bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract LB-392: Loss of Rev7 causes PARP inhibitor resistance in BRCA1;p53-deficient mouse mammary tumor cells
Authors: Xu Guotai , Bouwman Peter , Jaspers Janneke , Pieterse Mark , Kersbergen Ariena , Jonkers Jos , Borst Piet , Rottenberg Sven 
Published: August 2012

Abstract
We have previously shown that mammary tumors spontaneously arising in a genetically engineered mouse model for human BRCA1-associated breast cancer (K14Cre;Brca1F/F;p53F/F) are highly sensitive to the poly(ADP-ribose) polymerase (PARP) inhibitor olaparib due to their deficiency in homology-directed DNA repair (Rottenberg et al. PNAS 2008;105:17079-84). Despite the initial sensitivity, tumors are not eradicated and eventually develop drug resistance. In this project we aim to identify mechanisms that explain this resistance. In particular we are interested in alterations that result in restoration of DNA repair by homologous recombination (HR). For this purpose we performed a loss-of-function shRNA screen using Brca1; p53-deficient cell lines derived from a mouse mammary tumor. The CGH profile of these cell lines is highly similar to that of the original tumor. Moreover, these cells have successfully been transplanted orthotopically into syngeneic mice and they recapitulate the morphology and olaparib response of the donor tumor. In our screen we included 2000 hairpins from the Sigma Mission library which target 409 mouse genes involved in the DNA damage response. As a result we found enrichments for hairpins targeting Rev7 in olaparib-surviving colonies. This finding was validated with 3 individual hairpins which caused substantially decreased Rev7 mRNA levels. Moreover, Rev7-deficient Brca1−/−;p53−/− tumor cells are less sensitive to doxorubicin, carboplatin and cisplatin. Loss of Rev7 rescued mES cells from Brca1 deficiency and also correlated with the formation of Rad51 foci in both Brca1-deficient mES cells and Brca1−/−;p53−/− tumor cells after irradiation. We therefore think that homology-directed DNA repair is restored in Rev7-depleted Brca1−/−;p53−/− cells. We are currently confirming this finding using HR reporter assays and we are investigating whether the loss of Rev7 causes olaparib resistance in mouse tumors. Our data suggest that absence of REV7 function, like lack of 53BP1, contributes to PARP inhibitor resistance in vivo.
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 LB-392. doi:1538-7445.AM2012-LB-392
Abstract LB-394: Type II topoisomerases contribute to nitric oxide-induced DNA breakage during cancer-related inflammation
Authors: Li Tsai-Kun , Yang Yu-Chen , Shen Tang-Long 
Published: August 2012

Abstract
Activated inflammatory leukocytes generate a variety of reactive nitrogen and species (RNOS) which have been proposed to contribute to genome instability and cancer development. We previously reported that oxidative stress induces topoisomerase II (TOP2)-mediated DNA breaks via TOP2 cleavable complex (TOP2cc) formation. Moreover, drug-induced TOP2αcc and TOP2βcc are suggested to be anti-cancer and carcinogenic, respectively. Here we show that either inflammation-produced or chemical-released nitric oxide (NO), like TOP2-targeting etoposide (VP-16), induce TOP2cc-meidated DNA breakage, mutagenesis and carcinogenesis: (i) NO-releaser S-nitrosoglutathione (GSNO) induces formation of skin melanomas in 9,10-dimethyl-1,2-benzanthracene (DMBA)-initiated mice; (ii) the co-culture experiments revealed that inflamed macrophages causes activation of DNA damage response and chromosome DNA breakage in target cells (iii) NO production and two TOP2 isozymes are responsible for the generation of chromosome DNA breaks; (iv) consistently, treatment of a NO releaser GSNO induces hTOP2αcc and hTOP2βcc formation; (v) GSNO also increases mutation rate and kill cells in TOP2-dependent manner; and (vi) the incidences of GSNO- and VP-16-induced melanomas are found to be lower in skin-specific top2β-knockout mice. Thus, our results provide the first demonstration for the functional role of TOP2 in the NO-caused DNA damage, mutagenesis and carcinogenesis. The TOP2 involvement in pathological settings such as chronic inflammation-associated mutagenesis and subsequent cancer development were discussed.
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 LB-394. doi:1538-7445.AM2012-LB-394
Abstract LB-404: Genomic analysis reveals roles for chromatin modification and axon guidance in pancreatic cancer
Authors: Biankin Andrew V. , McPherson John D. , Gibbs Richard A. , Grimmond Sean M. ,   Australian Pancreatic Cancer Genome Initiative.
Published: August 2012

Abstract
Pancreatic cancer (PC) is the fourth leading cause of cancer death with an overall 5-year survival rate of &lt; 5%, a statistic that has not changed in almost 50 years. A deeper understanding of the underlying molecular pathophysiology is expected to advance the urgent need to develop effective therapeutic and early detection strategies for this disease. Genomic characterisation of Pancreatic Ductal Adenocarcinoma (PDAC), which accounts for over 90% of PC has to date relied on targeted PCR based exome sequencing of primary and metastatic lesions propagated as xenografts or cell lines. Here we use exome sequencing and copy number analysis to define genomic aberrations in a prospectively accrued clinical cohort (n = 142) of early (Stage I and II) PDAC. Detailed analysis of 99 informative tumours identified 1984 non-silent mutations and 1628 significant CNV events, and defined 439 significantly mutated genes based on stringent Significant Mutated Gene and GISTIC analysis. Integration with functional data from in vitro shRNA and in vivo Sleeping Beauty-mediated somatic mutagenesis screens provided supportive evidence for 182 of these as candidate driver mutations. Pathway based analysis recapitulated clustering of mutations in core signalling pathways in PDAC, and identified multiple new components in each, particularly in DNA damage repair mechanisms (ATM, TOP2A, RPA1, BRCC3). We also identified frequent and diverse somatic aberrations in genes involved in chromatin modification (SWI/SNF complex members, SETD2, EPC1), and novel mechanisms such as axon guidance (Semaphorin, Slit, Netrin and Ephrin signalling), extending the number of core perturbed pathways in PDAC. Aberrant expression of axon guidance genes co-segregated with poor patient survival, and in animal models was associated with disease development and progression, further implicating perturbation of the axon guidance pathway as a novel mechanism important in PDAC.
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 LB-404. doi:1538-7445.AM2012-LB-404
Abstract LB-75: Glucocorticoid receptor activation inhibits p53-induced apoptosis of MCF10A myc cells via induction of protein kinase C epsilon
Authors: Aziz Moammir H. , Shen Hong , Maki Carl G. 
Published: August 2012

Abstract
Glucocorticoid receptor (GR) is a ligand dependent transcription factor that can promote apoptosis or survival in a cell specific manner. Activated GR has been reported to inhibit apoptosis in mammary epithelial cells (MECs) and breast cancer cells by increasing expression of pro-survival genes. In the current report, activated GR inhibited p53-dependent apoptosis in MCF10Amyc cells, immortalized MECs that are p53 wild-type and overexpress the MYC oncogene. Specifically, GR agonists hydrocortisone or dexamethasone (Dex) inhibited p53- dependent apoptosis induced in these cells by Cisplatin (Cis), ionizing radiation (IR), or the MDM2 antagonist Nutlin-3. In contrast, the GR antagonist RU486 sensitized the cells to apoptosis by these agents. Apoptosis inhibition was associated with maintenance of mitochondria membrane potential, diminished caspase 3 and 7 activation, and increased expression at both the mRNA and protein level of the antiapoptotic PKC family member, PKCepsilon (PKCε). Knockdown of PKCε via siRNA targeting reversed the protective effect of Dex and restored sensitivity to Cis, IR, and Nutlin-3 (Nutlin)-induced apoptosis. These data provide strong evidence that activated GR can inhibit p53-dependent apoptosis through induction of the anti-apoptotic factor PKCε.
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 LB-75. doi:1538-7445.AM2012-LB-75
Abstract LB-77: Crm1-mediated nucleocytoplasmic transport inhibition perturbs multiple cellular pathways to trigger melanoma cell apoptosis
Authors: Pathria Gaurav , Wagner Christine , Wagner Stephan 
Published: August 2012

Abstract
Development of multiple resistance mechanisms in melanomas has necessitated the identification of novel drug targets, which when inhibited could impact multiple cellular pathways thus circumventing potential resistance mechanisms. By performing cDNA-microarray analysis, we identified four key components of the nucleocytoplasmic transport machinery, Chromosome Region Maintenance 1 (Crm1), Ran-GTPase, Ran-GTPase Activating Protein 1 (RanGAP1) and Ran Binding Protein 1 (RanBP1) to be overexpressed in human melanoma metastases. Crm1 inhibition, employing the highly specific Crm1 inhibitor Leptomycin B (LMB) induced a dramatic depletion of pro-survival/cytoplasmic Erk1/2 and p90RSK1 and mediated persistent Erk signaling hyperactivation. Consistently, Crm1 inhibition inflicted extensive apoptosis in melanoma cells while sparing immortalized melanocytes and primary lung fibroblasts. Apoptosis required both the intrinsic and extrinsic apoptotic pathways and was associated with a nuclear entrapment and down-regulation of anti-apoptotic Survivin. Apoptosis was preceded by a G1 cell-cycle arrest and even though Crm1 inhibition mediated dramatic p53 and p21 induction exclusively in wild-type p53 melanoma cells, latter's silencing or inactivation failed to alleviate ensuing apoptosis. Notably, Crm1 inhibition elicited cell line specific, G1 to S progression-retarding changes in the expression of multiple cell-cycle regulatory proteins (Cdk2, Cdk4, p27, p16 and p18) thus potentially explaining p53 dispensability. Based on our results, we propose Crm1 as a potential therapeutic target in human melanoma, whose inhibition initiates a multitude of cell context-dependent molecular events to trigger G1-arrest followed by massive apoptosis.
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 LB-77. doi:1538-7445.AM2012-LB-77
Abstract LB-81: Autophagic degradation of BCR/ABL by arsenic trioxide and the role of cysteine cathepsins
Authors: Goussetis Dennis , Gounaris Elias , Wu Edward J. , Vakana Eliza , Sharma Bhumika , Altman Jessica K. , Platanais Leonidas C. , Bogyo Matthew 
Published: August 2012

Abstract
Autophagy is increasingly an area of high potential therapeutic interest in hematopoietic malignancies, but its precise involvement in the control of leukemic cell growth and survival remain to be defined. We provide evidence that arsenic trioxide (As2O3) targets the BCR-ABL oncoprotein for degradation via autophagy, involving the p62/SQSTM1 and the protease cathepsin B. Utilizing either florescence probes or gold-conjugate antibodies we show co-localization of BCR-ABL and p62/SQSTM1 in autolysosomes. Also, by drug inhibition of either autophagy or cathepsin B, or by molecularly targeting p62/SQSMT1, Atg7 or cathepsin B, we documented reversal of the suppressive effect of As2O3 on BCR-ABL expressing cells, including primitive leukemic precursors from chronic myelogenous leukemia (CML) patients. Altogether, our data indicate that autophagy-induced degradation of BCR-ABL is critical for the generation of As2O3 antileukemic effects. These results raise the potential of targeting the autophagic machinery to enhance the antileukemic properties of arsenic trioxide on leukemia initiating stem cells.
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 LB-81. doi:1538-7445.AM2012-LB-81
Abstract LB-82: Modulation of autophagic flux by CPTH6, a Gcn5/pCAF histone acetyltransferase inhibitor with antitumoral activity
Authors: Gabellini Chiara , Ragazzoni Ylenia , Desideri Marianna , Nescatelli Riccardo , Carradori Simone , Secci Daniela , Trisciuoglio Daniela , Bufalo Donatella Del 
Published: August 2012

Abstract
The thiazole-derivative 3-methylcyclopentilidene-[4-(4′-chlorophenyl)thiazol-2-yl]hydrazone (CPTH6) is a Gcn5 and pCAF histone acetyltransferases inhibitor that induces apoptosis and cell cycle arrest in human leukemia cells. The aim of this study was to evaluate whether CPTH6-induced apoptosis is associated with other cell death mechanisms, such as autophagy. Herein, we show that CPTH6 interferes with autophagic flux in several human tumor cell lines of different origin. CPTH6 treatment increases microtubule-associated protein 1 light chain 3-II (LC3-II) levels and induces the appearance of typical LC3-II- associated autophagosomal puncta in a time- and dose-dependent manner. Moreover, this compound decreases the expression of autophagy promoting proteins beclin1, Atg5 and Atg12. Strikingly, combined treatment of CPTH6 with bafilomycin A1, a proton ATPase inhibitor, demonstrates that CPTH6 reduces autophagosomes turnover, through an impairment of their degradation pathway, rather than enhancing autophagosomes formation. According to these results, CPTH6 treatment enhances p62/SQSTM1 protein levels in several tumor cell lines, indicating a blockage of autophagic cargo degradation. CPTH6 also reduces the phosphorylation of several components of transduction signalling pathways, such as Akt, 4E-BP1 and eIF4E, ERK1/2 and GSK-3α/β while it activates p38 MAPK pathway. In vivo CPTH6 exposure does not produce any adverse effects on health in mice as monitored by diet consumption, body-weight loss, postural and behavioral changes. Most importantly, CPTH6 exerts antitumoral effect on U937 human leukemia xenografts. These findings demonstrate that CPTH6 induces apoptosis and interferes with autophagic flux in human cancer cells, supporting further exploration of CPTH6 and related molecules as potential anticancer agents.
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 LB-82. doi:1538-7445.AM2012-LB-82
Abstract LB-84: The role of survivin and survivin variants in the mitotic arrest-induced cell death
Authors: Cáceres Rodrigo E. , Andonegui Marco A. , Saavedra Alejandro Lopez , Herrera Luis A. 
Published: August 2012

Abstract
Eukaryotic cells rely on a mitotic checkpoint in order to preserve their proper ploidy. This mechanism stops mitosis progression before anaphase until each kinetochore is adequately bound to mitotic microtubules, and tension is generated which splits up chromatids towards opposite poles of the mitotic spindle. The resulting paused state of the cell cycle is known as mitotic arrest, and has been long known to induce cell death. However, the mechanisms driving mitotic arrest-mediated cell death have not yet been elucidated. It has been hypothesized that an anti-apoptotic/pro-apoptotic protein interplay might define the mitotic arrest outcome. We are interested in defining the role of survivin and its splicing variants, survivin Δex3 and survivin 2b, in the mitotic arrest-induced cell death. Survivin is a multifaceted member of the IAP family of proteins with functions in the chromosome passenger complex that has been shown to be over expressed in nearly every human tumor type. Noteworthy, Survivin Δex3 retains IAP activity but Survivin 2b has been shown to act as a pro-apoptotic factor. In this study, we defined the mitotic index (MI) of HCT116 cells in response to different concentrations of taxol and vinblastine. The results show that vinblastine induces a wide MI oscillation in contrast to taxol, which produces a homogeneous behavior in the cell population. This difference in population behavior might be explained by the different mechanisms of action of taxol and vinblastine. From the maximum taxol-induced MI point on, the percentage of sub-2n cells increased at the expense of mitotic cells, as assessed by flow cytometry. These results suggest that, in our model, cells die by exposure to taxol in a mitotic arrest-dependent manner. We also determined, by RT-PCR, that survivin variants are endogenously expressed in HCT116 cells. Furthermore, in immunoblot experiments, we found that survivin protein level decreases throughout taxol treatment in contrast to Bub1 levels, a member of the spindle assembly checkpoint. These results suggest that the decreased survivin level might be related to mitotic arrest-dependent cell death. The analysis of the intracellular localization of survivin variants throughout the mitotic arrest showed that survivin is localized in mitotic chromosomes throughout mitosis (before anaphase) independently of the time of treatment with taxol and vinblastine. Noteworthy, we also found that survivin Δex3 localized to the cytosol, and its level decreases throughout mitosis while survivin 2b protein was diffusely localized in the cytosol and mitotic chromosomes, and its level and localization remained unchanged.
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 LB-84. doi:1538-7445.AM2012-LB-84
Abstract LB-85: Ectopic expression of eukaryotic translation elongation factor eEF1A2 is a hallmark for human lung cancer and is associated with poor prognosis
Authors: Liu Xiao-Yun , Zhang Wei , Girard Luc , Gao Boning , Larsen Jill , Wistuba Ignacio Ivan , Frenkel Eugene , Toombs Jason , Brekken Rolf , Minna John , Gazdar Adi 
Published: August 2012

Abstract
Background: The elongation factor eEF1A is one of the most abundantly expressed cellular proteins. It exists in two forms, eEF1A2, expressed in neurons and striated muscle, and eEF1A1, expressed in all other cell types. No normal adult cell expresses both forms. We investigated their role in lung cancer. Methods: We studied over 500 NSCLC and SCLC lung cancers and over 170 cell lines, as well as corresponding non- malignant lung tissues and immortalized respiratory epithelial lines. Methods included microarray, qPCR, immunostaining and western blots for eEF1A1 and eEF1A2, genomic sequencing and SNP analyses. Results: All normal and malignant cells highly expressed eEF1A1. EEF1A2 was expressed in 70-80% of all forms of lung cancers and 95% of cell lines, while all non-malignant tissues were negative. Expression of eEF1A2 in neuroendocrine tumors was particular high. The ectopic expression of eEF1A2 was not the consequence of mutations or copy number gains. Use of demethylating agents and HDAC inhibitors resulted in expression of eEF1A2 in respiratory epithelial cells, indicating that epigenetic mechanisms prevented expression in non-malignant cells. Transient knockdown of the eEF1A2 expression inhibited proliferation and colony formation of lung cancer cell lines. Furthermore, the expression of eEF1A2 in resected NSCLC cancers was associated with poor survival. Conclusions: Highly specific ectopic expression of eEF1A2 gene is frequent in all types of lung cancer, plays an important role in tumor pathogenesis and is a potential diagnostic and prognostic factor.
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 LB-85. doi:1538-7445.AM2012-LB-85
Abstract SY02-02: Inhibition of methyltransferase EZH2
Authors: Dhanak Dashyant 
Published: August 2012

Abstract
Enhance of Zeste Homolog 2 (EZH2) is the biochemical activity of the Polycomb Repressive Complex 2 (PRC2) that transfers a methyl group from the cofactor S-adenosyl methionine (SAM) to histone H3 on lysine 27 (H3K27), resulting in epigenetic silencing of target gene expression. Activity of the multi-component PRC2 complex is crucial for normal development and differentiation. However, dysregulation of H3K27 methylation is implicated in tumorigenesis and occurs through multiple mechanisms. Elevated levels of EZH2 correlate with poor prognosis in a number of solid tumors including prostate, breast, kidney and lung. The increased EZH2 expression observed in many solid tumors has been linked to loss of one or more miRNAs including mir-101, mir-26A, and mir-214; aberrant E2F activity and chromosomal amplification. Inactivating mutations in UTX, an H3K27 demethylase which acts in opposition to EZH2, have been described in several tumor types including transitional cell bladder carcinoma, esophageal squamous cell carcinoma, renal cell carcinoma and multiple myeloma. Recently, somatic activating mutations in EZH2 have been identified in follicular lymphoma (FL) and GCB diffuse large B cell lymphoma (DLBCL). The frequency of the most prevalent mutation, Y641, is reported to be 7-12% in FL and as high as 22% in DLBCL. In view of the above, biochemical inhibitors of EZH2 may have therapeutic utility and herein we report on the identification and characterization of potent and selective small molecule EZH2 inhibitors with in vitro and in vivo antiproliferative activity in cancer cell lines and mouse xenografts. The studies provide a compelling rationale for the clinical evaluation of EZH2 inhibitors in EZH2 driven human cancers.
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 SY02-02. doi:1538-7445.AM2012-SY02-02