prolonged mitosis.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4952. doi:1538-7445.AM2012-4952
Abstract 4957: Mixed Lineage Kinase 3 mediates vanadium-induced cell death in cancer cells
Authors: Rangasamy Velusamy , Sondarva Gautam , Tuladhar Sushan , Rana Basabi , Rana Ajay 
Published: August 2012

Abstract
Vanadium is a transition metal and occurs naturally in a variety of minerals. In mammals, vanadium has been shown to promote cancer cell death and can also mimic insulin action, most probably through the inhibition of cellular tyrosine phosphatase and subsequent activation of signaling pathways. The mechanism by which vanadium causes cancer cell death is still not known. Interestingly, it has been shown that various mitogen activated protein kinase (MAPK) members are activated upon vanadium treatment. However, the contribution of any specific MAPK member that mediates vanadium-induced cell death has not been clearly delineated. It has been reported that JNK is activated by vanadium and therefore we investigated the role of Mixed Lineage Kinase 3 (MLK3) on vanadium-induced cell death. MLK3 is a MAP3K member that is known to specifically activate JNK pathway. We have earlier reported that MLK3 activation promotes cell death in cancer and neuronal cells. Our results demonstrated that endogenous MLK3 was activated by vanadium and MLK3 was highly phosphorylated on tyrosine residues. We also identified Src as a tyrosine kinase that phosphorylated MLK3 on specific tyrosine residues and phosphorylation of these tyrosine residues by Src was essential for MLK3 activation. Vanadium-induced cancer cell death was mediated by MLK3 or MLKs, because CEP-1347, a pan MLK inhibitor, prevented this cell death. Furthermore, the tyrosine phospho-deficient mutants of MLK3 also prevented vanadium-induced cell death. Interestingly, the activity of Src was seen to be in parallel with MLK3 kinase activity in human primary breast tumors. Taken together, our data demonstrate that tyrosine phosphorylation of MLK3 by oncogenic Src leads to MLK3 activation, which subsequently promotes vanadium-induced cell death in cancer cells. Our results also implicate a paradoxical pro-apoptotic role of Src in cancer cells, and thus it is conceivable that in tumors where both Src and MLK3/MLKs activities are higher, targeting of this axis might promote cell death.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4957. doi:1538-7445.AM2012-4957
Abstract 5044: Radiation modulates expression of microRNAs in breast cancer cell lines grown under adherent and stem cell promoting culture conditions
Authors: Debeb Bisrat G. , Xu Wei , Lacerda Lara , Li Li , Caimiao Wei , Reuben James M. , Ueno Naoto T. , Buchholz Thomas A. , Woodward Wendy A. 
Published: August 2012

Abstract
Although mounting evidence demonstrates that cancer stem/progenitor cells are radioresistant, explicit mechanisms of resistance have not been fully explored. MicroRNAs (miRNAs) are small noncoding RNAs that are involved in regulating cancer stem cell self-renewal and play an important role in response to cellular stress. Few studies have been conducted to investigate the role of specific miRNAs in cellular radiation response. Knowledge of how radiation therapy modulates miRNA expression in cancer stem cells vs. non-stem cells is critical to developing cancer stem cell sensitizers. We isolated total RNA from adherent (2D) and non-adherent mammosphere (3D) cultures of six breast cancer cell lines (MCF12F, MCF7, SUM190, SUM149, MDA-IBC-3, and SUM159) subjected to 0Gy or 4Gy radiation and examined differentially expressed miRNAs using Exiqon's miRCURY microarray. Analysis of the data showed 62 differentially expressed miRNAs between 2D and 3D independent of radiation treatment (fold change of at least 1.5, FDR &lt;0.1; P&lt;0.05). While no radiation based signature was observed when comparing all irradiated samples to unirradiated samples, assessment of each cell line indicated that the levels of specific microRNAs were altered in response to radiation treatment in 2D and 3D cells. Further studies to validate the functions of top candidate miRNAs using inhibitors or mimics to alter the self renewal and radiosensitivity of cancer stem cells are underway.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5044. doi:1538-7445.AM2012-5044
Abstract 5045: miR-10b mediates melanoma progression induced by BRAFV600E
Authors: Datar Ila J. 
Published: August 2012

Abstract
The protein kinase BRaf plays an important role in the mitogen-activated protein kinase (MAPK) pathway initiated by Ras. Raf, after activated by Ras activates Erk and its downstream effectors to carry out normal cellular functions, which include differentiation, proliferation, survival and senescence. BRafV600E mutation has been implicated in 50-60% of all melanoma cases. It is a constitutively active mutation that has been linked to the progression of melanoma. Many microRNAs have been implicated in cancer proliferation and metastasis. Of special interest is the miR-10b, which is known to play a crucial role in tumor invasion and metastasis as previously observed in a mouse mammary tumor model. Our preliminary data show that miR-10b was upregulated in melanoma cell-lines that carried either N-Ras gain-of-function mutation or BRafV600E. BRafV600E knockdown in melanoma cell lines reduces the expression of TWIST, a transcriptional activator of miR-10b, as well as the expression of miR-10b. Further, BrafV600E is known to mediate senescence through several factors including the transcriptional regulator DMTF1. Concordantly, we detected an increase in the expression of DMTF1 on BRafV600E knockdown. Thus, we hypothesize that in melanoma, BRafV600E activates the expression of TWIST which then activates miR-10b, leading to inhibition of DMTF1 and ultimately a failure to bring about cell-cycle arrest.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5045. doi:1538-7445.AM2012-5045
Abstract 5051: microRNA based classification of non-BRCA1/2 hereditary breast cancer tumors
Authors: Tanic Miljana , Marquez-Rodas Ivan , Fernandez Victoria , Benitez Javier , Martinez-Delgado Beatriz 
Published: August 2012

Abstract
Familial breast cancer comprises 5-10% of all breast cancer cases. Germline mutations in the currently known BRCA1 or 2 high risk-breast cancer genes are common in familial breast cancer, but they can explain, 20-25% of the overall familial risk. Still, the large majority of breast cancer cases that arise in families with strong familial aggregation are not explained by mutations in any know breast cancer susceptibility gene, and are designated as BRCAX tumors. MicroRNA (miRNA) deregulation has been extensively implicated in cancer pathogenesis. Specifically, in breast cancer, there are miRNA expression profiles associated to specific subtypes or biological features such as hormone receptor, HER2 status, metastasis, progression or proliferation. However, there are no publications describing miRNA expression profiles in hereditary breast tumors. We established the miRNA expression profiles associated to familial breast tumors from different genetic subtypes, BRCA1, BRCA2 and BRCAX. The discovery of differentially expressed miRNAs may improve the diagnosis of these tumors and will provide new insight into the molecular biology of the tumors. We selected tumor areas from 80 FFPE samples (66 hereditary breast tumors, 10 sporadic and 4 normal breast samples). The samples were analyzed by miRNA microarray expression profiling using LNA-based Exiqon platform and interesting miRNAs were validated by QT-PCR. Hierarchical clustering of BRCAX tumors revealed clear heterogeneity, with 4 apparent groups. For class discovery we have used Consensus clustering algorithm that confirmed the existence of 4 different subgroups among BRCAX tumors (A, B, C and D). Interestingly, Group C clusters with BRCA1/2 mutated tumors, while Group A clusters along with normal breast tissue. Group B appears as a homogenous group of tumors, while group D represents a very heterogeneous group, lacking a specific miRNA signature. Next, we identified miRNA signatures for each of the well defined groups (A, B, C) and we performed pathway enrichment analysis using IPA and identified associated biological processes for each of the miRNA clusters. We found that miRNAs contributed to a better definition of BRCAX group of tumors, which could potentially be subclassified into distinct groups. The identification of key target genes and pathways regulated by significant miRNAs would give as a better understanding of the mechanisms of tumorigenesis.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5051. doi:1538-7445.AM2012-5051
Abstract 5060: Identification of somatic retrotransposon insertions across cancer types using RetroSeq
Authors: Helman Elena , Lawrence Mike , Stewart Chip , Getz Gad , Meyerson Matthew 
Published: August 2012

Abstract
Retrotransposons comprise over 40% of the human genome and represent an important class of genetic variation. Though most elements are stationary ancient relics, it has recently been shown that some 100 elements remain highly active, copying and pasting themselves throughout the genome with each generation. Retrotransposon insertions can disrupt gene function, modulate gene expression, and lead to genomic rearrangement. These events have previously been implicated in cancer, including an account of insertional mutagenesis in APC as an early event in colon cancer progression. Due to the inherent difficulty in localizing repeat elements, however, an extensive investigation of retrotransposons’ role in cancer has not yet been performed. We developed RetroSeq, a computational framework to identify novel insertions of retrotransposons from paired-end sequencing data. In simulated data, RetroSeq identifies retrotransposon insertions with 99% sensitivity and 99% specificity. We ran RetroSeq on whole-genome sequencing data from a panel of tumors (including 9 colorectal, 20 non-small cell lung, 24 prostate and 22 breast tumors) and matched normal samples to determine the extent of somatic retrotransposon activity. We find a broad range of novel retrotransposon insertion events specific to each tumor, with some insertions falling in exonic as well as intronic and intergenic regions. These events were validated experimentally and integrated with expression and methylation data to provide a global view of retrotransposon activity in these samples. In sum, using RetroSeq we are able to localize novel retrotransposon insertions in paired-end sequencing data and provide evidence for the reactivation of retrotransposons in cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5060. doi:1538-7445.AM2012-5060