bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1191: Managing the cross talk: BRCA1 and its regulation of the p53 family, E2f1/Rb and apoptosis
Authors: Scata Kimberly A. , El-Deiry Wafik S. 
Published: August 2012

Abstract
Under constant assault from internal and external stresses, the cell constantly monitors cellular damage, repairing damage when it is able. If the cell deems the damage too great to repair, it activates the pathways that induce programmed cell death. This life or death decision is controlled, in part, by the activation of the tumor suppressor, p53. Upon stabilization and activation, p53 activates a variety of genes including those genes capable of inducing apoptosis. Our lab has previously demonstrated that the tumor suppressor, BRCA1, is capable of stabilizing p53 and directing it to cell cycle arrest genes at the expense of apoptotic genes. In our efforts to understand the mechanism by which BRCA1 is able to prevent expression of apoptotic genes, we have discovered that BRCA1 also stabilizes E2F1, an oncogene that is able to induce p53-dependent and p53-independent apoptosis. Interestingly, we have found that BRCA1 also induces DNp73, a pro-survival member of the p53 family. We hypothesize that BRCA1 may be interfering with the interaction between E2F1 and Rb that has been shown to be important for the apoptotic response to DNA damage. Furthermore, we are currently using siRNA to inhibit expression of these genes to determine the relative contribution of DNp63, DNp73 and E2F1/Rb signaling to control the cell's decision to undergo apoptosis in response to BRCA1 expression.
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 1191. doi:1538-7445.AM2012-1191
Abstract 1196: Identification of lung cancer associated oncoantigens as targets for active immunotherapy
Authors: Riccardo Federica , Quaglino Elena , Arigoni Maddalena , Ercole Elisabetta , Iezzi Mannuela , Longo Dario L. , Forni Guido , Cavallo Federica , Calogero Raffaele A. 
Published: August 2012

Abstract
Non small cell lung cancer (NSCLC) is the leading cause of cancer death in men and women. Therefore, the development of new therapeutic strategies is essential for improving the prognosis and treatment of patients. An interesting experimental model to study human lung adenocarcinoma is represented by p53R172HΔg/K-rasG12D mice. They develop aggressive NSCLC that metastasize to multiple sites and display a stepwise, directly age-related progression, mimicking several features observed in lung cancer patients. Lung cancer progression in p53R172HΔg/K-rasG12D mice was characterized by non-invasive magnetic resonance imaging (MRI), histopathological and immunohistochemical analysis. p53R172HΔg/K-rasG12D mice develop lung adenocarcinomas already evident in 10 week-old mice, with a variable degree of differentiation. A significant gender difference in tumor progression was observed, with females developing more tumors than males. Moreover, by using qRT-PCR, some of the antigens deregulated in human lung cancer turned out to be up-regulated also during cancer progression in our mouse model, suggesting that p53R172HΔg/K-rasG12D mice recapitulate the metastatic nature of human NSCLC. Identification of oncoantigens expressed during tumor development could provide an unprecedented opportunity to address the immune system against these molecules. RNA was extracted from lungs of 10, 20 and 30 week-old wild type (wt) and p53R172HΔg/K-rasG12D mice. Transcription profiling was done using Mouse Exon 1.0 ST arrays: we detected 282 genes significantly differentially expressed during different stages of cancer progression. Interestingly, some of the genes that were already deregulated in the early phases of the tumor development remained deregulated also in advanced stages, suggesting their possible application as early biomarkers or as vaccination targets. These genes were ranked to full-fill the minimal requirement for an oncoantigen; within the plasma membrane proteins we identified potential candidates: CXCR1, SLC16A6, SLC26A9 and ROS1. On the basis of the literature data and mouse data we consider ROS1 an interesting putative oncoantigen to be further investigated.
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 1196. doi:1538-7445.AM2012-1196
Abstract 1211: Antitumor effect of prostaglandin E2 receptor inhibitors in gastric carcinoma
Authors: Fukuoka Tatsunari , Yashiro Masakazu , Takeda Hiroshi , Maruyama Takayuki , Morisaki Tamami , Hasegawa Tsuyoshi , Hirakawa Toshiki , Aomatshu Naoki , Matsuoka Junko , Sakurai Katsunobu , Kimura Kenjiro , Nagahara Hisashi , Amano Ryosuke , Noda Eiji , Kubo Naoshi , Tanaka Hiroaki , Muguruma Kazuya , Yamada Nobuya , Maeda Kiyoshi , Ohira Masaichi , Ishikawa Tetsuro , Hirakawa Kosei 
Published: August 2012

Abstract
Introduction: Prostaglandins (PGs) have been suggested to play an important role for the proliferation and migration of cancer. Cyclooxygenase2(COX-2) stimulates PG synthesis. The selective COX-2 inhibitors have reported to show antitumor effects on various types of cancers, including colorectal cancer and gastric cancer. Gastric cancer remains to be poor prognosis because few anti-cancer drugs are available for advanced gastric cancer. PGE2 binds to PGE2 receptor, EP1, EP2, EP3 and EP4 and activates MAPKinase. The aim of this study is to investigate the effects of the EP2 inhibitors on the proliferation and motility of gastric cancer cells. Methods: Human gastric cancer cell lines (OCUM-2M and OCUM-12) were used in this study. Cell proliferation was studied by 3-(4,5-Dimethyl-2 thiazoyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay. Cell migration was studied by a wound healing assay. Results: PGE2 significantly stimulated proliferation and migration of gastric cancer cells, but not PGE1. EP2 and EP4 inhibitors significantly decreased the proliferation and migration ability of gastric cancer cells in a dose dependent manner, but not EP1, EP3. Conclusion: PGE2 is associated with progression of gastric cancer cells.PGE2 receptor inhibitors might be promising anti-cancer drug for gastric 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 1211. doi:1538-7445.AM2012-1211
Abstract 1212: The dual action antibody MEHD7945A targeting EGFR and HER3 enhances chemotherapy induced cytotoxicity in vitro and in vivo
Authors: Crocker Lisa M. , Fields Carter , Shao Lily , Sliwkowski Mark X. , Phillips Gail D. Lewis , Schaefer Gabriele 
Published: August 2012

Abstract
Dysregulation of the epidermal growth factor receptor family (EGFR, HER2, HER3, HER4) by mutation and/or overexpression plays an important role in tumorigenesis, and targeted agents directed against two members of the HER/ErbB family, epidermal growth factor receptor (EGFR/HER1), and HER2/ErbB2, are used in the treatment of cancer. Extensive crosstalk seen among these receptors implies that blocking signaling of more than one receptor may be more effective in inhibiting tumor growth and circumventing resistance mechanisms than targeting individual receptors. In particular, HER3 is considered a key mediator of resistance to many targeted agents. We generated a “two-in-one” antibody, MEHD7945A, that binds to EGFR and HER3 with high affinity, inhibits receptor function and is more broadly efficacious in various tumor types when compared to monospecific anti-EGFR or anti-HER3 antibodies. Given the ability of HER3 to potently activate the PI3K survival pathway, we investigated if antagonizing ligand-dependent HER signaling with MEHD7945A in the presence of chemotherapy augments cytotoxicity. We calculated combination index values the effects of combining MEHD7945A with commonly used chemotherapeutic agents in NSCLC and colorectal cell lines in vitro and in vivo. The NSCLC lines NCI-H292, NCI-H1666, NCI-H358 and HCC827 were treated with MEHD7945A plus gemcitabine over a wide range of drug concentrations. Cell proliferation data were analyzed using CalcuSyn software and all combination index values were &lt;1, demonstrating that the combination of MEHD7945A and gemcitabine inhibited proliferation synergistically in these cells. To further explore the enhanced cytotoxic effect we evaluated the combination of MEHD7945A and gemcitabine, versus each single agent, in the NCI-H1975 NSCLC xenograft model, and observed enhanced tumor regression. Similar results were observed when MEHD7945A was combined with a range of chemotherapeutic agents, including pemetrexed, docetaxel and irinotecan in H1975, H441 or SW948 xenograft models. In summary, these in vitro and in vivo results demonstrate that MEHD7945A potentiates various cytotoxic agents in a variety of tumor types.
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 1212. doi:1538-7445.AM2012-1212
Abstract 1218: PTPRO as a candidate phosphatase in regulating EGFR signaling in colorectal cancer
Authors: Asbagh Layka Abbasi , Vecchione Loredana , Sablina Anna , Tejpar Sabine 
Published: August 2012

Abstract
Background Protein tyrosine phosphatases (PTPs) are known to be responsible for the negative regulation of many receptor tyrosine kinases by serving as antagonists to tyrosine kinase signaling. Several PTPs have been identified as candidate regulators of EGFR phosphorylation such as PTP1B, RPTP-sigma, RPTP-kappa, and PTPRJ (DEP-1). Here, we focused on PTPRO, a member of R3 family. The Drosophila ortholog of this family, Ptp4E/Ptp10D, negatively regulates EGFR signalling. Gene expression analysis of 688 primary tumours led us to identify PTPRO as a gene with strongly reduced expression in colorectal cancers with poor prognosis in particular the ones belonging to the Braf mutant subgroup. This suggests that PTPRO could act as a tumour suppressor by negative regulation of EGFR in colorectal cancer. Material and methods HEK293 cells were transiently transfected with wild-type (WT) PTPRO and with its catalytic mutant (C/S) and stimulated with EGF. After cell lysis, extracts were analyzed by SDS-PAGE and probed by western blotting with an anti-phosphotyrosine antibody (pY99, 4G10). The total level of EGFR is detected with anti-EGFR antibody. EGFR phosphorylation antibody arrays are used to identify the specific tyrosine phosphorylation sites. Results and discussion Upon expression of the PTPRO (C/S) mutant, we observe a delay in EGF induced EGFR degradation. Our preliminary data suggests that PTPRO might play a role in EGFR trafficking through the endocytic pathway and its catalytic activity is required for efficient endocytic progression of EGFR. Ongoing experiments will answer to this question. WT-PTPRO over-expression specifically decreases the Tyr 845 phosphorylation of EGFR, a known Src family tyrosine kinase (SFK) phosphorylation site. SFKs also regulate receptor turnover both at the level of endocytosis and cbl-mediated ubiquitination by phosphorylation. However, underlying mechanism how PTPRO can modulate EGFR signalling through the regulation of endocytic machinery is not known yet.
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 1218. doi:1538-7445.AM2012-1218
Abstract 122: MiR-9-3 and miR-193a are targets for DNA methylation in non-small cell lung cancers
Authors: Heller Gerwin , Weinzierl Marlene , Noll Christian , Babinsky Valerie , Ziegler Barbara , Altenberger Corinna , Minichsdorfer Christoph , Lang György , Döme Balazs , End-Pfützenreuter Adelheid , Arns Britt-Madeleine , Grin Yuliya , Klepetko Walter , Zielinski Christoph C. , Zöchbauer-Müller Sabine 
Published: August 2012

Abstract
DNA methylation (referred to as methylation) is part of the epigenetic gene regulation complex which is relevant for the pathogenesis of different malignant diseases including non-small cell lung cancers (NSCLC). Recently, it has been reported that besides protein encoding genes also microRNA (miRNA) encoding genes may be targets for methylation in NSCLCs, however, the number of known methylated miRNA genes is still small. To investigate the role of methylation on miRNA gene silencing in NSCLCs, we performed microarray expression analyses of 856 miRNA genes in NSCLC A549 cells before and after treatment with the DNA methyltransferase inhibitor 5-aza-2′-deoxycytidine (Aza-dC) and with a combination of Aza-dC and the histone deacetylase inhibitor trichostatin A. Comparing microarray data of untreated and drug treated A549 cells, we identified 33 miRNA genes whose expression was upregulated after drug treatment and which are associated with a CpG island. Methylation of these miRNA genes was determined in 11 NSCLC cell lines by methylation-sensitive high resolution melting (MS-HRM) analysis and 30 of 33 (91%) miRNA genes were found to be methylated in at least 1 NSCLC cell line. In addition, methylation of the miRNA genes miR-9-3 and miR-193a was also analysed in primary tumors and corresponding non-malignant lung tissue samples of 101 stage I-III NSCLC patients and was found to be tumor-specific. Moreover, we compared miR-9-3 and miR-193a methylation results and clinico-pathological characteristics of NSCLC patients. We found a shorter disease-free survival of miR-9-3 methylated lung squamous cell carcinoma (LSCC) patients compared to miR-9-3 unmethylated LSCC patients by multivariate analysis (HR = 3.8, 95% CI = 1.3 to 11.2, p = 0.017) and a shorter overall survival of miR-9-3 methylated LSCC patients compared to miR-9-3 unmethylated LSCC patients by univariate analysis (p = 0.013). In conclusion, our results suggest that methylation is an important mechanism for silencing certain miRNA genes in NSCLCs and that miR-9-3 methylation may serve as a prognostic parameter in LSCC 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 122. doi:1538-7445.AM2012-122
Abstract 1226: Lapatinib could not prevent heregulin-induced HER2-HER3 signalling, and addition of pertuzumab to lapatinib increases drug sensitivity and inhibition of HER signalling
Authors: Leung Wing Yin , Kong Anthony H. 
Published: August 2012

Abstract
Lapatinib is an EGFR/HER2 tyrosine kinase inhibitor (TKI) that has been approved for clinical use in HER2 positive breast cancer patients who have progressed on previous Trastuzumab containing regimens. However, lapatinib monotherapy only delays tumour growth in HER2 positive xenograft models and has only modest clinical activity in breast cancer patients. There is a further need to understand its mechanisms of action and resistance. We aimed to assess the acute effect of lapatinib on HER2 phosphorylation in HER2 positive breast cancer cells since previous work from our lab showed that inadequate suppression of HER2 phosphorylation by gefitinib and trastuzumab may lead to acquired drug resistance. Traditionally, the phosphorylation status of HER proteins is determined by phosphor-tyrosine western blotting followed by immunoprecipitation. The limitation of this technique includes false positive due to signals from co-precipitated proteins of the same size as target, which is even more prominent with the HER family of protein. With the use of phosphorylated protein-specific antibody, we found that, contrary to general belief, lapatinib could not abolish HER2 phosphorylation in HER2 over-expressed breast cancer cell lines under serum-supplemented condition. It was thought that the growth factors in the serum activate other HER receptors to maintain HER2 phosphorylation. Indeed, Lapatinib could reduce phospho-HER2 level in serum-starved breast cancer cell lines; however, it failed to reverse heregulin-induced HER signalling activation and downstream MAPK and AKT signalling. The combination of lapatinib and pertuzumab drastically inhibited ligand-induced HER family phosphorylation and downstream signalling. HER3 was reported as an important biomarker for resistance in HER family targeted therapy. This novel combination could inhibit HER3 phosphorylation and its downstream AKT pathway more than lapatinib or pertuzumab alone; this finding also correlated with cancer cell viability, as the combination of lapatinib and pertuzumab reduced cell viability more than either drug alone. These results might indicate a new strategy of drug combination to tackle resistance in HER2 targeted 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 1226. doi:1538-7445.AM2012-1226
Abstract 123: DNA methylation of miRNA promoters in breast cancer
Authors: Vrba Lukas , Muñoz-Rodríguez José L. , Stampfer Martha R. , Futscher Bernard W. 
Published: August 2012

Abstract
MicroRNAs (miRNA) are short single-stranded RNA molecules that regulate gene expression and deregulation of their expression is linked to human diseases including cancer. Epigenetic mechanisms including DNA methylation play an important role in the regulation of miRNA expression, and a number of reports describe silencing of miRNA expression linked to the aberrant DNA methylation of individual miRNA genes in cancer. In this study, we have used a comprehensive miRNA custom tiling microarray to evaluate aberrant DNA methylation of miRNA gene promoters in human breast cancer, with selected hypermethylated promoters being validated by Sequenom MassARRAY technology. We found more than 25% of miRNA gene promoters analyzed have significant hypermethylated regions in breast cancer cell lines (CCL) relative to logarithmically growing normal pre-stasis finite lifespan human mammary epithelial cells isolated from healthy individuals. In addition to in vitro grown breast cancer cell lines, we analyzed DNA methylation of miRNA promoters in a dozen breast tumor tissue specimens and five normal breast specimens. Aberrant DNA hypermethylation of miRNA promoters in breast cancer specimens displayed a perfect overlap with those hypermethylated in breast cancer cell lines, albeit the number of miRNAs promoters was smaller in the heterogeneous tissue samples. These aberrantly methylated miRNA promoters readily clustered breast cancer samples and cell lines together, and separate from normal beast tissue and mammary cell strains. Integration of our data with publically-available H3K27me3 ChIP-Seq data from stem cells reveals that miRNA promoters targeted by aberrant DNA methylation in cancer cells significantly overlap with promoters targeted by polycomb repression complexes in stem cells, similar to the results other have seen with protein coding genes promoters in cancer. We have found previously that the proportion of miRNA genes targeted by polycomb repression in normal mammary cell types is about 27% - three times higher than seen in protein coding genes, perhaps explaining why the proportion of miRNA genes with aberrant DNA methylation in our analysis of breast cancer is so high. In summary, our data show that a large fraction of miRNA gene promoters are targets of aberrant DNA methylation in human breast cancer, and that the miRNA promoters aberrantly methylated in breast cancer cell lines are also targeted in tumor tissue samples, indicating that these changes in DNA methylation are not artifacts of cell culture and might thus have clinical relevance. Similar to protein coding genes, miRNA gene promoters targeted by polycomb complexes in stem cells are more prone to hypermethylation in 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 123. doi:1538-7445.AM2012-123
Abstract 1240: The role of hematopoietic protein kinases in GBM
Authors: Moncayo Gerald E. , Grzmil Michal , Wang Yuhua , Frank Stephan , Merlo Adrian , Brian Hemmings A. 
Published: August 2012

Abstract
Glioblastoma multiforme (GBM) is the most common and deadly form of brain cancer. Despite intensive research the median survival of GBM remains at 1 year, with less than 10 % of patients surviving over 5 years. Our analysis of fresh GBM, secondary GBM, high grade astrocytoma, oligodendroglioma, normal brain and normal human astrocytes showed increased expression of 19 novel protein kinases in GBM and targets previously associated with gliomagenesis (e.g. EGFR or PDGF). Two of these kinases which are mainly expressed in hematopoietic cells were the cytoplasmic kinases SYK and LYN. We confirmed the overexpression in GBM tumours and cell lines through western blot and immunohistochemistry analysis. More importantly, SYK expression was derived from the GBM tumours and not from infiltrating leukocytes as shown through colocalization with GFAP, and not with CD45. SYK was found strongly activated at the membrane after EGF and treatment with three specific small molecule inhibitors and siRNA targeting SYK strongly blocked proliferation and migration of GBM cells. This was confirmed through wtSYK and kinase dead SYK overexpression. In addition, SYK phosphorylation was found to be cell cycle regulated after synchronization. Due to our preliminary results we will test the therapeutic potential of SYK inhibitors and epistatic kinase interactions on our xenograft model measuring the efficacy of therapeutics crossing the blood brain barrier with the ultimate goal of discovering alternative treatments for GBM.
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 1240. doi:1538-7445.AM2012-1240