bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5206: Role of CtBP1 as a transcriptional corepressor in prostate cancer.
Authors: Chakravarthi Balabhadrapatruni V. S. K. , Pathi Satya , Zheng Heng , Siddiqui Javed , Kunju Lakshmi P. , Palanisamy Nallasivam , Varambally Sooryanarayana 
Published: August 2014

Abstract
Background: C-terminal Binding Protein 1 (CtBP1), a transcriptional co-repressor that regulates the expression of tumor suppressors and genes involved in cell death, is known to play a critical role in multiple cancers. Earlier, we showed that CtBP1 is overexpressed in metastatic prostate cancer. Furthermore, our studies indicated a role for CtBP1 in conferring radiation resistance to prostate cancer cell lines. We also demonstrated the functional role of CtBP1 in regulating prostate cancer cell growth in vitro and tumor growth and metastasis in vivo.
Methods and Results: Our gene expression profiling and bioinformatics analysis found that multiple potential tumor suppressors are reactivated upon CtBP1 knockdown in multiple prostate cancer cell lines. We next validated these targets of CtBP1-mediated repression by qRTPCR and western blotting using CtBP1 stable knockdown prostate cancer cell lines, and in normal prostate epithelial PrEC cells overexpressing CtBP1. Our studies confirmed that CtBP1 targets multiple genes including SP8 transcription factor and kallikrein-related peptidase 10 (KLK10) among others. Knockdown of the reactivated gene led to a reversion of these cells to a more aggressive phenotype. Furthermore, our studies confirmed that the CtBP1 target genes are down-regulated in metastatic prostate cancer.
Conclusion: Taken together, our studies demonstrated that dysregulated expression of CtBP1 plays an important role in prostate cancer progression by down-regulating the expression of multiple potential tumor suppressor genes. Thus, targeting CtBP1 in aggressive prostate cancer may have clinical significance.
Citation Format: Balabhadrapatruni V. S. K. Chakravarthi, Satya Pathi, Heng Zheng, Javed Siddiqui, Lakshmi P. Kunju, Nallasivam Palanisamy, Sooryanarayana Varambally. Role of CtBP1 as a transcriptional corepressor in prostate cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5206. doi:10.1158/1538-7445.AM2013-5206
Abstract 5210: KPT-330, a selective small molecule inhibitor of nuclear export, is active in bone and soft tissue sarcoma.
Authors: Nair Jayasree S. , Tap William , Vasudeva Shyamprasad Deraje , Sicklick Jason K. , Kauffman Michael , Shacham Sharon , Schwartz Gary K. 
Published: August 2014

Abstract
KPT-330 is a small molecule Selective Inhibitor of Nuclear Export (SINE) that irreversibly block the major nuclear export protein CRM1 (exportin 1, XPO1). The Chromosome Region Maintenance 1 (CRM1) protein is responsible for the nuclear export of snRNAs and of proteins bearing a leucine-rich nuclear export signal (NES). This class of drugs is expected to induce forced nuclear accumulation of tumor suppressor proteins (TSPs) and is believed to initiate a ‘genome survey’ leading to the death of cancer cells with normal cells undergoing transient, reversible cell cycle arrest. Our effort was to investigate the effects of KPT-330 in sarcomas and the mechanism by which it exerts the effect of tumor suppression. Our data clearly shows KPT-330 as active against a broad panel of human bone and soft tissue sarcoma cell lines at low nanomolar concentrations. The effect was mainly due to the induction of apoptosis. Target specificity of the drug was confirmed by the decrease in CRM1 protein level. An induction of p53 and p21 protein levels was observed. However, the effect of apoptosis or inhibition in proliferation seems to be independent of p53 status of the cell line. The effect of KPT-330 was further tested in xenograft models using malignant peripheral nerve sheath (MPNST) and de-differentiated liposarcoma (LS141) cell lines. Tumor suppression was observed in both the sarcoma models and its target specificity was confirmed in the xenografts. KPT-330 may represent a new drug for the treatment of bone and soft tissue sarcoma.
Citation Format: Jayasree S. Nair, William Tap, Shyamprasad Deraje Vasudeva, Jason K. Sicklick, Michael Kauffman, Sharon Shacham, Gary K. Schwartz. KPT-330, a selective small molecule inhibitor of nuclear export, is active in bone and soft tissue sarcoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5210. doi:10.1158/1538-7445.AM2013-5210
Abstract 5217: Integrative sequencing reveals novel alterations in untreated and castration resistant prostate cancer.
Authors: Annala Matti J. , Waltering Kati K. , Ylipää Antti , Kartasalo Kimmo , Tuppurainen Kirsi , Karakurt Serdar , Latonen Leena , Saramäki Outi , Leppänen Simo-Pekka , Seppälä Janne , Rauhala Hanna E. , Tammela Teuvo LJ , Yli-Harja Olli , Zhang Wei , Visakorpi Tapio , Nykter Matti 
Published: August 2014

Abstract
Prostate cancer is the third most common source of male cancer deaths in developed countries. The standard of care for aggressive prostate cancer is androgen ablation, which prolongs survival until the tumor acquires a castration resistant phenotype. The molecular pathology underlying prostate cancer progression is not yet fully understood. We used integrative high throughput sequencing to study cancer-associated alterations in 53 prostate cancer related neoplasia at the DNA, RNA and epigenetic levels. The cohort included both hormone-naive and castration resistant prostate cancers, along with two neuroendocrine prostate cancers. We identified two new fusion genes, one of which associated with neuronal differentiation and castration resistance. We also identified a number of novel prostate cancer associated transcripts, including transcripts specific to castration resistant tumors. Based on ChIP-seq data from prostate cancer cell lines, many of the novel transcripts were regulated by known oncogenes such as ERG and AR. Methylation sequencing revealed a near-identical pattern of promoter hypermethylation in both hormone-naive and castration resistant tumors. Enrichment of hypermethylation was observed at EZH2 binding sites, supporting the role of EZH2 in the recruitment of DNA methyltransferase in prostate cancer. Promoter hypermethylation suppressed the expression of hundreds of genes, but a subset of genes characterized by promoter H3K27 trimethylation responded to hypermethylation with increased expression.
Citation Format: Matti J. Annala, Kati K. Waltering, Antti Ylipää, Kimmo Kartasalo, Kirsi Tuppurainen, Serdar Karakurt, Leena Latonen, Outi Saramäki, Simo-Pekka Leppänen, Janne Seppälä, Hanna E. Rauhala, Teuvo LJ Tammela, Olli Yli-Harja, Wei Zhang, Tapio Visakorpi, Matti Nykter. Integrative sequencing reveals novel alterations in untreated and castration resistant prostate cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5217. doi:10.1158/1538-7445.AM2013-5217
Abstract 522: The epithelial-mesenchymal transition-related transcription factor ZEB suppresses Claudin expression in breast cancer cells.
Authors: Arima Yoshimi , Hosonaga Mari , Saya Hideyuki 
Published: August 2014

Abstract
Triple-negative breast cancer (TNBC) is classified as a heterogeneous group, because TNBCs are defined as breast cancer negative for the estrogen receptor (ER), progesterone receptor, and human epidermal growth factor receptor 2 (HER2). We show that TNBC cell lines can be divided into those which express the repressor of transcription Zinc finger E-box binding homeobox 1 (ZEB1) and the tight junction protein claudin-1. ZEB1 has been identified as a key transcription factor eliciting epithelial-mesenchymal transition (EMT) and cancer progression. We found that knockdowns of ZEB1 in TNBC cells induce an epithelial-like morphology and induce the mRNA expression of claudin-1.&gt; The claudin family is the principal constituent of tight junctions in epithelial cells. We also found that ZEB1 binds to a claudin-1 promoter sequence by DNA-mediated pull-down assay. Furthermore, in breast cancer specimens, we observed a reciprocal expression of ZEB1 and claudin-1. These findings suggest that ZEB1 represses claudin-1 expressions in TNBCs. We then analyzed the association of clinical outcomes with ZEB1 and claudin-1 expressions by using a publicly available gene expression database of breast cancer patients. The overall survival rates in the category which tested positive for ZEB1 and claudin-1 is poor. To further characterize the effects of ZEB1-positive breast cancer cells on this phenotype of cancer, we investigated tumor formations following the co-inoculation of ZEB1-expressing MDA-MB-231 cells and claudin-1-expressing HCC1937 cells into nude mice. Although HCC1937 cells alone didn't form tumors in our orthotopic xenograft models, tumor formations were observed when the cells were mixed with MDA-MB-231 cells. These data suggest that the ZEB1-expressing breast cancer cells do promote tumorigenicity of claudin-1-positive cancer cells. We hypothesized that the heterogeneity on gene expressions within the tumor tissue is associated with malignancy and therapeutic resistance of breast cancers.
Citation Format: Yoshimi Arima, Mari Hosonaga, Hideyuki Saya. The epithelial-mesenchymal transition-related transcription factor ZEB suppresses Claudin expression in breast cancer cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 522. doi:10.1158/1538-7445.AM2013-522
Abstract 5225: Single-cell gene-expression programs and basal-like breast cancer.
Authors: Wang Chun-Chao , Jamal Leen , Bajikar Sameer S. , Atkins Kristen A. , Janes Kevin A. 
Published: August 2014

Abstract
Basal-like carcinoma is a subtype of breast cancer that is characterized by poor prognosis and high intratumor heterogeneity. In basal-like breast epithelia, we have identified two anticorrelated gene-expression programs that arise among single extracellular matrix (ECM)-attached cells during organotypic 3D culture. The first program contains multiple TGFβ-related genes including TGFBR3, and its heterogeneous induction is critical to suppress ductal branching. The second program contains JUND together with the basal-like marker, KRT5. Homogenizing JUND expression in single cells leads to 3D acini with bridged lumina that are similar to cribiform ductal carcinoma in situ. TGFBR3 and JUND together comprise a circuit that is interconnected via four negative-feedback loops. Computational modeling of the circuit predicts damped, antiphase oscillations upon stimulation with endogenous impulses of TGFβ-like ligand, and we directly observe these spontaneous responses in 3D culture by live-cell imaging. The TGFBR3-JUND circuit is remarkably conserved in early basal-like tumors that heterogeneously express KRT5, suggesting that asynchronous circuit dynamics are active in this patient subset. We further show that the circuit is strongly dependent on ECM engagement, as detachment leads to a rewiring that is triggered by RPS6 dephosphorylation and maintained by juxtacrine signaling from tenascin C. Breast tumor heterogeneity need not stem from partial basal-like differentiation and could instead reflect dynamic toggling of individual cells between expression states.
Citation Format: Chun-Chao Wang, Leen Jamal, Sameer S. Bajikar, Kristen A. Atkins, Kevin A. Janes. Single-cell gene-expression programs and basal-like breast cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5225. doi:10.1158/1538-7445.AM2013-5225
Abstract 5226: Understanding single cell variability in oncogene induced pathway aberration in lung cancer.
Authors: Deb Dhruba , Rajaram Satwik , Larsen Jill , Minna John , Wu Lani , Altschuler Steven 
Published: August 2014

Abstract
Progression of normal epithelial cells towards malignancy is marked by alteration in signaling pathways involved in cellular growth and development. However, at any given stage of oncogenic progression, it is unknown to what extent different signaling pathways are altered and whether the degree of signaling change is similar from cell to cell. A quantitative survey of signaling alterations that are associated with common oncogenic changes will allow us to connect the widely observed signaling heterogeneity in cancer to the genetic changes leading to its disease states.
Here, we study an isogenic series of human bronchial epithelial cells (HBECs) that have been oncogenically transformed with the sequential addition of common lung cancer mutations (p53null, p53null+KRASV12, p53null+KRASV12+c-myc). To quantify the degree of signaling alteration, we performed immuno-fluorescence assays and acquired images of HBECs stained with signaling markers representing important lung cancer pathways including WNT, JAK/STAT, TGFβ, IFNγ, MAPK, AKT and TNFα pathways. We extracted intensity-based features from individual cells using our in-house image analysis platform. This single-cell analysis revealed a high degree of signaling change within each of our HBEC populations, suggesting that signaling alteration can be different from cell to cell and from pathway to pathway.
We further quantified the degree of pathway alteration along our sequential oncogenic manipulations by using standard machine learning techniques. Our analysis revealed significant changes in the WNT, TGFβ and MAPK pathways upon oncogenic progression. Loss of p53 alone caused a major shift in TGFβ signaling; addition of mutant KRASV12 altered the MAPK, TNFα and JAK/STAT pathways; Addition of a third genetic manipulation, C-MYC, induced dramatic shifts in the WNT and IFNγ pathways. We are currently in the process of inferring crosstalk among multiple pathways in HBECs and a panel of ten lung cancer cell lines. Taken together, our results suggest that the degree of signaling alteration across diverse signaling pathways can be correlated with a specific oncogenic state in lung cancer.
Citation Format: Dhruba Deb, Satwik Rajaram, Jill Larsen, John Minna, Lani Wu, Steven Altschuler. Understanding single cell variability in oncogene induced pathway aberration in lung cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5226. doi:10.1158/1538-7445.AM2013-5226
Abstract 5227: Quantitative network models of signaling and drug response in melanoma.
Authors: Korkut Anil , Wang Weiqing , Molinelli Evan , Miller Martin , Kaushik Poorvi , Aksoy Arman , Sander Chris 
Published: August 2014

Abstract
Use of targeted drug combinations are potentially key to preventing emergence of resistance to initially successful single agents such as RAF inhibitors. Thus, systematic nomination of novel drug combinations is important to develop effective therapeutic strategies. Here, we present an experimental-computational network pharmacology method to infer quantitative signaling networks in tumor cells, predict response to perturbations, and ultimately, nominate targeted drug combinations that will generate a desired phenotypic response. We use a series of targeted drugs, singly or in combination to perturb cancer cells. We measure quantitative proteomic (total and phoshpo-protein levels) and phenotypic (e.g. cell viability, apoptosis, cell cycle progression) response profiles to perturbations. Proteomic responses are measured with the reverse phase protein array technology. Next, we infer quantitative network models, using the response profiles as training sets. Solution space of all network model configurations is prohibitively large and Monte Carlo based inference algorithms fail to generate accurate network models in sizes relevant for cancer biology. In order to solve the inference problem, we have adapted an iterative and probabilistic inference algorithm, belief propagation from statistical physics. Resulting network models are based on simple non-linear differential equations and quantitatively link signaling events to phenotypic changes. We have generated quantitative network models of signaling in RAF inhibitor resistant melanoma cell lines in sizes (i.e. ∼100 nodes) unreachable by other network inference algorithms. We have nominated novel combination therapies through combinatorial in silico perturbations of all nodes in derived networks and experimentally tested the predicted phenotypic responses.
Citation Format: Anil Korkut, Weiqing Wang, Evan Molinelli, Martin Miller, Poorvi Kaushik, Arman Aksoy, Chris Sander. Quantitative network models of signaling and drug response in melanoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5227. doi:10.1158/1538-7445.AM2013-5227
Abstract 5231: Highly conserved ceRNA regulatory interactions cooperate with genomic variability to modulate drivers of tumorigenesis.
Authors: Chiu Hua-Sheng , Yang Xuerui , Martínez María Rodríguez , Iyer Archana , Sumazin Pavel , Califano Andrea 
Published: August 2014

Abstract
MicroRNAs (miRs) have been repeatedly linked to tumorigenesis and tumor progression, suggesting their potential value as biomarkers and targets for therapeutic intervention. Recent evidence suggests that mRNAs compete for binding and regulation by a finite pool of miRs, thus regulating each other as competitive endogenous RNAs (ceRNAs). The extent of this new regulatory layer and its potential to alter the expression of cancer genes has been shown in several tumor types, but the actual impact of ceRNA interactions on disease remains unclear.
In this study, using TCGA (The Cancer Genome Atlas) tumor datasets, we provide evidence that ceRNA play an important role in tumor etiology. Leveraging millions of shRNA-mediated perturbations from LINCS (Library of Integrated Network-based Cellular Signatures), we extensively validated ceRNA interactions in breast and prostate cancer. Moreover, we identified over 160,000 ceRNA interactions that are conserved across tumor types despite being implemented by miR programs with tumor type-specific expression. We present evidence that these ultraconserved interactions are mechanistically responsible for the dysregulation of the majority of oncogenes and tumor suppressors through TCGA-profiled genomic alteration of their cognate ceRNA regulators. Using targeted biochemical validation in cell lines, we verified the potential of ceRNA regulators to target ESR1, an established oncogene and drug target in breast cancer, and APC, an established tumor suppressor in colon adenocarcinoma.
Our analysis suggests that ceRNA interactions are implemented through competition for multiple miRNAs, rendering them virtually independent of single miRNA kinetics and availability, and more likely to be conserved across contexts. Using TCGA samples, we demonstrated that conserved ceRNA interactions enable systematic identification of genomic alterations that contribute to aberrant expression of hundreds of cancer genes in each of eight distinct tumor contexts. We submit this network as a resource for analyzing ceRNA regulation in datasets where reverse engineering context-specific networks is infeasible due to low sample number or lack of miRNA expression profiles.
Citation Format: Hua-Sheng Chiu, Xuerui Yang, María Rodríguez Martínez, Archana Iyer, Pavel Sumazin, Andrea Califano. Highly conserved ceRNA regulatory interactions cooperate with genomic variability to modulate drivers of tumorigenesis. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5231. doi:10.1158/1538-7445.AM2013-5231
Abstract 5232: Salivary proteome as an in vivo model to study breast cancer progression.
Authors: Streckfus Charles F. 
Published: August 2014

Abstract
Background: To date, because of the complexity and heterogeneity of breast cancer, no individual model recapitulates all aspects of this disease. Since both the mammary and salivary glands are exocrine glands and that the literature has shown cross-talk between the two glands, we hypothesize that, secondary to breast cancer, the malignancy's rapid growth alters the proteomic content of the tissue microenvironment and that these changes may manifest in up or down regulation of salivary protein concentrations, which can be used as a sentinel body fluid for breast cancer modeling. Verification that salivary proteomic content can be used to model breast cancer progression employing HER2 biology would provide strong support for immediate translational testing in clinical trial settings that would further be accelerated with the use of saliva-based testing as one of the most easily accessible body fluids.
Objective: The objective of this study was to compare the salivary protein profiles of pooled saliva specimens from individuals diagnosed with ductal carcinoma of the breast with and without HER2/neu overexpression as a potential alternate to current HER2/neu assessment methodologies.
Methods: Pooled (n=10 subjects/pooled specimen) stimulated whole saliva specimens from women were analyzed. One pooled specimen was from healthy women, another was from women diagnosed with Stage IIa (T2N0M0) invasive ductal carcinoma (IDC) without positive HER2/neu receptor status. A third pooled specimen was from women diagnosed with Stage IIa (T2N0M0) IDC with a positive HER2/neu receptor status. Isotopically tagging proteins in the tumor groups and comparing them to the healthy control group measured differential expression of proteins. Experimentally, saliva from each of the pooled samples was trypsinized and the peptide digests labeled with the appropriate iTRAQ reagent. Labeled peptides from each of the digests were combined and analyzed by reverse phase (C18) capillary chromatography on an LC-MS/MS mass spectrometer equipped with an LC-Packings HPLC. Results: The results of the analyses yielded approximately 174 differentially expressed proteins in the saliva specimens. There were 20 proteins unique to HER2/neu positive receptor status and 28 proteins that were unique to HER2/neu negative status. Conclusions: The study suggests that saliva is a fluid suffused with solubilized by-products of oncogenic expression and that these proteins may be differently expressed in the presence of HER2/neu positive receptor status. It also provides support to the novel idea of using salivary secretions to study breast cancer progression
Citation Format: Charles F. Streckfus. Salivary proteome as an in vivo model to study breast cancer progression. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5232. doi:10.1158/1538-7445.AM2013-5232