bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 81: Role of GRM1 in breast cancer
Authors: Mehta Madhura S. , Dolfi Sonia , Bronfenbrener Roman , Bilal Erhan , Medina Daniel , Haffty Bruce , Toppmeyer Deborah , Ganesan Shridar , Hirshfield Kim M. 
Published: August 2012

Abstract
Despite epidemiologic studies suggesting a link between melanoma and breast cancer, molecular mechanisms leading to these associations have not been elucidated. Overexpression of metabotropic glutamate receptor 1 (GRM1) has been implicated in melanomagenesis. Its primary action occurs through activation of the MAPK signaling pathway and other pathways through intracellular calcium release. A recent study implicated GRM1 as playing a role in angiogenesis in hormone receptor negative breast cancer. However, the role of GRM1 in hormone receptor positive disease is yet to be described. Given the associations between melanoma and breast cancer, we evaluated three SNPs in GRM1 for genotype associations with breast cancer clinicopathologic variables using DNA isolated from peripheral blood of 1,096 breast cancer patients. Our study found that a SNP in GRM1 resulting in a proline to serine substitution correlates with age at diagnosis of breast cancer and reflects the receptor status of the breast cancer, e.g. for progesterone receptor positive (PR+) disease, proline carriers were diagnosed 8 years earlier than serine carriers. Genotype-specific associations with risk of developing specific molecular subtypes of breast cancer were observed, i.e. serine carriers were twice as likely to develop estrogen receptor positive (ER+) and PR+ disease. Furthermore, carrying the proline isoform also correlated with higher risk of recurrence of breast cancer and shorter time to recurrence. Immunohistochemical evaluation of breast microarrays showed that GRM1 expression is higher in breast cancers as compared to normal tissue and is higher in ER+ as compared to ER- breast cancers. This parallels higher expression observed in ER+ breast cancer cells lines in comparison to ER- lines. In vitro studies with breast cancer cell lines were also performed to evaluate the expression of GRM1 as a function of hormone exposure and cell line receptor status. Treatment of ER+ cell lines with estradiol resulted in increased GRM1, while tamoxifen decreased expression. Gene expression data on ER+ breast cancers treated with tamoxifen were reanalyzed for association between GRM1 expression and recurrence. Analysis of breast cancers treated with tamoxifen from an independent cohort demonstrated that high expressors of GRM1 have a worse distant recurrence free survival. The results of these studies implicate GRM1 in hormone receptor positive breast cancer biology. Additional knowledge regarding the interaction between GRM1 and hormone signaling could have significant implications in breast cancer risk, prevention, and 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 81. doi:1538-7445.AM2012-81
Abstract 821: Developing a molecular understanding of non small cell lung cancer (NSCLC) resistance to platin-taxane chemotherapy
Authors: Dalvi Maithili P. , Behrens Carmen , Suraokar Milind , Girard Luc , Xie Yang , Wistuba Ignacio , Minna John D. 
Published: August 2012

Abstract
Purpose: While chemotherapy has improved lung cancer patient survival, relapse rates after neoadjuvant or adjuvant chemotherapy (minimal residual disease settings) are high. This could be due to cancer cells acquiring resistance to therapy or selective survival of pre-existing resistant cells. The molecular basis for primary or acquired resistance to standard platinum doublet chemotherapies are unknown and their elucidation is necessary for developing curative therapy that can be personalized for each patient. Methods: 3 complementary approaches were used to explore mechanisms underlying NSCLC resistance to platin-taxane chemotherapy: A) NSCLC lines were exposed in vitro to cycles of paclitaxel + carboplatin to mimic clinical treatment and resistance validated with cell viability and colony formation assays. Genome wide mRNA expression profiles of resistant and parental lines were compared using Illumina arrays and qRT-PCR. B) A large dataset of clinically and molecularly annotated NSCLC tumor specimens obtained after no chemotherapy or neoadjuvant platin-taxane chemotherapy were subjected to mRNA microarray analysis. C) Lung cancer xenografts were treated with chemotherapy in vivo in mice and profiled for mRNA expression. Biostatistical and bioinformatics approaches were used to identify genes that are differentially expressed in resistant cells in these three settings, and their function studied using over-expression or shRNA mediated knockdown. Results: NSCLC lines H1299 and H1355 were treated in vitro with paclitaxel + carboplatin and showed progressive increases in resistance to chemotherapy (after 5 to 15 cycles) ultimately achieving 30 (H1299) or 60 fold (H1355) differences compared to parental cells. In addition, multiple single cell clones also demonstrated chemotherapy resistance. Resistant NSCLC strains were also resistant to platin+docetaxel and platin+pemetrexed combinations. Expression profiles revealed upregulation of ABCB1/MDR1, down regulation of epithelial-specific genes suggesting EMT, differences in expression of epigenetic modulators as well as cancer testis family of GAGE genes and many of these genes had expression correlated with recurrence after neoadjuvant chemotherapy and with poor survival. Resistance was only partially reversed by verapamil indicating that it can be only partly explained by MDR mechanisms. Mechanistic studies of genes identified by these three approaches provide opportunities for overcoming chemotherapy resistance and developing novel therapies for NSCLC. Grant support: UT-Lung SPORE (5 P50 CA70907-11) and DoD PROSPECT (W81XWH-07-1-0306)
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 821. doi:1538-7445.AM2012-821
Abstract 83: Differential regulation of PTEN in ERα positive and negative ovarian cancer cells during cisplatin induced apoptosis
Authors: Singh Mohan , Chaudhry Parvesh , Asselin Eric 
Published: August 2012

Abstract
The phosphatase and tensin homolog deleted on chromosome 10 (PTEN) tumor suppressor is a central negative regulator of the PI3K/AKT signaling cascade and suppresses cell survival as well as cell proliferation. PTEN is found to be either inactivated or mutated in various human malignancies. In the present study we have investigated the regulation of PTEN levels during cisplatin induced apoptosis in estrogen receptor alpha (ERα) positive (OVCAR-3 and SKOV-3) and negative (A2780 and A270-CP) ovarian cancer cell lines. Cells were treated with 10μM cisplatin for 24hrs. Transcript and protein levels were analysed by reverse transcriptase-polymerase chain reaction (RT-PCR) and western blotting, respectively. The results showed that PTEN levels were significantly decreased in ERα-negative A2780 cells at both the transcript and protein levels; however, there was no change in PTEN levels in ERα-positive cells and cisplatin resistant cells (A2780-CP) in the presence of cisplatin. The decrease in PTEN was accompanied with an increase in the levels of Akt phosphorylation in A2780 cells. Cisplatin treatment induced the activation of caspase-3, -7, -8, -9 and cleavage of Parp in all the cell lines tested in the study except A2780-CP cells. In A2780 cells, restoration of PTEN levels was achieved upon pre-treatment with Z-VAD-fmk (caspase inhibitor) and not with MG132 (proteasome inhibitor), suggesting that, in addition to the regulation of PTEN at transcript level, caspases are also involved in the decrease of PTEN protein levels in A2780. The decrease in pro-apoptotic PTEN levels both at the transcriptional and post-translational levels and increase in survival factor pAkt in ERα-negative ovarian cancer cells suggest that cisplatin treatment could further exacerbates drug resistance in ERα-negative ovarian cancer 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 83. doi:1538-7445.AM2012-83
Abstract 834: Inhibition of Gli1 results in altered c-jun activation, inhibition of cisplatin-induced up-regulation of ERCC1, XPD, and XRCC1, and inhibition of platinum-DNA adduct repair
Authors: Gavin Elaine J. , Kudo Kenji , Das Shamik , Amable Lauren , Shevde Lalita A. , Reed Eddie 
Published: August 2012

Abstract
The transcription of ERCC1 and other nucleotide excision repair genes is strongly influenced by c-jun. C-jun is transcriptionally regulated by Gli proteins of the Hedgehog pathway. We therefore studied the possible relationships between Gli1, c-jun, and the upregulation of ERCC1, XPD, and XRCC1 in cisplatin-resistant human ovarian cancer cells. We studied the paired human ovarian cancer cell lines A2780 and A2780-CP70. We used a shRNA construct that specifically degrades Gli1 message; which has been previously published by one of the co-authors (Shevde-Samant et al., 2009). Genes we assessed for mRNA and/or protein levels included: c-jun, ERCC1, XPD, XRCC1, Gli1, Gli2, SHH, IHH, GAPDH, and β-tubulin. Platinum-DNA adduct repair was assessed by atomic absorbance spectrometry with Zeeman background correction. Use of the anti-Gli1 shRNA in cisplatin-resistant cells, resulted in a block of the cells’ ability to up- regulate genes in response to cisplatin treatment, including: c-jun, ERCC1, XPD, and XRCC1. This block in upregulation of c-jun was concurrent with a change in the phosphorylation pattern of the c-jun protein, shifting that pattern from a Ser63/73 dominant pattern, to a Thr91/93 dominant pattern. A2780-CP70 cells were treated at their cisplatin IC50, and DNA repair was assessed after pretreatment with anti-Gli1 shRNA or scrambled shRNA control. Control cells repaired 78% of platinum-DNA adducts at 12 hours; compared to 33% repair in cells pretreated with anti-Gli1 shRNA; a 2.4 fold difference. Pretreatment of A2780-CP70 cells with anti-Gli1 shRNA resulted in supra-additive cell killing with cisplatin; shifting the cisplatin IC50 from 30 µM to 5 µM. Pretreatment of these cells with cyclopamine, did not shift the cisplatin IC50. We conclude that the transcriptional protein Gli1 is important in the upregulation of these three DNA repair genes in human ovarian cancer cells. And that Gli1 thereby strongly influences platinum-DNA adduct repair, and cellular sensitivity to cisplatin. This Gli1 role has c-jun as an intermediate in the pathway.
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 834. doi:1538-7445.AM2012-834
Abstract 838: A metabolomic analysis revealed the involvement of deoxycytidine kinase and CTP synthase in the sensitivity of human pancreatic cancer cells to gemcitabine
Authors: Nishi Koji , Fujimura Yurika , Nishimuta Akito , Sugimoto Masahiro , Soga Tomoyoshi , Tanigawara Yusuke 
Published: August 2012

Abstract
Gemcitabine (GEM), a pyrimidine nucleoside analogue, is used in patients with pancreatic cancer as the standard chemotherapeutic agent. However, pancreatic cancer cells often show resistance to GEM in vivo and vitro. In this study, we explored the factors involved in the sensitivity of GEM in human pancreatic cancer cells, Miapaca-2 and AsPC-1, by a metabolomic analysis using capillary electrophoresis time-of-flight mass spectrometry (CE-TOFMS). The sensitivity of Miapaca-2 (IC50: 66 nM) to GEM was higher than that of AxPC-1 (IC50: 16 nM), whereas there were little differences in the growth rates of these cells. This result indicates that the difference in the sensitivities between Miapaca-2 and AsPC-1 is not dependent on their growth rates. At 12 hr after adding GEM, intracellular level of GEM in Miapaca-2 was higher than that in AsPC-1, whereas levels of GEM monophosphate, diphosphate and triphosphate in Miapaca-2 were lower than that in AsPC-1. In addition, expression level of deoxycytidine kinase (dCK), which catalyzes the reaction from GEM to GEM monophosphate, in Miapaca-2 was lower than that in AsPC-1. Expression levels of human equilibrium transporter (hENT1), which is known to major transporter of GEM, were similar in both cells. These results suggest that dCK is rate-limiting enzyme in GEM phosphorylation and one of the factors involved in the sensitivity. In pyrimidine metabolism, GEM was observed to inhibit CTP synthase, which converts UTP to CTP, resulting increase in UTP level, decrease in CTP level and depletion of dCTP in both cells at 12 hr after adding GEM. The degree of increase in UTP and decrease in CTP was lower in Miapaca-2 than that of AsPC-1. Indeed, the ratio of UTP to CTP in Miapaca-2 was about 2.5, whereas that of AsPC-1 was about 11. In addition, the expression level of CTP synthase in Miapaca-2 was higher than that in AsPC-1. Ribonucleotide reductase, which catalyzes the conversion of CDP to dCDP, is known to be inhibited by GEM diphosphate and be involved in the sensitivity of pancreatic cancer cells to GEM. GEM decreased CDP in AsPC-1. This may be caused by inhibiting CTP synthase. Expression level of ribonucleotide reductase in Miapaca-2 was higher than that in AxPC-1. Therefore, ribonucleotide reductase also may be involved in the sensitivity to GEM. Furthermore, we previously found that GEM mainly inhibited CTP synthase in pyrimidine metabolism, resulting in depletion of dCTP. Our current study suggests that dCK, CTP synthase and ribonucleotide reductase are involved in the sensitivity of pancreatic cancer cells to GEM.
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 838. doi:1538-7445.AM2012-838
Abstract 84: Evidence supporting a role of FKBP51 in melanoma pathogenesis
Authors: Srivastava Sanjeev K. , Arora Sumit , Bhardwaj Arun , Scammell Jonathan G. , Owen Laurie B. , Grizzle William E. , Singh Ajay P. , Singh Seema 
Published: August 2012

Abstract
Melanoma accounts for the majority of skin tumor-related deaths worldwide. The tumors originate from melanocytes and are associated with risk factors such as ultraviolet radiation exposure, fair skin type, and predisposing gene mutations. Although there has been some progress in early melanoma diagnosis, current therapeutic modalities still fail frequently in treating this deadly malignancy once it has metastasized. FKBP51 is a high molecular weight FK506-binding protein involved in the regulation of diverse biological processes. Importantly, it has been shown to be overexpressed in melanoma, activate anti-apoptotic NF-kB signaling, and inhibit apoptosis in irradiated melanoma cells. In this study, we investigated the role of FKBP51 in melanoma pathogenesis in a set of in vitro experiments. FKBP51 was stably repressed in two metastatic melanoma cell lines, A375-SM and FEMX-1, through short-hairpin RNA (shRNA)-mediated silencing and its effect on melanoma phenotype was examined. Silencing of FKBP51 led to a decrease in growth, clonogenicity, motility and invasiveness of both the melanoma cell lines, whereas enhanced cell-cell interaction was observed. Immunoblot analysis demonstrated loss of mesenchymal markers N-cadherin, vimentin, Slug and Snail and gain of epithelial marker, E-cadherin in FKBP51-silenced A375-SM and FEMX-1 cells, indicating a role of FKBP51 in epithelial to mesenchymal transition (EMT) of melanoma cells. Interestingly, in FKBP51-silenced melanoma cells, we also observed a decreased production of interleukin-8 (IL-8/CXCL-8), a chemokine that has earlier been shown to promote melanoma growth, metastasis and angiogenesis. Altogether, these studies provide experimental evidence for a functional role of FKBP51 in altered growth and malignant behavior of the melanoma 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 84. doi:1538-7445.AM2012-84
Abstract 842: Proteomics-based comparative analysis of mitochondria isolated from human cisplatin-sensitive and resistant ovarian carcinoma cell lines
Authors: Chappell Nicole P. , Teng Pang-ning , Hood Brian L. , Hamilton Chad A. , Maxwell G. Larry , Conrads Thomas P. 
Published: August 2012

Abstract
Epithelial ovarian cancer (EOC) is the leading cause of death among women with gynecologic malignancies and the fifth leading cause of cancer death in women in the United States. Cisplatin is one of the most effective and active agents in the treatment of advanced EOC, however, development of chemoresistance is a major obstacle. A recurrent theme is emerging that mitochondria and mitochondrial dysfunction are centerpiece in contributing to an aggressive carcinogenic phenotype. Similarly, we hypothesized that changes in the mitochondrial proteome are required to support development of cisplatin resistance in human EOC. We applied an organellar proteomics approach to elucidate quantitative alterations in protein abundance in mitochondria enriched from an isogenic pair of cisplatin sensitive (A2780) and resistant (A2780-CP20) human EOC cells. Protein isolates from mitochondria were analyzed by high resolution liquid chromatography-tandem mass spectrometry (LC-MS/MS) and quantitative determination of changes in the relative abundance level of identified proteins was accomplished by spectral counting. This analysis confirmed that there are substantial alterations in the mitochondrial proteomic composition in cisplatin resistant EOC cells. Differential proteins selected for western blot validation include hypoxia up-regulated protein 1 (HYOU1), activated leukocyte cell adhesion molecule (ALCAM), isoform 1 of dynamin-like 120kDa protein (OPA1), A kinase anchoring protein 12 (AKAP12), and ferredoxin reductase (FDXR). Our proteomic analysis demonstrated overexpression of HYOU1, ALCAM, AKAP12, and OPA1 in the resistant EOC cells. This panel of protein candidates have been implicated in other tumor types and are involved in relevant cell mechanisms to include evasion of apoptosis, increased tumor invasiveness, tumor hypoxia, cellular respiration, and mitochondrial fragmentation.
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 842. doi:1538-7445.AM2012-842
Abstract 854: Patient stratification strategies for NVP-BGJ398, a selective pan-FGFR inhibitor in phase I clinical trials
Authors: Porta Diana Graus , Guagnano Vito , Stamm Christelle , Woehrle Simon , Kauffmann Audrey , Yao Yao , Brümmendorf Thomas , Bordas Vincent , Douget Mickaël Le , Zhang Yun , Chen Zhi , Ito Moriko , Li Fang , Monahan John , Gaither Alex , Borawski Jason , Wilson Christopher J. , Venkatesan Kavitha , Hofmann Francesco , Sellers William 
Published: August 2012

Abstract
The mammalian fibroblast growth factor/fibroblast growth factor receptor (FGF/FGFR) family comprises 22 FGF ligands, which exert their action through 4 highly conserved transmembrane tyrosine kinase receptors (FGFR1, FGFR2, FGFR3 and FGFR4). This highly complex signaling network regulates fundamental developmental pathways and physiological processes in the adult organism. A growing body of evidence linking deregulation of the FGF/FGFR system, as a consequence of genetic alterations, to the pathogenesis of cancer makes these receptors attractive targets for therapeutic intervention. To this purpose we have developed NVP-BGJ398, an orally bioavailable, selective pan-FGFR kinase inhibitor which is currently in clinical Phase I dose escalation trial. In order to preclinically identify and validate patient stratification biomarkers that accurately predict for response to NVP-BGJ398 in the clinic, we have utilized the Cancer Cell Line Encyclopedia (CCLE). The CCLE is a collection of almost 1000 cancer cell lines representing multiple tumor types that, in a collaborative effort between The Novartis Institutes for BioMedical Research and the Broad Institute, has been comprehensively annotated in terms of genome-scale mRNA expression, gene copy number alterations and gene mutations (http:/www.broadinstitute.org/ccle). In addition, over half of these cell lines were subjected to high-throughput cell viability assays in the presence NVP-BGJ398, with the aim of generating cell line sensitivity data. Here we show the validation of predictive biomarkers of response in primary human tumor xenografts, revealed through the analysis of the CCLE, as well as the identification of potentially new indications for NVP-BGJ398.
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 854. doi:1538-7445.AM2012-854