bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A58: Wnt signaling pathway components are associated with telomerase activity in breast cancer
Authors: Listerman Imke , Gazzaniga Francesca S. , Heiser Laura M. , Lukas Jason J. , Goldstein Ted , Haussler David , Gray Joe W. , Blackburn Elizabeth H. 
Published: June 2012

Abstract
Telomerase is a ribonucleoprotein complex that adds TTAGGG repeats to telomeres in a highly regulated fashion. Telomerase activity is absent in normal somatic cells, thus limiting their number of cell divisions due to telomere shortening. In contrast, the large majority of tumor cells upregulate telomerase activity, consistent with their ability to maintain stable telomere lengths and to divide indefinitely. Telomerase activity is detectable in over 90% of breast tumors, and it is well established that telomerase overexpression is an important step in the progression of normal epithelium to invasive breast cancer. In addition to telomerase upregulation, deregulation of various signaling pathways promotes tumor progression and metastasis. To better understand in which cellular pathway telomerase and telomeres are involved, we comprehensively quantified telomerase activity and telomere length in a panel of 52 extensively characterized breast cancer cell lines and correlated these metrics with the expression profiles of the cell lines. Across the entire panel of breast cancer cell lines, expression of 530 genes was significantly correlated with telomerase activity (FDR-corrected p-val &lt; 0.2), while expression of 585 genes was significantly correlated with telomere length. Secondary G0-term analysis revealed that telomere length was significantly associated with genes involved in Alzheimer's disease, apoptosis regulation and negative regulation of transcription. Genes significantly correlated with telomerase activity were associated with apoptosis regulation, DNA repair, nucleotide metabolism and Wnt signaling. Several Wnt target genes, including MYC, KLF5, and FGF18 were also correlated with telomerase activity. We also used the network analysis tool PARADIGM (1) to identify cellular pathways associated with telomerase activity and telomere length. Notably, Wnt signaling components were significantly correlated with telomerase activity. Given the recent evidence that the telomerase component TERT can act as a transcriptional modulator of the Wnt/beta-catenin signaling pathway (2), we are currently testing how Wnt signaling is altered due to telomerase perturbation in breast cancer cells.
(1) Vaske, C. J. et al. Inference of patient-specific pathway activities from multi-dimensional cancer genomics data using PARADIGM. Bioinformatics 2010; 26:i237–245
(2) Park, J. I. et al. Telomerase modulates Wnt signaling by association with target gene chromatin. Nature 2009; 460:66–72
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the Second AACR International Conference on Frontiers in Basic Cancer Research; 2011 Sep 14-18; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2011;71(18 Suppl):Abstract nr A58.
Abstract A61: 14-3-3gamma transforming ability is determined by a motif outside the conserved phosphoamio-acid binding domain
Authors: Radhakrishnan Vijayababu M. , Putnam Charles W. , Martinez Jesse D. 
Published: June 2012

Abstract
The 14-3-3 proteins are a set of seven highly conserved scaffolding proteins that have been implicated as having a role in human tumorigenesis. However, despite the striking similarity of amino acid sequences and structures of the eukaryotic 14-3-3 family of proteins, there is increasing evidence that the seven human isoforms manifest disparate functions. For instance 14-3-3gamma functions as an oncogene and 14-3-3sigma acts as a tumor suppressor. To gain insight into how specific functions are manifested we constructed chimeric proteins by swaping various regions between gamma and sigma. Chimeric proteins were then utilized in NIH3T3 cell transformation assays. We found that transforming ability was associated with a small variable 40 amino acid region in the N-terminus of the gamma protein and that the transforming ability of gamma was dominant to the tumor suppressor activity of sigma. Importantly, the transforming motif was located outside the conserved 14-3-3 phosphoamino acid binding motif. Hence, transforming ability of 14-3-3 proteins is determined by a variable region that does not involve the phosphoamino acid binding site.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the Second AACR International Conference on Frontiers in Basic Cancer Research; 2011 Sep 14-18; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2011;71(18 Suppl):Abstract nr A61.
Abstract B10: Germline copy number variation in Li-Fraumeni syndrome patients with TP53 mutations
Authors: Silva Amanda G.S. , Achatz Maria Isabel W. , Brentani Ricardo , Krepischi Ana Cristina V. , Rosenberg Carla 
Published: June 2012

Abstract
Li-Fraumeni syndrome (LFS) is an autosomal dominantly inherited disorder characterized by a remarkably increased risk of early-onset and multiple cancers, including breast, brain tumors and other neoplasms in individuals carrying germline TP53 mutations. The specific presence of constitutional copy number variation of large DNA segments (CNV) in LFS individuals may either represent a cancer susceptibility factor or result from a genetic instability. We used a 180K oligoarray platform from Agilent to estimate the CNV frequencies in 21 unrelated Li-Fraumeni patients carrying TP53 mutations. We compared the resulting frequencies between these individuals (n=21) to a population based control group (n=100), and defined as “rare genomic alterations” those located in coding regions and covered by ≤3 individual CNVs described in DGV (Database of Genomic Variants). Similar frequencies of CNVs were found in both patients and control groups with an average of 7–8 CNVs per genome. Rare CNVs were significantly more frequent among cancer patients (average of 0.8 per individual) than among controls (average of 0.3 per individual) (p&lt;0.0001). Some of the genes encompassed by the rare germline CNVs from Li-Fraumeni patients have been previously reported to be altered in tumors, but are here described for the first time as altered in germline.
Funding by Fapesp and CNPq.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the Second AACR International Conference on Frontiers in Basic Cancer Research; 2011 Sep 14-18; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2011;71(18 Suppl):Abstract nr B10.
Abstract B16: Tumor suppressive functions by ATF2/7 transcription factors in a cMyc-driven B-cell lymphoma model
Authors: Walczvnski Jacek , Jones Nic , Breitwieser Wolfgang 
Published: June 2012

Abstract
ATF2 and the highly homologous ATF7 are members of the AP-1 transcription factor family which regulate expression of genes involved in development and stress response. In cancer, ATF2 has been reported to function both as a tumor suppressor and tumor promoter. The aim of the project was to investigate the possible roles of ATF2/7 in cMyc-driven B-cell lymphoma development and to characterize their interaction with the cMyc oncogene. Previously, cMyc, which is frequently deregulated in Burkitt's lymphoma (Rabbitts et al, 1984), was shown to prolong the half-life and induce phosphorylation of ATF2 (Miethe et al, 2001). In addition, the MAP kinase JNK and its substrate ATF2 are frequently found upregulated in B-cell lymphomas (Kersten et al, 2004; Gururajan et al, 2005).
We established a mouse B-cell lymphoma model by crossing B-cell specific knockouts of Atf2/7 (Atf2ΔBC, Atf7−/−) with Eμ-Myc transgenic animals. Eμ-Myc mice express the cMyc proto-oncogene driven by the immunoglobulin heavy chain enhancer (Eμ) and develop B-cell lymphomas with high frequency. We compared timing of tumor onset between Eμ-myc, Atf2ΔBC, Atf7−/− Eμ-myc, Atf2ΔBC/+, Atf7−/−, and Eμ-myc, Atf7−/−. In addition, we derived cell lines fom Eμ-Myc-driven lymphomas and characterized growth, apoptosis, and drug sensitivity in the presence or absence of functional Atf2/7.
Atf2 and its phosphorylated (activated) form were found to be upregulated in cells obtained from tumor samples from Eμ-Myc mice in comparison to normal B lymphocytes. Analysis of tumor-free survival showed that Eμ-myc, AtfΔBC, Atf7−/− develop B-cell lymphomas at significantly faster rates than controls. In vitro deletion of Atf2 in cell lines derived from cMyc-driven lymphomas resulted in a marked reduction in the basal levels of apoptosis. Furthermore, Atf2/7-deficient Eμ-myc tumor cells were significantly more resistant to genotoxic stress (e.g., doxorubicin) induced apoptosis. Gene expression analysis identified proapoptotic members of the Bcl-2 family as possible transcriptional targets of Atf2.
In this study, we show a novel tumor suppressive role of ATF2 in cMyc-induced lymphomagenesis and suggest the potential functions of ATF2 in regulating programmed cell death. The results also imply that the evaluation of levels of activated ATF2 in clinical samples of B-cell lymphoma may give an indication of their sensitivity to chemotherapeutic agents.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the Second AACR International Conference on Frontiers in Basic Cancer Research; 2011 Sep 14-18; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2011;71(18 Suppl):Abstract nr B16.
Abstract B42: Structure-activity study of tubulin precipitation by thiol-reactive compounds
Authors: Mi Lixin , Chung Fung-Lung 
Published: June 2012

Abstract
Tubulin, a major constituent of microtubules, has been established as an important chemotherapeutic target. Its expression is tightly regulated at the transcriptional level and not affected by tubulin targeting agents including taxanes and vinca alkaloids. Recently, we reported that benzyl isothiocyanate (BITC) and phenethyl isothiocyanate (PEITC), two isothiocyanates (ITCs) derived from cruciferous vegetables, induce rapid and significant precipitation and degradation of both α- and β-, but not γ-, tubulin at 10 μM through covalent binding to cysteine residues. In contrast, sulforaphane and erucin, two hydrophilic ITCs, and N-methylphenethylamine, an analog of PEITC without electrophilic functional group, show no activity as well as little downstream effects such as cell cycle arrest at mitosis and apoptosis induction at the same concentration. Because ITC are electrophiles, these findings suggest that thiol-reactivity may be the triggering event, the structure of compounds is associated with its activity, and tubulin precipitation and degradation are biologically important. In this study, we report that other thiol-reactive compounds, such as N-benzylmaleimide, phenylarsine oxide, and phenylmercuric chloride, also induce significant tubulin precipitation. They were much more potent than their hydrophilic counterparts, such as N-maleoyl-beta-alanine, arsenic oxide, and mercury chloride. These results shed lights onto structure-activity relationships. More importantly, their potencies of precipitating tubulin correlate well with not only their affinity to tubulin cysteines but also induction of G2/M phase arrest and apoptosis in human lung cancer cells A549. The results support the notion that cysteine modification is an upstream event for tubulin instability and cytotoxicity. The study presents critical knowledge on the rational design and screening of thiol-reactive compounds targeting the stability of tubulin.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the Second AACR International Conference on Frontiers in Basic Cancer Research; 2011 Sep 14-18; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2011;71(18 Suppl):Abstract nr B42.
Abstract B53: Evaluation of HIF-1α mRNA inhibitor as antimultiple myeloma agent
Authors: Borsi Enrica , Perrone Giulia , Terragna Carolina , Durante Sandra , Martello Marina , Baccarani Michele , Cavo Michele 
Published: June 2012

Abstract
Hypoxia-inducible factor-1 alpha (HIF-1α) is a transcription factor that plays a critical role in survival and angiogenesis. In solid tumors, elevated expression of HIF-1α, in response to hypoxia or activation of growth factor pathways, is associated with tumor proliferation, metastasis, and drug resistance and correlated with poor prognosis. In contrast to solid tumours, the role of HIF-1α in hematological malignancies is not completely known. In particular in multiple myeloma (MM) HIF-1α has been suggested to be constitutively expressed and HIF-1α knockdown cell lines have shown higher sensitivity to standard chemotherapy, suggesting a role in the pathophysiology of MM. In the present study, we explored the effect of EZN2968, an antisense oligonucleotide against HIF-1α, as a molecular target in MM.
We showed that the expression of HIF-1α in several MM cell lines is detectable in either normoxia or hypoxia conditions and is increased in the presence of growth stimuli (IL-6 and stroma cells). In vitro, EZN2968 induced selective and stable down-modulation of HIF-1α mRNA and protein expression, either in normoxia or hypoxia conditions. Immunofluorescence analysis confirmed the reduction of the protein after 24 hours of treatment, as well as a lower expression of VEGF.
Clinically achievable doses of EZN2968 induced cell cycle arrest and cell death (10% to 60% of apoptotic cells compared to the controls after 24 to 96 hours, respectively) in MM cell lines. The activation of the apoptotic pathway was confirmed by western blot analysis at different time points. Moreover we observed an irreversible commitment to cell death after 48 hours of exposure. To evaluate the effect of microenvironment, MM cells treated with EZN2968 were exposed to IL-6 and stroma cells for additional 24 hours. EZN2968 overcame the proliferative effect induced by cytokines. EZN2968 showed moderate increase in efficacy in combination with conventional agents such as Melphalan, and immunomodulatory agents (Thalidomide and Lenalidomide).
No significant effect on cell viability was observed on peripheral blood mononuclear cells and CD34+ cells from healthy donors treated with increasing doses of EZN2968.
Evaluation of gene expression profiling modulation induced by EZN 2968 is ongoing.
Our data suggest that HIF-1α inhibitor is an attractive therapeutic target for MM patients and provide the rationale for clinical evaluation of HIF inhibitor in combination with currently used MM agents.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the Second AACR International Conference on Frontiers in Basic Cancer Research; 2011 Sep 14-18; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2011;71(18 Suppl):Abstract nr B53.
Abstract B58: Differential mechanisms control steady state expression of breast cancer antiestrogen resistance 3 (BCAR3) in non-invasive and invasive breast cancer cell lines
Authors: Guerrero Michael , Bouton Amy H. 
Published: June 2012

Abstract
The overexpression of breast cancer antiestrogen resistance 3 (BCAR3) has been shown to reduce the antagonistic effects of tamoxifen and fulvestrant in estrogen receptor positive (ER+) breast cancer cell lines. BCAR3 also has a role in the regulation of the migratory and invasive potential of both ER+ and ER- breast cancer cells. A tight correlation between BCAR3 expression and breast cancer cell phenotype exists such that non-invasive, early stage cells express very low levels whereas more invasive, mesenchymal-like cells express very high levels of BCAR3. Because of this correlation, it is important to understand the temporal and spatial regulation of BCAR3. In this study, we set out to define potential mechanisms that regulate BCAR3 expression to better understand, predict, and reverse the consequences of elevated expression. In MCF7 and T47D cells (non-invasive, early stage ER+), high plating density coincident with abundant cell-cell junctions resulted in low levels of both BCAR3 mRNA and protein. Conversely, BCAR3 expression was found to be elevated under conditions in which cell-cell junctions were reduced (low density plating). In the more invasive BT549 and MDA-MB-231 cell lines, BCAR3 mRNA and protein expression was found to be dependent upon the stable expression of its binding partner p130Cas (Cas). Interestingly, we previously showed that BCAR3 expression positively correlates with the tyrosine phosphorylation state of Cas, activation of the tyrosine kinase c-Src, and the physical interaction between Cas and c-Src. We are currently investigating whether cell-cell junction formation and differential expression alters the subcellular localization of BCAR3. Taken together, we propose a role for BCAR3 in driving the transition from localized disease to a more invasive and aggressive breast tumor phenotype.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the Second AACR International Conference on Frontiers in Basic Cancer Research; 2011 Sep 14-18; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2011;71(18 Suppl):Abstract nr B58.
Abstract B61: HEF1-dependent Aurora A kinase phosphorylation activates HDAC6
Authors: Kozyreva Varvara K. , McLaughlin Sarah L. , Kelley Laura , Pugacheva Elena N. 
Published: June 2012

Abstract
Histone deacetylase 6 (HDAC6) is known to be important participant of many tumorgenesis processes including cytoskeleton rearrangement, cell migration and invasion. Activation of HDAC6 promotes cell motility and proteolytic degradation of the extracellular matrix which thereby facilitates invasion and metastasis of cancer cells. But precise mechanisms of HDAC6 regulation are still unknown. Human enhancer of filamentation 1 (HEF1/Cas-L/Nedd9) is scaffolding protein implicated in essential normal cell functions like cell division as well as pathologic conditions such as in cancer progression. It has been shown that HEF1 is over-expressed in multiple tumor types and is well known marker of malignancy. HEF1 possesses a key role in cancer development by acting as a signaling hub to coordinate tumor associated signaling. Among numerous targets which are regulated by HEF1 one of the most important is Aurora A kinase (AurA). It is known that up-regulation of AurA launches a cascade of reactions promoting oncogenic cell transformation. In our experiments, we demonstrated that HEF1 knockdown leads to impairment of cell capability to invade into extracellular matrix. We hypothesize that invasion deficiency in HEF1 depleted cells is directly linked to inability of AurA to phosphorylate/activate HDAC6. We have shown previously that depletion of HEF1 decreases AurA activity and demonstrated that HDAC6 is a substrate of AurA kinase. In this work we have determined AurA phosphorylation sites in HDAC6 using site-directed mutagenesis and in vitro kinase assay with wild-type HDAC6 and HDAC6 phospho-mutants. We revealed that AurA phosphorylates HDAC6 at Ser479/Thr481. We will test the effect of this AurA phosphorylation event on HDAC6 activation. Biological effect of such regulation will be explored in breast cancer cell lines. Our observation allows us to establish a mechanistic pathway that describes the convergent roles of HDAC6, AurA and HEF1 in tumor progression.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the Second AACR International Conference on Frontiers in Basic Cancer Research; 2011 Sep 14-18; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2011;71(18 Suppl):Abstract nr B61.
Abstract C10: Complete genome sequencing of complex tumors and matched normals results in sensitive detection of somatic events
Authors: Jacobs Sharoni , Baccash Jonathon , Ghosh Srinka , Nilsen Geoff , Pant Krishna 
Published: June 2012

Abstract
For a comprehensive understanding of the tumor genome, it is important to identify all somatic event types: point mutations, small insertions and deletions, copy number aberrations, translocations, inversions, gene fusions, and more. Complete genome sequencing and analysis of paired tumor and normal samples yields a comprehensive view of the mutational landscape in the tumor. An integrated pipeline for the sequencing, computational analysis and annotation of complete human cancer genomes has been developed. Sequencing is performed on Complete Genomics DNA nanoarrays using a nonsequential, unchained read technology to generate 70base-pair paired end reads. Assembly, mapping, and variation calling are performed using methods that have recently been optimized for more sensitive detection of variants of low allelic fraction, as would occur in heterogeneous and/or aneuploid tumor genomes. Algorithmic enhancements designed to accommodate non-diploid genomes result in increased call rates and higher accuracy. Higher coverage levels also help to reduce error rates and improve the sensitivity of somatic variation detection. Approaches adopted to ensure a highly accurate and sensitive representation of tumor genomes will be presented.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the Second AACR International Conference on Frontiers in Basic Cancer Research; 2011 Sep 14-18; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2011;71(18 Suppl):Abstract nr C10.
Abstract C18: Identification of epigenetically silenced tumor suppressor genes in colorectal cancer
Authors: Khamas Ahmed , Ishikawa Toshiaki , Iida Satoru , Ishiguro Megumi , Shimokawa Kazuro , Mizushima Hiroshi , Uetake Hiroyuki , Sugihara Kenichi 
Published: June 2012

Abstract
Background: The importance of gene inactivation by promoter CpG island hypermethylation has encouraged the unearthing of silenced tumor suppressor genes (TSGs) in various cancers. We aimed to identify and examine novel methylation silenced TSGs in colorectal cancer (CRC).
Method: We employed Oligonucleotide microarray to find changes in global gene expression of five colon cancer cell lines (HCT116, RKO, Colo320, SW480, and HT29) that were analyzed before and after treatment with the demethylating agent 5-aza-2′-Deoxycitidine (5-aza-dC), expression of the responding genes was compared with microarray expression data of CRC tissue samples. Five genes (ASPP1, GADD45B, LIFR, SCARA5, and THSD1), which had a putative 5′ CpG islands in their promoter, were subjected to methylation-specific PCR (MSP) using 13 colon cell lines and 23 paired tumor and normal CRC tissues.
Result: Seventy-two genes were up-regulated in demethylated cell lines and were simultaneously down-regulated in primary colorectal carcinomas, including genes that were known to be frequently hypermethylated and silenced in CRC. Among 13 colon cancer cell lines, hypermethylation was identified for three of five candidate genes, LIFR (61%), SCARA5 (15%), and THSD1 (23%). The methylation status of LIFR, SCARA5, and THSD1 was subsequently investigated in 23 colorectal tumors, hypermethylation was detected in (87%), (17%), and (9%), respectively. Data from normal colorectal mucosa demonstrated that the observed promoter hypermethylation was cancer-specific in the latter two genes.
Conclusion: The use of a refined microarray screening led to the identification of two TSGs affected by hypermethylation with a cancer-specific manner in CRC. SCARA5 and THSD1 may have a role in CRC tumorigenesis.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the Second AACR International Conference on Frontiers in Basic Cancer Research; 2011 Sep 14-18; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2011;71(18 Suppl):Abstract nr C18.