bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4852: cFLIP-regulated and caspase-8-mediated limited cleavage of RIP1 promotes NF-kB activation and inhibits cell death induced by TRAIL
Authors: Habelhah Hasem , Zhang Laiqun , Janz Siegfried , Workman Lauren , Blackwell Ken 
Published: August 2012

Abstract
Although TRAIL is considered a potential anti-cancer agent, many types of cancer cells possess intrinsic or acquired resistance to TRAIL. In addition, TRAIL has been found to activate NF-κB and enhance metastasis in apoptosis-resistant cancer cells. Notably, caspase-8 activity and RIP1 expression have been shown to be essential for TRAIL-induced NF-κB activation. RIP1 is a dual-function molecule that can be either prosurvival or prodeath depending on the cellular context. RIP1 contains an N-terminal kinase domain (KD), a C-terminal death domain (DD) and an intermediate domain (ID) between the KD and DD domains. The ID domain of RIP1 is essential for its activation of the NF-κB pathway, whereas the KD domain is required for its induction of apoptosis and necrosis. We have discovered that, in apoptosis-sensitive cells, caspase-8 cleaves RIP1 in the KD and ID domains in response to TRAIL treatment, resulting in rapid depletion of RIP1 and the induction of apoptosis. In apoptosis-resistant cells, however, cFLIP inhibited caspase-8-mediated RIP1 cleavage in the ID but not in the KD domain, producing a KD domain-deleted C-terminal fragment, p51RIP1c. Stable expression of p51RIP1c in RIP1−/− cells significantly promoted NF-κB activation and inhibited cell death induced by TRAIL. Moreover, stable expression of the cleavage sites-mutated form of RIP1 in RIP1−/− cells, not only sensitized the cells to apoptosis induced by TRAIL, but also to necrosis induced by oxidative stress. Importantly, in Hodgkin's lymphomas that overexpress cFLIP, as well as in tumor tissues derived from iMyc-Bcl-XL double transgenic mice, a portion of RIP1 is constitutively processed to p51RIP1c. Collectively, these data suggest that cFLIP-regulated and caspase-8-mediated limited cleavage of RIP1 promotes NF-κB activation and inhibits cell death, and that such cleavage occurs constitutively in certain types of cancers. Thus, inhibiting cFLIP-regulated RIP1 cleavage could be a new target for maximizing the effectiveness of TRAIL as an anti-cancer agent.
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 4852. doi:1538-7445.AM2012-4852
Abstract 4853: Constitutively decreased TGF-β signaling and risk for colorectal cancer
Authors: Pennison Michael J. , Bellam Naresh , Zimmerman Jacquelyn , Zeng Qinghua , Sadim Maureen , Kaklamani Virginia , Li Nengjun , Zhang Kui , Stram Daniel O. , Pasche Boris 
Published: August 2012

Abstract
Background: Approximately one third of all colorectal cancers (CRC) are inherited, but less than 7% are attributable to known gene mutations. Germline variants within the TGF-β signaling pathway may account for colorectal cancer risk since TGF-β inhibits early tumor development through the activation of SMAD proteins. We have previously shown that Tgfbr1 haploinsufficiency is a potent modifier of colorectal cancer development in mice and humans. We have recently shown a significant association between a 3 SNP TGFBR1 haplotype and constitutively decreased TGFBR1 allelic expression, a phenotype found to occur frequently in patients with CRC. In this family-based study, we aimed at determining the association of TGFBR1 and SMAD7 with colorectal cancer risk. Methods: We studied 1,558 colorectal cancer cases and 2,640 healthy controls recruited by the Colorectal Cancer Family Registry (CCFR). We genotyped 14 TGFBR1 haplotype tagging SNPs as well as a SMAD7 SNP associated with CRC in prior GWA studies. SNPs were genotyped in all cases and controls using ABI's TaqMan platform, and associations were determined using logistical regression analysis (significance set at p&lt;0.05). Main effects (Cockerham model) and risk prediction accuracy (receiver operating characteristic curves) were also determined. Functional assessment was conducted with derived lymphoblastoid cell lines (LCLs). Results: TGFBR1 rs7034462 and SMAD7 rs4939827 were strongly associated with colorectal cancer risk (see Table). Functional assessment performed with 3 matched pairs of patient-derived LCLs showed significantly reduced TGF-β mediated SMAD signaling in cells carrying these two SNPs. Conclusions: Our study provides the first evidence that a combination of TGFBR1 and SMAD7 variants is associated with constitutively decreased TGF-β signaling and risk for 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 4853. doi:1538-7445.AM2012-4853
Abstract 4855: KLLN, which shares a bidirectional promoter with PTEN, is an AR-regulated tumor suppressor, and induces p53-dependent and -independent apoptosis in breast cancer
Authors: Wang Yu , He Xin , Eng Charis 
Published: August 2012

Abstract
70% of breast cancer patients are diagnosed after menopause where the ovaries cease androgen production. Maintaining functional androgen receptor (AR) has been reported to correlate with good prognosis and better survival among breast cancer patients. We and others have shown that AR inhibits proliferation and induces apoptosis in breast cancer cells. However, the mechanism of AR's anti-tumor effect in breast cancer is still not fully understood. KLLN is a newly identified gene whose function has never been studied in tumorigenesis. KLLN and tumor suppressor gene PTEN, both located in 10q23.31, share the same promoter region but are transcribed in opposite directions. To perform in silico comparisons of KLLN expression between normal breast and breast cancer tissues, we selected 56 normal breast and 1170 tumor tissues from patients without exposure to any treatment using publicly available whole genome transcriptome datasets. We found that KLLN is significantly downregulated in breast carcinomas and that loss of KLLN expression is associated with increasing histological grade in invasive carcinomas. By using MCF-7 and MDA-MB-453 breast cancer cell lines as our models, we show that AR activates this bi-directional promoter, resulting in the upregulation of both KLLN and PTEN expression. For the first time, we identified KLLN as an AR-activated tumor suppressor, inhibiting breast cancer cell proliferation and suppressing tumor cell invasiveness in both cell lines. In MCF-7 cells, overexpression of KLLN directly activates TP53 expression as a transcription activator, accompanied by significant increase of PARP cleavage and apoptosis. We also found that KLLN could promote TP73 expression in both MCF-7 (p53-wildtype) and MDA-MB-453 (p53-null) cells at the transcriptional level, resulting in p53-independnt apoptosis. Therefore, we discovered a new pathway, which mediates AR-induced growth inhibition and apoptosis in breast cancer cells. Our study also indicates KLLN as a potential prognostic marker and novel therapy target for breast carcinomas.
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 4855. doi:1538-7445.AM2012-4855
Abstract 4866: The atypical kinase SgK223 is a novel mediator of cell invasion in pancreatic cancer
Authors: Tactacan Carole M. , Humphrey Emily S. , Biankin Andrew V. , Daly Roger J. 
Published: August 2012

Abstract
Pancreatic cancer still remains one of the most aggressive and lethal of human cancers, with a lack of effective treatments contributing to its poor prognosis and high mortality. Perturbations in tyrosine kinase signaling are characteristic of many human cancers. In order to detect aberrant protein tyrosine phosphorylation events in pancreatic cancer, and to subclassify pancreatic cancer cell lines based on their tyrosine phosphorylation patterns, tryptic digests from a wide panel of pancreatic cancer cell lines were subjected to anti-phosphotyrosine immunoprecipitation, then analysed by liquid chromatography coupled with tandem mass spectrometry (MS/MS). Proteins were ranked according to differences in median phosphorylation levels across the cell line panel, and those that exhibited significantly variable phosphorylation levels were selected as candidates for further evaluation as biomarkers and therapeutic targets. One candidate identified by this approach was SgK223, a 175 kDa atypical kinase with substitutions in the DFG motif of its kinase domain. Since this is one of the conserved motifs critical for full catalytic activity, SgK223 may be catalytically inactive. Western blotting revealed that SgK223 protein expression varied across the panel, with a subset of pancreatic cancer lines exhibiting overexpression relative to normal human pancreatic duct epithelial (HPDE) cells. To further interrogate the role of SgK223 in pancreatic cancer, SgK223 was overexpressed in HPDE cells. This resulted in an elongated cell morphology and increased cellular migration and invasion in transwell assays, with no effect on cellular proliferation or Erk and Akt activity. MS/MS analysis determined that SgK223 was phosphorylated on tyrosine residues 159 and 413. Since the former is a candidate Stat3 binding site, we characterised Stat3 signalling in this model. SgK223 overexpression led to enhanced Stat3 tyrosine phosphorylation and transcriptional activity. These data identify a role for SgK223 as a mediator of cell invasion in pancreatic cancer, and support the use of MS-based phosphoproteomic profiling as an effective discovery tool for cancer-associated signaling proteins.
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 4866. doi:1538-7445.AM2012-4866
Abstract 4873: Comprehensive analysis of 160 whole-genome sequences reveals striking telomere alteration patterns in 9 pediatric cancers
Authors: Parker Matthew D. , Wu Gang , Chen Xiang , Rusch Michael , Bahrami Armita , Ding Li , Mardis Elaine , Mullighan Charles , Gilbertson Richard , Dyer Michael A. , Wilson Richard K. , Downing James , Zhang Jinghui 
Published: August 2012

Abstract
Although telomere shortening has long been recognized as a feature of cancer genomes, a comprehensive characterization of telomere alteration in pediatric cancer has not yet been performed. As part of the St. Jude Children's Research Hospital-Washington University Pediatric Cancer Genome Project (PCGP), we are performing whole genome sequence analysis on 600 pediatric cancers and matched germ line samples. This database will allow us to carry out a systematic investigation of telomere alteration across a broad range of pediatric cancers. To characterize the relative level of telomere length within a tumor, we have developed an approach that utilizes the WGS data and identifies all sequencing reads containing the telomeric repeat (TTAGGG)4. This read count is then normalized for genome-wide coverage and compared to the result from the matched germline sample to define the relative level of telomere amplification or loss in the tumor. To date we have analyzed 160 tumor/normal pairs collected from 9 distinct pediatric cancers types (Early T Progenitor Acute Lymphoblastic Leukemia (ALL), Infant ALL, Hypo-diploid ALL, Medulloblastoma, Retinoblastoma, Neuroblastoma, Osteosarcoma, Rhabdomyosarcoma, and Adrenocortical Carcinoma). Our analysis revealed normal telomere length or minimal loss in Early T Progenitor Acute Lymphoblastic Leukemia (ALL), Hypo-Diploid ALL, Infant-ALL, Medulloblastoma, Retinoblastoma, and Rhabdomyosarcoma. By contrast a subset of three distinct tumor types (Neurobalstoma, Oteosarcoma, and Adrenocortical Carcinoma) were characterized by marked increases in the number of telomere reads in the tumor consistent with telomere lengthening. These latter findings were validated in neuroblastoma by quantitative polymerase chain reaction (13/14) and fluorescence in situ hybridization (7/7). The presence of long telomeres was statistically associated with an increase in the number of somatic structural variations in tumor, with this association most evident in osteosarcoma. These data suggest that some pediatric cancers are associated with marked abnormalities in telomere maintenance leading to expansion in the telomere repeats. Defining the specific mutational processes that are responsible for these telomere defects and expanding the dataset to all 600 cancers in the project should help to define the mechanisms through which these alterations contribute to the transformed phenotypes.
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 4873. doi:1538-7445.AM2012-4873
Abstract 4878: The fallopian tube is the origin of high-grade serous ovarian carcinomas in a mouse model
Authors: Kim Jaeyeon , Coffey Donna M. , Creighton Chad J. , Yu Zhifeng , Hawkins Shannon M. , Matzuk Martin M. 
Published: August 2012

Abstract
Ovarian cancer is a lethal disease primarily because it is often not detected until it spreads beyond the female reproductive tract. Early detection is thus the key to successful intervention in ovarian cancer. Yet it is not known how this cancer arises and metastasizes. In the last decade, new evidence has challenged the dogma that the ovary is the main source of these cancers. The fallopian tube has been proposed instead as the primary origin of high-grade serous ovarian cancer _ the subtype causing 70% of ovarian cancer deaths. To understand the origin and early progression of this serous cancer, we have generated double knockout (DKO) mice by conditionally disabling in the reproductive tract two critical genes _ Dicer, an essential gene for microRNA synthesis, and Pten, a tumor suppressor that negatively regulates the PI3K pathway. These DKO mice develop high-grade serous carcinomas that arise from the fallopian tube. These high-grade serous cancers spread to engulf the ovary and then extensively metastasize throughout the abdominal cavity, causing ascites and killing 100% of the mice by 13 months. This is the first mouse model demonstrating that the fallopian tube is capable of initiating and developing high-grade serous carcinomas with similar clinical manifestations shown in the human serous ovarian carcinomas. Intriguingly, analyzing these DKO tumors at early time points also reveals that these epithelial cancers begin in the stroma of the fallopian tube, suggesting that the cancers arise through a mesenchymal-to-epithelial transition (MET) _ a novel mechanism of carcinoma initiation. This study thus presents a new paradigm for the origin and initiation of deadly high-grade serous ovarian 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 4878. doi:1538-7445.AM2012-4878
Abstract 4879: Distinct roles of p53 and p19ARF in MYC-dependent tumor oncogene addiction
Authors: Adam Stacey J. , Yetil Alper , Gevaert Olivier , Jojic Vladimir , Gentles Andrew , Felsher Dean W. 
Published: August 2012

Abstract
Acute T-cell lymphoblastic leukemia (T-ALL) is a pediatric malignancy in which the MYC oncogene is frequently overexpressed. Although, T-ALL responds to standard therapies, in 20% of cases, treatment fails to induce sustained remission, resulting in reduced patient survival. Inhibition or restoration of the mutant gene products that drive tumorigenesis can reverse the aberrant cell growth and result in elimination of tumor cells through the phenomenon of oncogene addiction. In order to recapitulate tumor regression and recurrence, we have developed conditional mouse models of MYC-dependent T-ALL, thereby allowing for the investigation of therapeutic resistance. Recently, we have shown oncogene addiction in our MYC-driven murine model of T-ALL occurs through both tumor cell-intrinsic mechanisms, such as cellular senescence and apoptosis, and tumor cell-extrinsic, host-dependent mechanisms, including inhibition of angiogenesis, immune system-dependent tumor clearance, and autocrine/paracrine survival signaling. We now present evidence that loss of either p53 or p19ARF facilitates tumor recurrence through distinct mechanisms. p53 utilizes host-dependent mechanisms by allowing tumors to maintain angiogenesis, while p19ARF employs tumor-cell intrinsic mechanisms to circumvent senescence upon oncogene inactivation in vivo. To further interrogate the mechanisms that underlie p53- and p19ARF-dependent tumor recurrence, we performed gene expression analysis on MYC wild-type, MYC/p53-/-, and MYC/p19-/- tumors before and after MYC inactivation. Utilizing novel computational techniques to compare gene expression from our T-ALL cells to gene expression of normal hematopoietic differentiation from the Immunologic Genome Project, we have delineated the regulatory pathways underlying the effects of tumor suppressor loss in human MYC-driven lymphoma cells in the presence of targeted MYC-inactivation. We have also utilized expression analysis to establish gene signatures from unique to our MYC/p53-/- and MYC/p19-/- murine T-ALL models and shown them to be prognostic for specific human T-ALL subtypes, as well as patient relapse-free survival. Overall, we have utilized whole transcriptomic analysis to further define the underlying cell signaling by which loss of p53 and p19 facilitate tumor recurrence and demonstrated that loss of these tumor suppressors can predict outcome in human patients.
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 4879. doi:1538-7445.AM2012-4879
Abstract 488: Investigating the molecular mechanisms of tumor cell invasion
Authors: Clancy James , Sedgwick Alanna , Method Michael , Chari Vandhana , D'Souza-Schorey Crislyn 
Published: August 2012

Abstract
Increased MAPK signaling, small GTPase activation, cytoskeletal rearrangements and the directed targeting of proteases to sites of extracellular matrix (ECM) degradation, all accompany the process of tumor cell invasion. We have shown that nucleotide cycling on ARF6, a Ras-related small GTP-binding protein, regulates the release of protease-loaded, plasma membrane-derived microvesicles from tumor cells into the microenvironment to promote ECM degradation. These ‘invasive’ microvesicles can be isolated from peripheral body fluids and thereby, represent a source of disease and tissue specific markers. They are distinct from invadopodia, which also mediate cell invasion, rather they appear to be linked to amoeboid motility of tumor cells. While pre-invasive tumor cells shed microvesicles, the amount of shed microvesicles increases with invasiveness. We suggest that the release of protease-loaded microvesicles potentially serves as a mechanism to bring about matrix degradation and also deposit paracrine information at distal locations, creating paths of “least resistance” as tumor cells traverse distances and invade through surrounding tissue. Invadopodia, on the other hand, facilitate pericellular proteolysis of the ECM at the cell's invasive front and appear to be linked to mesenchymal type of tumor cell motility. Rho GTPase signaling in part governs whether tumor cells produce invadopodia or adopt the amoeboid type movement and release microvesicles. Moreover, the specific targeting of distinct cargo to each of these sites enables the biogenesis of each invasive structure. Understanding the interplay between these two invasive cell programs will provide new and important insights into the progression toward pathophysiological states.
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 488. doi:1538-7445.AM2012-488
Abstract 4880: Disruption of STAT3 signaling promotes K-Ras induced lung tumorigenesis
Authors: Grabner Beatrice , Schramek Daniel , Mueller Kristina M. , Zwick Ralf Harun , Penninger Josef , Poli Valeria , Moriggl Richard , Sibilia Maria , Popper Helmut , Eferl Robert , Casanova Emilio 
Published: August 2012

Abstract
Lung cancer related and unrelated to smoking is still leading cause of cancer deaths worldwide with an overall survival rate of 15%. Several genetic alterations have been associated with lung cancer: loss of tumor suppressor genes such as p53, INK4a, LKB1 and mutations/amplifications in several oncogenes like K-Ras, EGFR, or c-Myc. Most frequent smoking-related mutations impair GTP hydrolysis in K-Ras, an oncogene downstream of the EGFR pathway, causing persistent cell growth and proliferation in 20-30% of lung adenocarcinomas. Another important downstream effector of EGFR signaling is the signal transducer and activator of transcription (STAT)-3. STAT-3 regulates important pathways in tumorigenesis, through upregulation of genes encoding apoptosis inhibitors (Bcl-XL, Bcl-2, Mcl-1, survivin). In patient samples and NSCLC cell lines nuclear, phosphorylated STAT3 is enhanced and correlates with subsequent suppression of apoptosis of NSCLC tumors. However, the role of STAT-3 in lung cancer in vivo has not yet been established. In order to investigate the role of STAT-3 in lung tumors, we have established a genetic mouse model that allows inducing K-RasG12D-dependent lung tumors and simultaneously genetically ablating STAT-3. Survival analysis of this model showed a significant advantage of K-RasG12D male mice harbouring STAT-3 compared to K-RasG12D mice lacking one or both alleles of Stat-3, indicating a hapoloinsufficient tumor suppressor role in oncogenic K-RasG12D tumor formation. Furthermore, animals with deleted STAT-3 and activated K-RasG12D have a significant increase in tumor burden and develop more adenomas and adenocarcinomas than age-matched animals, harbouring only oncogenic K-RasG12D. This data suggest that disruption of STAT-3 signaling promotes tumorigenesis in K-Ras induced tumors. We are currently investigating the molecular and cellular mechanisms responsible for this observation.
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 4880. doi:1538-7445.AM2012-4880