bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4962: TLE1 is an anoikis regulator and is downregulated by Bit1 in breast cancer cells
Authors: Biliran Hector R. , Jennings Scott , Ireland Shubha Skale , Brunquell Chris , Chen Renwei , Ruoslahti Erkki 
Published: August 2012

Abstract
TLE1 is a Groucho related transcriptional repressor protein that exerts survival and anti-apoptotic function in several cellular systems and has been implicated in the pathogenesis of cancer. In the present study, we found that TLE1 is a critical regulator of anoikis in normal mammary epithelial and breast carcinoma cells. The induction of apoptosis following loss of cell attachment to the extracellular matrix (ECM) (anoikis) in untransformed mammary epithelial MCF10A cells was associated significant downregulation of TLE1 expression while forced expression of exogenous TLE1 in these cells promoted resistance to anoikis. In stark contrast, TLE1 expression was significantly upregulated following detachment from the ECM in malignant and anoikis resistant breast cancer cell lines, MDA-MB-231 and MCF7. Importantly, enforced suppression of TLE1 in these cells resulted in attenuation of anoikis resistance and decreased anchorage-independent growth with no impact on cell viability in adherent conditions. Consistently, enforced ectopic TLE1 expression further enhanced the anoikis resistance and anchorage-independent growth of MDA-MB-231 cells. The pro-survival and anti-apoptotic role of TLE1 during loss of cell attachment is in part attributed to its ability to inhibit the caspase-independent anoikis function of Bit1. Interestingly, the TLE1 protein is channelled to proteosomal degradation by Bit1 during anoikis. Taken together, these findings indicate a novel role for TLE1 in the maintenance of anoikis resistance in breast cancer cells. This conclusion is supported by an immunohistochemical analysis of a breast cancer tissue array illustrating that TLE1 is selectively upregulated in invasive breast tumors relative to noninvasive ductal carcinoma in situ (DCIS) and normal mammary epithelial tissues.
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 4962. doi:1538-7445.AM2012-4962
Abstract 4963: Tanshinone IIA induces JNK-dependent intrinsic apoptosis via suppressing astrocyte-elevated gene 1 expression in chronic myelogenous leukemia KBM-5 cells
Authors: Kim Ji-Hyun , Jeong Soo-Jin , Yun Sun-Mi , Jung Ji Hoon , Lee Hyo-Jung , Lee Hyo-Jeong , Lee Eun-Ok , Lee Min-Ho , Kim Sung-Hoon 
Published: August 2012

Abstract
Tanshinone IIA (Tan IIA) is a phytochemical isolated from the root of Salviae miltiorrhizae (Danshen) and has been reported to have various biological activities such as anti-inflammation, anti-oxidation and anti-cancer. However, the underlying molecular mechanisms to control anti-cancer effect of Tan IIA in chronic myelogenous leukemia (CML) have not been fully understood yet. In the present study, we investigated whether Tan IIA has the anti-cancer potential by inducing apoptosis in CML cells. Tan IIA significantly decreased the viability of human CML KBM-5 cells, but not normal peripheral blood lymphocytes. Tan IIA induced apoptotic cell death by increasing the sub-G1 cell populations and stimulating atypical shrunken of nucleus and DNA fragmentation. Also, Tan IIA significantly reduced the mitochondrial membrane potential, stimulated the release of cytochrome C from mitochondria into the cytosol and activated intrinsic caspase cascade. Furthermore, Tan IIA enhanced phosphorylation of JNK and suppressed the expression of astrocyte-elevated gene-1 (AEG-1). In contrast, blocking JNK activity using JNK inhibitor SP600125 reversed Tan IIA-induced apoptosis and AEG-1 expression. Taken together, our findings suggest that Tan IIA induces JNK-dependent intrinsic apoptosis via suppressing AEG-1 expression in KBM-5 cells as a valuable candidate agent for CML therapy.
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 4963. doi:1538-7445.AM2012-4963
Abstract 4968: Phosphorylation of caspase-8 (Thr263) by ribosomal S6 kinase 2 (RSK2) mediates caspase-8 ubiquitination and stability
Authors: Peng Cong , Cho Yong-Yeon , Zhu Feng , Li Haitao , Li Xiang , Xie Hua , Bode Ann M. , Dong Zigang 
Published: August 2012

Abstract
The ribosomal S6 kinase 2 (RSK2) is a member of the p90 ribosomal S6 kinase (p90RSK) family of proteins and plays a critical role in proliferation, cell cycle and transformation. Here, we report that RSK2 phosphorylates caspase-8 and Thr263 was identified as a novel caspase-8 phosphorylation site. Phosphorylation of Thr263 is associated with the ubiquitination and degradation of caspase through the proteasome pathway. Results suggested that RSK2 regulates caspase-8 stability through its phosphorylation of this caspase. These data provide a direct link between RSK2 and caspase-8 and identify a novel molecular mechanism for caspase-8 modulation by RSK2.
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 4968. doi:1538-7445.AM2012-4968
Abstract 497: Arousal of the stroma: Fibroblasts lead pancreatic cancer cell invasion
Authors: Brentnall Teresa A. , Lai Lisa , Bronner Mary , Chen Ru 
Published: August 2012

Abstract
Background: Cancer-associated fibroblasts, comprised of activated fibroblasts or myofibroblasts, are found in the stroma surrounding solid tumors; these myofibroblasts are thought to promote invasion and metastasis of cancer cells. Mechanisms regulating the activation of the fibroblasts and the initiation of the invasive tumorigenesis are of great interest. Upregulation of the cytoskeletal protein, palladin, has been detected in the stromal myofibroblasts surrounding many solid cancers and in expression screens for genes involved in invasion. Using a pancreatic cancer model, we investigated the functional consequence of overexpression of exogenous palladin in normal fibroblasts in vitro and the affect it could have on the early stages of tumor invasion. Findings: Palladin expression in cancer-associated fibroblasts occurs very early in tumorigenesis. In vivo, concordant expression of palladin and the myofibroblast marker, alpha smooth muscle actin (α-SMA), occurs early at the dysplastic stages in peri-tumoral stroma and progressively increases in pancreatic tumorigenesis. In vitro introduction of exogenous 90kD palladin into normal human dermal fibroblasts (HDFs) induces activation of stromal fibroblasts into myofibroblasts as marked by induction of α-SMA and vimentin, and through the physical change of cell morphology. Moreover, palladin expression in the fibroblasts enhances cellular migration, invasion through the extracellular matrix, and creation of tunnels through which cancer cells can follow. The fibroblast-led invasion and creation of tunnels results from the development of invadopodia-like cellular protrusions (“feet”) which express invadopodia proteins and proteolytic enzymes. Palladin expression in fibroblasts is triggered by the co-culture of normal fibroblasts with k-ras-expressing epithelial cells. Abrogation of palladin with shRNA reverses the ability of cancer cells to invade by blocking the transition of fibroblasts into myofibroblasts and dampening of the myofibroblast-cancer cell partnership. Conclusions: Fibroblasts are active partners in pancreatic cancer cell invasion. Palladin expression can impart myofibroblast properties, in turn promoting the invasive potential of these peri-tumoral cells with invadopodia-driven degradation of extracellular matrix. Palladin expression in fibroblasts can be triggered by k-ras expression in adjacent epithelial cells. This data supports a model whereby palladin-activated fibroblasts facilitate stromal-dependent metastasis and outgrowth of tumorigenic epithelium.
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 497. doi:1538-7445.AM2012-497
Abstract 5041: Characterization of the miR-125b1 promoter in breast cancer cell lines
Authors: Soberanis Fernanda Cisneros , Reyes Ernesto Soto , Castro Clementina , Targa Felix Recillas , Herrera Luis A. 
Published: August 2012

Abstract
In cancer cells, transcriptional gene silencing has been associated with genetic and epigenetic defects. The disruption of DNA methylation patterns and covalent histone marks has been associated with cancer development. Until recently, microRNA (miRNA) gene silencing was not well understood. In particular, miR-125b1 has been suggested to be a miRNA with tumor suppressor activity, and it has been shown to be deregulated in various human cancers. In this study, we characterized the promoter of the miR-125b1 and the modifications associated with gene silencing. We studied in silico the miR-125b1 locus to delimit the promoter region and then, we characterized the promoter activity by the luciferase assay, cloning a fragment in the 5′ extreme close to the transcriptional start site of the miR-125b1 gene. We found that this sequence has promoter activity and it is unidirectional. Subsequently, we analyzed the DNA methylation status in the CpG island promoter and found that it was methylated in breast cancer cell lines compared with a non-transformed breast cell line. To determine the effect of DNA methylation in the CpG island of miR-125b1 on the expression of this gene, we performed a qRT-PCR assay. We observed a significant reduction on the expression of miR-125b1 in cancer cells lines in comparison with a non-transformed cell line, suggesting that DNA methylation at the CpG island might reduce the expression of miR-125b1. Our data suggest that the fragment in the 5′ extreme close to the transcriptional start site of the miR-125b1 gene is a functional and unidirectional promoter. Also, the CpG island in this region is methylated in breast cancer cell lines and this methylation is associated with the silencing of the miR-125b1 gene. This work was supported by the Consejo Nacional de Ciencia y Tecnología (CONACyT: 83959) and the Programa de Apoyo a Proyectos de Investigación e Innovación Tecnológica of the Universidad Nacional Autónoma de México (PAPIIT, IN213311).
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 5041. doi:1538-7445.AM2012-5041
Abstract 5049: Serum miRNAs as an early marker for breast cancer
Authors: Godfrey Ashley C. , Xu Zongli , Weinberg Clarice R. , Wade Paul A. , Deroo Lisa A. , Sandler Dale P. , Taylor Jack A. 
Published: August 2012

Abstract
MicroRNAs (miRNAs) are small, non-coding, single-stranded RNAs between 18-22 nucleotides that regulate gene expression by affecting mRNA translation and degradation. It has been proposed that miRNAs could be master regulators of gene expression by regulating entire gene networks. Expression of miRNAs is altered in tumor compared to normal tissue and there is growing evidence that miRNA profiles in serum may differ in cancer cases as compared to healthy controls. However, these studies use samples collected after diagnosis so treatment and/or disease effects cannot be excluded. We are using serum samples from the Sister Study, a prospective cohort study of 50,000 women who had never had breast cancer at the time of enrollment, but were at increased risk because they had a sister previously diagnosed with breast cancer. We are exploring whether serum miRNA profiles can be used as prediagnostic markers of breast cancer. In an initial pilot analysis comparing 5 women diagnosed with breast cancer 1-2 months after their blood draw to 5 controls, there were 25 miRNAs significantly different at the 0.05 level (paired T test). Of those 25 miRNAs, 7 have been previously associated with breast tumor tissue in published studies showing differential expression in tumor tissue or in breast cancer cell lines. We have now completed a larger follow up study examining 205 women diagnosed with breast cancer within 18 months of their blood draw compared to 205 controls frequency matched to cases by age, 2 month interval of blood draw and race. We are using Affymetrix miRNA microarrays to profile miRNA expression in serum samples, and have optimized this platform for use with less than .5mLs of serum. After normalization and background correction, we found 439 miRNAs (of 1105 human miRNAs on the chip) expressed above background in at least 50 samples. When the average expression of controls was compared to cases using logistic regression, we found 16 miRNAs significantly different at the .05 level. For cases, the mean time between blood draw and cancer diagnosis was 10 months. We hypothesize that, if miRNA is a prediagnostic marker, cases with a longer time between blood draw and diagnosis would have a more control-like miRNA profile. To examine this, we are conducting a more detailed analysis among cases with a short time between blood draw and diagnosis. The next steps of our analysis will be to examine how far in advance of cancer diagnosis can we detect case-control differences in miRNA expression profiles.
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 5049. doi:1538-7445.AM2012-5049
Abstract 505: Jagged 2 knockdown inhibits invasion in colorectal cancer cell lines
Authors: He Wan , Wong SC Cesar , Chan Charles ML , Ho WS , Au Thomas CC , Lam Money YY , Chan Anthony TC 
Published: August 2012

Abstract
Background: The notch pathway is involved in control of cell differentiation in various tissues including pancreas, muscle and bone marrow. Jagged 2 (JAG2) is a ligand for the notch pathway and was found to be overexpressed in malignant plasma cells from patients with multiple myeloma, causing the secretion and release of IL-6, VEGF, and IGF-1 in the microenvironment supporting myeloma cell growth. In breast cancers, it was found to be overexpressed at the hypoxic invasive front and was significantly correlated with metastasis free survival. Furthermore, up-regulation of JAG2 expression in mouse lung adenocarcinoma cells promoted its metastasis in mice. However, the expression pattern and function of JAG2 in colorectal cancer (CRC) is not clear. Therefore in this study, we examined the expression of JAG2 in CRC cell lines and determined the effect(s) of JAG2 knockdown by RNA interference in CRC cell lines. Materials and Methods: The expression of JAG2 protein was examined in four CRC cell lines (SW480, SW620, HCT116, DLD-1) and also in 1 normal colon epithelial cell line (CCD18co) using the western blot. To investigate the effects JAG2 knockdown in CRC cell lines, a pool of 4 siRNAs against JAG2 was transfected into the 4 CRC cell lines listed above. The effects on cell growth was then determined by the CellTiter 96® AQueous One Solution Cell Proliferation Assay (the MTS assay) and the Matrigel invasion assay was performed to assess its effects on invasive capability. Results: Western blot results showed that JAG2 protein was expressed in all 4 colorectal cancer cell lines including SW480, SW620, HCT116 and DLD-1 but not in the CCD18co normal colon epithelial cell line. The MTS assay showed that cell growth was not affected by JAG2 knockdown in the CRC cell lines. Interestingly, the invasive capability of HCT116 and DLD-1cells was reduced after JAG2 knockdown. Conclusions: Results from this study suggest that JAG2 may play a role in the invasiveness of CRC cell lines but not in cell proliferation. JAG2 may be a promising therapeutic target for inhibition of metastasis in colorectal 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 505. doi:1538-7445.AM2012-505
Abstract 5059: Exome and targeted sequencing to discover and validate candidate genes in advanced and lethal prostate cancer
Authors: Kumar Akash , MacKenzie Alexandra P. , O'Roak Brian J. , Coleman Ilsa , Morrissey Colm , Lee Choli , White Thomas A. , Dumpit Ruth F. , True Lawrence D. , Corey Eva , Vessella Robert L. , Nelson Peter S. , Shendure Jay 
Published: August 2012

Abstract
Prostate carcinoma is the most common malignancy and the second leading cause of cancer mortality in men. In order to understand the genetic composition of lethal and advanced prostate cancer, we used exome sequencing to identify protein-altering mutations within a panel of 23 prostate cancer xenografts that represent a wide spectrum of advanced disease phenotypes. Although corresponding normal tissue was not available for most tumors, we were able to take advantage of increasingly deep catalogs of human genetic variation to remove most germline variants. On average, each tumor genome contains ∼200 novel nonsynonymous variants, of which the vast majority was specific to individual carcinomas. Based on the prevalence of rare nonsynonymous variants, we identified a subset of 30 genes including TP53, DLK2, GPC6 and SDF4 as putative candidates involved in tumor progression. To ascertain the frequency of mutations in these candidate genes across a large panel of tumors, we developed a molecular inversion probe (MIP) based protocol that enables efficient targeting and sequencing of tens of genes across hundreds to thousands of samples. The method requires as little as 50 nanograms of DNA as input, and is compatible with DNA isolated from both frozen and formalin formalin-fixed paraffin embedded (FFPE) tissues. We have applied this method to capture and deeply sequence the nearly ∼1,000 exons of the 30 candidate genes across 150 prostate cancer metastases on a single lane of an Illumina HiSeq2000 platform. Unexpectedly, our exome survey identified three tumors with substantially higher mutation frequencies, with 2,000-4,000 novel coding variants per exome. We used whole genome sequencing to characterize the global patterns of mutation in one of these tumors, and found a high prevalence of transition mutations within CpG islands. Experiments to determine whether hypermutation is the result of loss of DNA repair pathway function are ongoing. Collectively, our results indicate that exome sequencing combined with efficient screening of candidate genes is a powerful method to understand the genetics of advanced prostate cancer. We also report a previously undescribed subtype of prostate cancers exhibiting “hypermutated” genomes, with potential implications for resistance to cancer therapeutics.
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 5059. doi:1538-7445.AM2012-5059
Abstract 5062: Integrated analysis of the whole exome sequencing (WES) identifies novel mutations and suggests patient selection hypothesis
Authors: Lezhnin Sergey 
Published: August 2012

Abstract
Whole exome sequencing was done on 257 breast and 102 ovarian tumors using next generation sequencing. Seven gigabases of sequencing data were generated for each sample or 100x coverage of the whole exome, which enable to determine sequence variations with &gt;99% confidence. The results of the mutation calls were compared with recently published TCGA breast and ovarian datasets. Genes with large number of passenger mutations were called out and frequency of passenger mutations per sample was linked to MMR signature. In ovarian tumors, a high prevalence of p53 and BRCA1 mutation was confirmed in serous tumors. A signature of BRCA1/2 deficient tumors was developed and cross-validated between the datasets. In no-serous tumors, a high prevalence of mutations MAPK pathway and beta-catenin pathway were found. FOXL2 mutation was identified in 100% of granulose ovarian tumors and linked to high levels of EMT signature. In addition we showed a significant overlap between genes found to be mutated in TCGA datasets and in our dataset, suggesting a larger number of potentially significantly mutated genes than previously reported. In breast tumors, known high frequency of mutations was confirmed in PIK3CA and TP53 genes and validated with respective pathway specific gene expression signatures. In addition, prevalent mutations were identified in MAPK and PI3K pathways and linked with respective pathway signatures. These findings strengthen and enrich our understanding of molecular subtypes of ovarian and breast tumors and can be used for identification of novel targets and for development of responder hypothesis.
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 5062. doi:1538-7445.AM2012-5062
Abstract 5075: Genome-wide analysis of DNA copy number variations in osteosarcoma
Authors: Gokgoz Nalan , Wunder Jay S. , Andrulis Irene L. 
Published: August 2012

Abstract
Objectives: Copy number variations (CNVs) such as deletions, amplifications and duplications across the whole genome may contribute to Osteosarcoma (OS) tumorigenesis. Detection of genomic regions containing these changes is extremely important for both the basic understanding of OS and its diagnosis. In this study we performed Whole Genome Genotyping (WGG) using high-density SNP arrays to detect CNVs in OS tumors and blood. A major advantage of this technology is the simultaneous detection of both allelic frequencies and CNVs. Methods: WGG analysis was performed using 35 high-grade intramedullary OS and 8 parosteal sarcoma tumor DNAs. 10 matching germline DNAs from blood were also included into the analysis. 250 nanograms of DNA were hybridized onto the Illumina 610 Quad BeadChips using the Infinium II WGG assay. The WGG data was analysed using Bead Studio and Partek software. Results: SNP array based Whole Genome Genotyping revealed a large number of chromosomal aberrations in OS. Preliminary analysis of 35 OS tumor DNAs showed high levels of recurrent amplification of 1p36, 3p12.1, 6q14, 12q13-15, 17p11.2, 20p12; and deletion of 3q26.31, 6p21, 6q16.3, 7q21, 7q35, 8q24.13, 9p21 and 17p13 regions. Parosteal tumor DNAs displayed a high level of amplification of the 12q13-15 amplicon. Amplification status of genes from 17p11.2 (PMP22, NCOR1, COPS3 and TOM1L2) and 12q14 (CDK4 and MDM2) was validated by Real-Time PCR. Some tumors exhibited whole chromosome arm deletions and/or duplications. Conclusions: OS tumors exhibit chromosomal alterations that can be detected using WGG. Comparison of normal and tumour DNAs from the same subjects can be used to identify CNV associated with OS development and progression. Current analyses include comparisons of CNV data and gene expression profiles of the same OS tumours to discover genes that may be biologically relevant targets in OS.
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 5075. doi:1538-7445.AM2012-5075