bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3836: Enhancement of doxorubicin cytotoxicity in breast cancer by NIM811, A non-immunosuppressive cyclosporine A analog
Authors: Zeng Xianke , Zheng Jiamao , Feeney Y'vonne , Harrington Katie , Clevenger Charles 
Published: August 2012

Abstract
Cyclophilin A (CypA) is a member of the immunophilin family of peptidyl prolyl isomerases (PPI) that catalyze the cis-trans interconversion of proline imide bonds of peptides. In this role, cyclophilins have been found to function as signaling switches, regulating the activity of receptors, kinases and transcription factors. The PPI activity of CypA is inhibited by the immunosuppressive drug cyclosporine A (CsA), and in turn the CypA-CsA complex inhibits calcineurin-mediated NFAT activation. Our laboratory has demonstrated that CypA is necessary for the prolactin (PRL)-induced activation of Jak2/Stat5 signaling and gene expression (Cancer Res 68:7769, 2008). In addition, we have also shown that CsA inhibits the in vitro and in vivo growth and progression of both ER+ and ER- breast cancer cell lines. Here, we show that the non-immunosuppressive CsA analog NIM811 blocked PRL-stimulated activation of the Jak2/Stat5, PI3K/AKT and MAPK pathways in T47D cells. NIM811 also inhibited ER+, ER-, and Her2+ breast cancer cell proliferation, survival, motility and anchorage independent growth in a dose-dependent manner. NIM811 inhibited PRL induced gene expression, such as CISH and Cyclin D1. NIM811 also blocked the PRL-induced association between Stat5 and cMyb, and at higher doses, triggered PARP cleavage and activate Caspase 3. Furthermore, NIM811 increased the effects of doxorubicin in inhibiting monolayer cell growth and soft agar colony growth in vitro. In vivo, NIM811 alone significantly induced the primary tumor central necrosis and inhibited lymph node metastasis; combining NIM811 with a low dose of doxorubicin significantly inhibited MDA-MB-231 breast cancer xenograft tumor growth and distant organ metastasis. In summary, these results indicate that non-immunosuppressive cyclophilin inhibitor NIM811 has significant potential as both a single agent or in combination with cytotoxic agents for breast cancer 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 3836. doi:1538-7445.AM2012-3836
Abstract 3991: Protein phosphatase 2A (PP2A) downregulation is associated with androgen-independent and aggressive phenotypes in prostate cancer
Authors: Bhardwaj Arun , Srivastava Sanjeev K. , Singh Seema , Arora Sumit , Honkanen Richard E. , Grizzle William E. , Reed Eddie , Singh Ajay P. 
Published: August 2012

Abstract
First line of therapy for advanced prostate cancer (PCa) is androgen-deprivation through surgical or chemical castration; however, in majority of cases, tumors relapse in an androgen-independent (AI) form. Once the PCa has recurred in AI form, it progresses to a highly aggressive disease with frequent metastasis and poses an increased risk of morbidity and death. Previously, we demonstrated that PPP2CA, which encodes for alpha-isoform of the protein phosphatase 2A (PP2A) catalytic subunit, is downregulated in prostate cancer. Furthermore, we showed that PP2A activity is inversely associated with AI growth of PCa cells through a novel mechanism, whereby loss of PP2A-mediated checkpoints leads to the activation of Akt and ERK and partially sustains androgen receptor (AR) signaling under steroid-deprived condition. Since AI phenotype of PCa is associated with enhanced metastatic potential, we have investigated, in this study, a role of PPP2CA in the aggressive behavior of the PCa cells. For this, we overexpressed PPP2CA in AI (C4-2 and PC-3) PCa cells, while silenced its expression in AD (LNCaP) PCa cells. We observed that overexpression of PPP2CA in C4-2 and PC-3 cells not only decreased their AI growth and clonogenic ability, but also led to reduced motility and invasion and enhanced cell-cell interaction. Conversely, we observed increased cell motility and invasion and decreased cell-cell interaction upon PPP2CA silencing in LNCaP cells. Immunoblot analyses demonstrated gain of epithelial and loss of mesenchymal markers in PPP2CA-overexpressing PCa cells or vice versa indicating a role of PP2A in opposing epithelial to mesenchymal transition (EMT). Altogether, these studies provide evidence for a functional role of PPP2CA in aggressive behavior of AI PCa 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 3991. doi:1538-7445.AM2012-3991
Abstract 3997: TUSC3 (N33) affects protein N-glycosylation and proliferation of prostate cancer cells
Authors: Horak Peter , Tomasich Erwin , Anees Mariam , Marhold Maximilian , Gerschpacher Marion , Pils Dietmar , Krainer Michael 
Published: August 2012

Abstract
Prostate cancer is the most prevalent cancer in males in developed countries. Molecular aberrations in the pathogenesis of this disease are numerous, though losses on the short arm of chromosome 8 are highly prevalent. In our previous studies, hypermethylation and diminished TUSC3 expression turned out to be significantly associated with poor progression free and overall survival in ovarian cancer. Additionally, expression profiling of TUSC3 negative cancer cell lines revealed deregulation of genes involved in ‘cell structure and motility’ and ‘development processes’, further supporting our hypothesis of TUSC3 as a tumor suppressor. In silico prediction of TUSC3 shows a high homology of TUSC3 to the Ost3p subunit of the oligosaccharyltransferase (OST) complex in yeast, hinting to its role in protein glycosylation. In this project, we characterized TUSC3 (N33), a putative tumor suppressor gene on 8p, in prostate cancer. To study the prognostic role of TUSC3 in prostate cancer we used a comprehensive prostate cancer tissue microarray, comprised of samples from 143 prostate cancer patients. Serum DNA methylation was studied in an additional cohort of 67 prostate cancer patients. Statistical analysis demonstrated low or missing TUSC3 protein expression in 56.6% of prostate cancer patients based on immunohistochemical staining. Methylation of the TUSC3 promoter was observed in 38.8% of prostate cancer patients’ serum DNA, confirming our previous findings of TUSC3 promoter hypermethylation as a possible epigenetic regulatory mechanism. In our prostate cancer cohorts, however, neither expression nor hypermethylation of TUSC3 had a significant effect on overall survival, possibly due to the relatively short follow-up period. Next, we studied the function of TUSC3 in N-glycosylation and in particular its influence on carcinogenesis using a cell culture model. We downregulated TUSC3 expression in prostate cancer cell lines DU145 and PC3 using shRNA mediated knockdown and analyzed them for their proliferative and carcinogenic properties in vitro. We could show that loss of TUSC3 expression confers growth advantage of prostate cancer cell lines, in particular under conditions of serum starvation. We also observed increased migratory properties of prostate cancer cell lines upon TUSC3 knockdown. Further, influence of TUSC3 downregulation on several putative targets of N-linked glycosylation has been analyzed in vitro. In our study, we characterized TUSC3 expression and/or methylation in prostate cancer patients and obtained a first mechanistic insight into its function in N-glycosylation and carcinogenesis.
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 3997. doi:1538-7445.AM2012-3997
Abstract 4002: Functional investigation and identification of dephosphorylation targets of tumor-suppressive protein tyrosine phosphatase, PTPRG
Authors: Cheung Arthur KL , Lung Hong Lok , Ko Josephine MY , Ip Joseph CY , Zabarovsky Eugene , Stanbridge Eric J. , Lung Maria L. 
Published: August 2012

Abstract
Background and aims: PTPRG was identified as a candidate tumor suppressor gene. It belongs to a family of membrane-bound receptor tyrosine phosphatases. However, the function and the dephosphorylation targets of PTPRG still remain to be elucidated. The aim of this current study was to identify the downstream dephosphorylation targets of PTPRG. Methods: A tetracycline-inducible system was used to obtain PTPRG-expressing clones. The dephosphorylation targets were identified by an antibody array. The anti-angiogenesis function of PTPRG was investigated by HUVEC tube formation assay. Results: The c-jun phosphorylation level was found to be down-regulated after re-expression of PTPRG. Re-expression of PTPRG can inhibit tube formation in the HUVEC tube formation assay by down-regulating the AP1 downstream target, VEGF, secretion. Conclusions: Re-expression of PTPRG can reduce the phosphorylation of c-jun and, thus, inhibit angiogenesis by down-regulating the important angiogenesis regulator, VEGF. The results suggest the importance of PTPRG in regulating tumor formation. It is a good candidate tumor suppressor gene, which warrants further study. Acknowledgements: This work was supported by the Research Grants Council and the University Grants Council of the Hong Kong Special Administrative Region, People's Republic of China (AoE/M-06/08, to M.L.L.) and the University of Hong Kong Small Project Fund (Grant 200907176081, to A.K.L.C.).
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 4002. doi:1538-7445.AM2012-4002
Abstract 4005: Active SHP2 mutant induces lung hyperproliferative lesions and adenoma in transgenic mice
Authors: Schneeberger Valentina , Luetteke Noreen , Lopez Alex S. , Chen Liwei , Radisky Derek , Coppola Domenico , Wu Jie 
Published: August 2012

Abstract
SHP2 is a protein tyrosine phosphatase encoded by the PTPN11 gene. SHP2 is normally auto-inhibited by its regulatory N-SH2 domain. It is activated by several receptor tyrosine kinases and positively regulates the RAS/ERK and other signaling pathways by mechanisms that remain incompletely defined. Furthermore, gain-of-function activating SHP2 mutants have been found in human hematologic malignancies and solid tumors, including lung, colon, and prostate cancer. Previous studies have demonstrated the oncogenic activity of gain-of-function SHP2 mutants in the hematopoietic system. To investigate the biological functions of mutant SHP2 in vivo, we generated transgenic mice harboring a tetO-SHP2E76K transgene for tetracycline-inducible expression of the constitutively active SHP2E76K mutant. This allows us to examine the roles of the cancer-associated, Glu-76 mutant SHP2 in various tissues in bitransgenic mice. tetO-SHP2E76K mice were crossed with CCSP-rtTA or SPC-rtTA mice for inducible expression of SHP2E76K in the lung type II pneumocytes. Elevated levels of active Erk1/2 and Src were detected in the lungs of bitransgenic mice induced with doxycycline. Focal hyperplasia of bronchioloalveolar epithelial cells was observed within one month of doxycycline induction in bitransgenic mice, which progressed to more extensive atypical adenomous hyperplasia and adenoma after six months. These results suggest that Shp2 is a proto-oncogene of lung carcinoma.
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 4005. doi:1538-7445.AM2012-4005
Abstract 4030: Wnt antagonist SFRP4 acts as a tumor suppressor gene in gastric carcinomas
Authors: Kim Jin , Lee Hee Eun , Jee Chang Do , Kim Woo Ho 
Published: August 2012

Abstract
Secreted frizzled-related proteins (SFRPs) function as Wnt signaling antagonists and have important implications in carcinogenesis. SFRP4, a member of the SFRP family, have been found to be down-regulated by promoter hypermethylation in various cancers. However, functional significance of SFRP4 has not been investigated in gastric carcinoma. In this study, we examined aberrant DNA methylation and expression of SFRP4 in gastric cancer cell lines, and we found that SFRP4 was hypermethylated and down-regulated in 9 out of 10 (90%) gastric cancer cell lines. Bisulfite DNA sequencing confirmed the densely methylated SFRP4 promoter region and addition of the demethylating agent 5-aza-2α-deoxycytidine and/or histone deacetylase inhibitor trichostatin A restored the mRNA expression of SFRP4. Methylation-specific PCR (MSP) analysis showed that SFRP4 gene promoter is frequently methylated in gastric cancer tissues (75%) but not in adjacent normal gastric tissues. We then investigated whether methylation of SFRP4 is associated with age, sex, tumor stage, histology, and overall survival. No significant association was found between the methylation status of SFRP4 and these clinicopathological variables. However, promoter methylation of SFRP4 was found to be significantly correlated with poor survival in gastric carcinomas (p = 0.045). Restoration of SFRP4 function in non-expressing gastric cancer cells induced tumor suppressor-like features such as induces gastric cancer cell apoptosis, inhibits cell proliferation, colony formation, migration, and invasion. Conversely, knocking down SFRP4 by small interfering RNA in gastric cancer cell lines promotes cell proliferation and inhibits apoptosis. In addition, over-expression of SFRP4 repressed Wnt target genes and induced changes in the expression of numerous genes related to cell cycle, proliferation, invasion, metastasis, and apoptosis in gastric cancer cells. Our results suggest that promoter hypermethylation is one of the important mechanisms of SFRP4 gene silencing in gastric carcinogenesis and that SFRP4 methylation in gastric carcinoma is associated with a poor outcome in such 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 4030. doi:1538-7445.AM2012-4030
Abstract 4097: Integrative analysis of epigenetic and transcriptional alterations in head and neck squamous cell carcinomas
Authors: Gaykalova Daria A. , Vatapalli Rajita , Wei Yingying , Hennessey Patrick , Khan Zubair , Westra William , Khan Tanbir , Zaboli David , Sidransky David , Ochs Michael , Califano Joseph A. 
Published: August 2012

Abstract
Objective: Head and Neck Squamous Cell Carcinoma (HNSCC) is the sixth most common cancer worldwide with a 50% patient survival rate 5 years post-diagnosis despite current therapeutic strategies. A direct comprehensive genome wide integrated analysis of epigenetic and transcriptional alteration in primary HNSCC has not been performed before. Such data would greatly enrich our knowledge about HNSCC biology and would be beneficial for the development of the individual targeted therapy. Experimental Design: 44 primary HNSCC and 25 normal mucosal samples were used in the Affymetrix GeneChip Human Exon 1.0 array and for the Illumina Infinium Human Methylation 27 array. To analyze the data we employed a novel screening approach based on Cancer Outlier Profile Analysis (COPA). With use of this approach we determined 81 significant differentially expressed and 37 significant differentially methylated genes with both oncogenic and tumor suppressing properties. Results: Out of total 118 candidate genes we picked 36 candidate tumor suppressing genes with strong correlation between hypermethylation and decrease of expression in tumor samples, such as BANK1, ADFP, MAPK4, ZNF71 and others. 20 genes out of total 36 were validated by bisulfite sequencing in a separate cohort of 32 primary HNSCC tumor and 16 normal mucosal tissues. Out of the total 20 genes, 13 demonstrated at least 40% difference in methylation, most notably for BANK1 81% of tumors were more methylated as compared to normals. 7 of these newly discovered genes out of the 36 belong to Zinc Finger Proteins (ZNF) group and they have never been reported as tumor suppressors in HNSCC before. Bisulfite sequencing and quantitative real time PCR (qRT-PCR) analysis of ZNFs revealed that they are strongly hypermethylated and underexpressed in HNSCC tumor samples. Conclusions: Our new screening approach allowed identification of 36 candidate tumor suppressor genes aberrantly methylated and transcriptionally suppressed in HNSCC. Validation of gene expression and methylation allowed the detection of ZNF genes whose downregulation may play a significant role in HNSCC tumor development.
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 4097. doi:1538-7445.AM2012-4097
Abstract 416: Radiation-induced reprograming of breast cancer cells
Authors: Lagadec Chann H. , Vlashi Erina , Dekmezian Carmen , Pajonk Frank 
Published: August 2012

Abstract
Breast cancers are thought to be organized hierarchically with a small number of breast cancer stem cells (BCSCs) able to re-grow a tumor while their progeny lack this ability. Recently, several groups reported enrichment for BCSCs when breast cancers were subjected to classical anticancer treatment. However, the underlying mechanisms leading to this enrichment are incompletely understood. Using non-BCSCs sorted from patient samples, we found that ionizing radiation reprogrammed differentiated breast cancer cells into induced BCSCs (iBCSCs). iBCSCs showed increased mammosphere formation, increased tumorigenicity and expressed the same stemness-related genes as BCSCs from non-irradiated samples. Reprogramming occurred in a polyploid subpopulation of cells, coincided with re-expression of the transcription factors Oct4, Sox-2, Nanog, and Klf4, and could be partially prevented by Notch inhibition. We conclude that radiation may induce a BCSC phenotype in differentiated breast cancer cells and that this mechanism contributes to increased BCSC numbers seen after classical anti-cancer treatment.
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 416. doi:1538-7445.AM2012-416
Abstract 4202: Genetic re-programming of the AML cell line HL-60 during differentiation: Roles of the EGR/NAB and NR4A transcription factors
Authors: Roberts Michael , Briceno Nicole , Bugel Jamie , Campbell Catherine , Dickinson Mary , McCarthy Trevor , Oldach Phoebe , Stanley Natalie , Forrester Jeffrey 
Published: August 2012

Abstract
HL-60 cells represent an established line of human acute myeloid leukemia cells that can be induced to differentiate along several distinct myeloid lineages. Phorbol esters activate a signaling network, which includes the protein kinase C (PKC) pathway, causing the leukemia cells to differentiate into macrophage-like cells. As the leukemia genetic program is converted to the macrophage program, the cells exit the cell cycle, undergo morphological changes, become adherent, display other macrophage properties, and ultimately initiate apoptosis. This study provides a detailed DNA microarray analysis with qRT-PCR validation of the genetic network of the leukemia cell during first 24 hours post-induction of differentiation. We present data describing the global changes in gene expression at the RNA-level at 0.5, 1, 3, 6, 12, and 24 hours post-PMA treatment and information about specific genes with regard to their RNA and protein expression levels. Approximately 2,000 genes were identified that exhibit significant changes in mRNA levels from the leukemia expression program. A cluster analysis was performed to group these genes by their pattern of expression resulting in a collection of distinct expression profiles and associated functional profiles. These genes encode transcription factors, intracellular signal transducers, receptors, cytokines and a variety of other proteins. Of particular interest in understanding the genetic re-programming of the leukemic cells is the transcription factor expression profile. In addition to the established roles of the NF-kappa-B and AP-1 transcription factors in HL-60 cell differentiation, we present possible roles for the EGR/NAB and NR4A transcription factor families in both differentiation and initiation of apoptosis. A variety of biological analysis strategies using the expression data to define regulatory groupings that characterize the changing genetic network in these cells, including interaction networks and pathway activations have been carried out. Taken together, we seek to better understand the genetic program defining leukemia cells and the mechanisms by which oncogenic mutations can be overridden to achieve cell cycle arrest, differentiation and 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 4202. doi:1538-7445.AM2012-4202