bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A29: The Notch ligand Jagged2 promotes metastasis through a GATA3/miR-200 regulatory loop
Authors: Yang Yanan , Ahn Young-Ho , Gibbons Don L. , Zang Yi , Lin Wei , Thilaganthan Nishan , Moreira Daniel C. , Creighton Chad J. , Goodall Gregory J. , Kurie Jonathan M. 
Published: May 2012

Abstract
Metastatic disease originates from populations of tumor cells that have the propensity to undergo epithelial-to-mesenchymal transition (EMT), but the signals that initiate EMT in these cells have not been fully defined. Here we addressed this question in mice that develop metastatic lung adenocarcinoma owing to expression of mutant K-ras and p53. We found that metastases arose from a population of tumor cells that had high expression of Notch ligands. Jagged2 promoted EMT by a Notch-dependent suppression of microRNA-200 (miR-200), a family of miRs that negatively regulates ZEB transcriptional repressors. We identified an upstream miR-200 promoter element that is a direct target for GATA3 and, reciprocally, GATA3 mRNA sequences that are direct targets for miR-200, indicating that a double-negative feedback loop tightly controls the levels of GATA3 and miR200. Abrogating miR-200 suppression through knockdown of JAG2 or GATA3 blocked metastasis. In conclusion, Notch promotes metastasis by activating a GATA3/miR-200 regulatory loop.
Citation Information: Cancer Res 2009;69(23 Suppl):A29.
Abstract A35: Tyrosine kinase inhibitors block PDGFR-β signaling and suppress growth in malignant endothelial cells
Authors: Marley Kevin , Helfand Stuart C. 
Published: May 2012

Abstract
Tyrosine kinase inhibitors (TKIs), including imatinib and dasatinib, have shown remarkable efficacy in controlling chronic myelogenous leukemia and gastrointestinal stromal tumors. Their role in treating other solid tumors is less clear. We are investigating the potential to control malignant endothelial cell (EC) growth with TKIs using a spontaneous canine hemangiosarcoma (HSA) model. Canine HSA is a highly malignant EC cancer with cellular features reminiscent of primitive endothelium. Controlling HSA cell growth has implications for improved outcomes of human and canine patients affected with EC cancer as well as for design of antiangiogenic strategies. We evaluated the effects of imatinib and dasatinib on constitutive tyrosine phosphorylation of platelet derived growth factor receptor-beta (PDGFR-β) that we previously determined to be abnormal in HSA cell cultures. Further, we correlated effects of these TKIs on HSA proliferation in vitro to determine if abnormal activation of PDGFR-β contributes to the HSA malignant phenotype. Dasatinib was approximately ten-fold more potent than imatinib in suppressing HSA cell growth. Dasatinib (100 nM) rapidly abrogated signal from full length and a possible truncated form (120 kDa) of phospho-PDGFR-β. Cells with constitutive activation of PDGFR-β also showed tyrosine phosphorylation of extracellular related kinase-1 (ERK-1), ERK-2, and Src suggesting these could be downstream partners of PDGFR-β in aberrant HSA signaling. Dasatinib markedly suppressed phosphorylation of Src in HSA cells. Taken together; these data suggest that tyrosine kinase inhibitors may affect endothelial cell growth in malignancy by blocking PDGFR-β or its downstream signaling partners.
Citation Information: Cancer Res 2009;69(23 Suppl):A35.
Abstract A37: Mechanistic study involving antiproliferative effect of Etoricoxib, a highly selective COX-2 inhibitor on human cancer cell lines
Authors: Tripathi Shweta , Chandna Sudhir , Dwarkanath B.S. , Saluja Daman , Chopra Madhu 
Published: May 2012

Abstract
Introduction: Cyclooxygenase (COX), also known as prostaglandin endoperoxidase or prostaglandin G/H synthase, is a rate limiting enzyme involved in the conversion of arachidonic acid to prostaglandins. Two forms of cyclooxygenase, COX-1 and COX-2, have been identified. COX-1 is constitutively expressed in many tissues, while COX-2 is an inducible enzyme involved in inhibition of apoptosis, potentiation of cell growth and angiogenesis and as such is a target for drug development. Recently clinical, cellular and animal experimental studies have indicated its relevance to tumor invasion and metastasis. Etoricoxib is a novel non-steroidal anti-inflammatory drug (NSAIDs) that stops the production of inflammatory prostaglandins, without stopping the production of prostaglandins that protect the stomach and intestine. There is persuasive evidence that COX-2 inhibitors suppress tumor growth due to their ability to inhibit cell proliferation and induce apoptosis. The purpose of this study was to elucidate the mechanism of action by which Etoricoxib induces the arrest of Human cervical tumor cells growth.
Methods: Cell viability was measured by MTT assay and trypan blue exclusion method. Apoptosis was examined by DNA fragmentation and Comet Assay and the distribution of cells in the cell cycle was estimated by flow cytometry. Western blotting was used to explore various mechanisms of Etoricoxib induced apoptosis.
Results: Etoricoxib in the concentration range of 100–200 µM was 2–3 fold more cytotoxic (MTT assay) in the tumorigenic cell lines HeLa (cervical COX-2 positive), C-33A (cervical COX-2 negative), U-87, MCF-7, Hep3B, MiaPaCa-2 as compared to the non-tumorigenic cell lines (Cos-7, NIH3T3, HEK). These results correlated well with the observations on inhibition of cell growth and were comparable to the results reported for Celecoxib, another COX-2 selective inhibitor. Interestingly, Methotrexate widely used anticancer agent, showed 70–80% cytotoxicity in the non tumorigenic cell lines as compared to only 20% cytotoxicity with etoricoxib, suggesting thereby that it is selectively toxic to tumor cells unlike many other anticancer drugs. Comet assay results in HeLa cells showed a dose and time dependent increase in DNA damage suggestive of drug induced DNA damage at early times, followed by apoptotic DNA fragmentation and necrotic DNA degradation at later times. Western blotting results confirms the downregulation of the NF-κB pathway. In conclusion this study shows that in the human cervical cancer cell lines, HeLa & C33A, Etoricoxib suppresses proliferation, induces apoptosis and causes cell death by DNA damage in both Cox-2 dependent as well as independent pathway.
Citation Information: Cancer Res 2009;69(23 Suppl):A37.
Abstract A39: An oncogenomics-based in vivo cDNA screen pinpoints coamplified Ccnd1 and Fgf19 as therapeutic targets for liver cancer
Authors: Sawey Eric T. , Cai Chunlin , Bakleh Amy , Liu Qing , Lowe Scott W. , Powers Scott 
Published: May 2012

Abstract
Human cancer genome profiling is becoming increasingly effective at revealing novel recurrent genomic aberrations, but it remains challenging to identify the underlying driver genes. Here we describe an oncogenomic cDNA screen used to identify genes involved in liver tumorigenesis. Using array CGH analysis, we first identified recurrent focal amplicons present in hepatocellular carcinoma (HCC). Next, we assayed their tumorigenic potential by introducing pools of cDNAs corresponding to genes found in focal amplicons into sensitized liver progenitor cells. We identified 18 genes that promote tumor formation, including known oncogene Ccnd1 and co-amplified Fgf19, which we show cooperate during tumorigenesis. These two closely linked genes are co-amplified and co-overexpressed in 15% of human HCC. Knockdown of either Ccnd1 or Fgf19 inhibited colony formation of amplified human HCC cell lines and inhibited tumorigenicity. Knockdown in non-amplified human cell lines was without phenotypic effect. Downstream analysis revealed that FGF-19 leads to the activation of β-catenin and increased levels of CyclinD1. These results show that gene amplification predicts response to both Ccnd1 and Fgf19 inhibition, and that oncogenomic cDNA screens are an effective new tool to identify therapeutic strategies that are directly linked to cancer genotypes.
Citation Information: Cancer Res 2009;69(23 Suppl):A39.
Abstract A40: Six1 is dependent on its coactivator Eya2 to mediate tumor progression in the MCF7 mammary carcinoma cell line
Authors: Farabaugh Susan M. , Welm Alana L. , Ford Heide L. 
Published: May 2012

Abstract
The homeobox transcription factor Six1 is a critical mediator of embryonic development. In adults, upregulation of Six1 has been associated with a number of cancers where it not only promotes proliferation and survival, contributing to tumorigenesis, but also upregulates the TGFβ pathway, brings about an EMT-like transformation, and promotes metastasis. The Eya coactivator family is critical for Six1-mediated transcriptional activation in development. Our research is aimed at identifying what role the Eya family plays in Six1-mediated breast cancer progression. Examination of publicly available microarray data sets revealed that although high levels of Six1 significantly correlates with a shortened time to metastasis in breast cancer patients, presence of the Eya1-Six1 or Eya2-Six1 transcriptional complex correlates with a further reduced time to metastasis as well as with a significant decrease in survival time in breast cancer patients. Utilizing Six1 overexpressing MCF7 breast carcinoma cells with stable knock down of Eya2, we have found that lack of Eya2 reverses Six1-induced upregulation of the TGFβ pathway. Additionally, most Six1-induced EMT properties, including increased β-catenin responsive transcription and increased levels of the mesenchymal marker Fibronectin, were reversed with loss of Eya2. Overall, these data implicate Eya2 as a critical coactivator that is necessary for most of the metastasis-associated properties induced by Six1. Thus, as Six1 and Eya are not normally expressed in most adult tissues, the Six1-Eya interaction may be a valuable future drug target whose inhibition should result in limited side effects while potently targeting the tumor and its associated metastases.
Citation Information: Cancer Res 2009;69(23 Suppl):A40.
Abstract A41: Impact of vitamin D receptor and the vitamin D hydroxylase CYP27B1 on morphology and gene expression in the mouse mammary gland
Authors: Matthews Donald G. , Lloyd-Coronado Teresa M. , Welsh JoEllen 
Published: May 2012

Abstract
Multiple epidemiological studies have demonstrated correlations between vitamin D status and incidence of many types of cancer, including colon and breast. Our long term goal is to understand the mechanisms by which the vitamin D signaling pathway impacts on breast cancer. Upon absorption or endogenous synthesis, vitamin D is metabolized into 25-hydroxyvitamin D (25D) and 1,25-dihydroxyvitamin D (1,25D) in multiple tissues. 1,25D is a high-affinity ligand for the nuclear vitamin D receptor (VDR) that alters gene expression and inhibits growth of normal and transformed mammary cells. However, 25D and other steroid-like compounds such as bile acids, can also activate VDR in vitro. Although studies with VDR knockout (KO) mice have demonstrated that VDR affects proliferation, differentiation and apoptosis in the mammary gland, the specific ligands that trigger VDR signaling in mammary tissue have yet to be identified. Generation of 1,25D from 25D is mediated by the mitochondrial enzyme CYP27B1 (also known as 25-hydroxyvitamin D 1α-hydroxylase) which is present and developmentally regulated in mammary gland. Studies with the VDRKO mouse have formally established that its phenotype is different from mice lacking CYP27B1, supporting the concept that other VDR ligands exist, and/or that the VDR may act in the absence of ligand. In our studies, we are using animal models to determine whether VDR exerts 1,25D-independent effects on growth, apoptosis or differentiation of mammary epithelial cells in vivo. Glands from VDRKO and CYP27B1KO mice during puberty, pregnancy, lactation, involution and aging have been collected for analysis of gross morphology, histology, and genomic profiling in comparison to age-matched control mice. Our data indicate that mammary glands from VDRKO mice display accelerated branching, enhanced sensitivity to estrogen and progesterone and altered gene expression during puberty and early pregnancy. Surprisingly, initial studies indicate that similar changes are not observed in glands from CYP27B1KO mice, suggesting that 25D or other VDR ligands may substitute for 1,25D in control of mammary cell turnover in vivo. Alternatively, our results are consistent with the concept that unoccupied VDR may function in the mammary gland. To further explore the role of VDR and CYP27B1 in the glandular epithelial compartment, mice with mammary epithelial-specific deletion of VDR or CYP27B1 were generated by crossing MMTV-cre mice with mice carrying floxed alleles of VDR or CYP27B1. Quantitation of VDR and CYP27B1 expression in mammary gland, and characterization of the phenotype of these cre-flox mouse strains is in progress. Collectively, these studies have identified novel roles for the VDR and its ligands in mammary gland development that provide insight into the relationship between vitamin D status and breast cancer. Supported by NIH CA69700.
Citation Information: Cancer Res 2009;69(23 Suppl):A41.
Abstract A42: Small molecule activators of p53 for the treatment of inflammatory breast cancer
Authors: Chatterjee Namita , Ensslin Courtney J. , Tenniswood Martin P. 
Published: May 2012

Abstract
Although rare, inflammatory breast cancer (IBC) is the most aggressive form of breast cancer with a 5 year survival of 40% compared to 85% for ductal carcinoma in situ. The standard therapy for this disease is chemo- and radiation therapy; however there are currently no targeted therapies for IBC. Histopathology data suggests that 40–70% of IBC tumors express wild type p53, while approximately 40% are estrogen receptor positive (ER+). The disease is characterized by early and diffuse intravasation of the breast lymphatic vessels by the tumor cells which form emboli that block the drainage of the ducts leading to swelling of the affected breast and erythema. Efforts to increase survival from this often lethal disease have been hindered by the paucity of model systems for studying the underlying biology of IBC. We have used the SUM 149PT and SUM 190PT cell lines, which were originally derived from IBC to investigate the utility of two histone deacetylase (HDAC) inhibitors (CG-1521 and TSA), alone and in combination with anti-estrogens as a novel therapy for the disease. In prostate cancer cell lines CG-1521 has been shown to acetylate p53 at Lys 373 and induce cell death, while TSA induces specific acetylation of Lys382 and induces cell cycle arrest. Both SUM 149PT and SUM 190PT express ERα and ERβ, although neither cell line requires estradiol for cell growth. SUM149PT cells express wild type p53, while the SUM 190PT express a truncated isoform of the protein. CG-1521 induces DNA fragmentation and cell death in both cell lines. While TSA also induces cell death in the SUM 149PT cells, it only induces cell cycle arrest in the SUM 190PT cells, which we attribute to the truncation of the p53 protein. Treatment of SUM149PT cells with low doses of either tamoxifen or CG-1521 individually does not induce apoptosis but in combination, causes a substantial decrease in cell number and indicates that the two compounds act synergistically in this context. These data suggest that HDAC inhibitors such as CG-1521 and TSA, which target specific Lys residues in p53 may be useful for the treatment of IBC.
Citation Information: Cancer Res 2009;69(23 Suppl):A42.
Abstract A50: Interleukin-1β induced HIF-1α transcriptional activity in glioma cells is regulated by Ras via NFκB
Authors: Sharma Vivek , Koul Nitin , Mehta Veer Singh , Sen Ellora 
Published: May 2012

Abstract
Purpose: We observed elevated levels of the pro-inflammatory cytokine IL-1β in glioblastoma multiforme (GBM) tumor samples. Since Hypoxia-inducible factor-1α (HIF-1α) plays a crucial role in linking inflammatory and oncogenic pathways, we investigated the effect of IL-1β on HIF-1α expression in glioma cells under normoxia.
Experimental Procedures: Cytokine bead array was performed to determine the status of pro-inflammatory cytokine IL-1β in control and GBM human tissues. The effect of IL-1β on HIF-1α expression and transcriptional activity in glioma cell lines was determined by immunoblotting and reporter assay. The pathways involved in IL-1β mediated HIF-induction was determined by examining NFκB transcriptional activity and Ras activity, siRNA and immunoblotting blotting. To dissect the existence of autocrine loop between IL-1β and HIF-1α Chromatin immunoprecipitation (ChIP) assay was performed.
Results and Conclusions: IL-1β levels were elevated in GBM tissue compared to adjacent normal tissue as assessed by cytokine bead array. IL-1β induced HIF-1α expression and transcriptional activity in glioma cells under normoxia. Antagonizing of IL-1β signaling by blocking MyD88 activation downstream of the IL-1R or direct NFκB inhibition abolished HIF-1α activity, indicating a role of IL-1β induced NFκB in HIF-1α regulation. IL-1β mediated increased Ras activity is responsible for increased HIF-1α activity as down regulation of Ras resulted in a significant reduction in both NFκB and HIF-1α of IL-1β activity. These results implicate Ras as an upstream mediator of IL-1β induced NFκB and HIF-1α activation. Increased Ras expression was accompanied by increased phosphorylation of Ras effectors AKT, ERK, JNK and p38MAPK. However, inhibition of these effectors failed to block IL-1β mediated increase in HIF-1α induction. Interestingly, IL-1β elevated Wnt-1 expression in a Ras dependent manner and siRNA mediated knock-down of Wnt-1 decreased HIF-1α activity. Although Wnt-1 mediated HIF-1α was independent of the canonical Wnt/β-catenin signaling pathway, it regulated HIF-1α through NF-κB. IL-1β induced HIF-1α expression resulted in its increased interaction with HIF responsive element (HRE) on the IL-1β promoter, as demonstrated by chromatin immunoprecipitation (ChIP) assay.
Conclusions: Our studies suggest that under normoxia, IL-1β induced IL-1β HIF-1α autocrine loop establishes a vicious cycle of IL-1β secretion and HIF-1α stabilization.
Citation Information: Cancer Res 2009;69(23 Suppl):A50.
Abstract A51: Development and initial characterization of isogenic cell lines stably overexpressing prostate cancer candidate genes
Authors: Kacprzyk Lukasz , Blaich Stephanie , Wittig Rainer , Hudler Melanie , Sültmann Holger , Mollenhauer Jan 
Published: May 2012

Abstract
Microarray analyses of global changes in gene expression patterns have recovered a large number of genes, which are deregulated in prostate cancer, when compared to normal prostate tissue. In order to successfully translate these data into clinical intervention strategies, it is crucial to determine genes that truly contribute to tumor development (which may be referred to as ‘driver genes’) and to separate them from the majority of secondary anomalies in expression levels (‘passenger genes’). To obtain the missing functional information, we construct isogenic cell line libraries derived from commonly used prostate (RWPE-1) and prostate cancer (LNCaP, PC-3) cell lines and subject them to a range of functional assays.
Using a system for rapid generation of stably-transfected isogenic cell lines, that was developed in our group, we create a prostate cancer library in a two-step procedure. At first, acceptor clones are generated from cancer and normal prostate cell lines by stable integration of a plasmid carrying a recombinase target sequence. Incorporation of a second expression plasmid with the gene of interest is then mediated by site-specific recombination. This procedure allows a facilitated transgene integration into a predefined, transcriptionally active locus. It also minimizes the influence of genetic background, as clones generated within such a library differ among each other only by the presence of the gene of interest in the same chromosomal location. Therefore, in contrast to traditional knock-in strategies, our system ensures that readily interpretable phenotypes are obtained and thereby provides a highly standardized resource for functional gene analysis. The technology is well suited for medium throughput and was designed to link data from high-throughput genomic analyses with functional gene analysis in animal models.
LNCaP and PC-3 acceptor cell lines have been generated and characterized. Recombination of PC-3 with several well-described, cancer-relevant genes under the control of an inducible promoter indicated the feasibility of the method. The next step will include initial screening of the library of roughly 100 recombinants for changes in the cell viability and proliferation. The most promising effectors from the primary screen will be followed with an expanded range of functional assays, addressing their impact on cell cycle, apoptosis and cell migration. This can then serve as a starting point for an individual characterization of the novel prostate cancer genes.
Citation Information: Cancer Res 2009;69(23 Suppl):A51.
Abstract A56: Role of p63 in cell cycle progression in epidermis and in squamous cell carcinoma
Authors: Antonini Dario , Russo Monia T. , Missero Caterina 
Published: May 2012

Abstract
Genomic amplification and/or overexpression of the p63 gene are one of the most frequently observed abnormalities in human cutaneous and noncutaneous squamous cell carcinoma (SCC), however, in spite of several studies in genetically engineered mouse models and in human tumors, the contribution of p63 in SCC development is still controversial. As a member of the p53 family, p63 can bind to the canonical p53-binding site, transactivating or repressing a subset of p53 or p73 target genes in vivo, while it also affects a subset of specific target genes. In contrast to p53, p63, and more specifically its DeltaNp63 alpha isoform, has a tissue-restricted pattern of expression in stratified epithelia and its impact on tumorigenesis is likely to be tumor-specific as well.
Here we present data indicating that p63 is required for proliferation and G1 progression in a p53 independent manner in mouse primary keratinocyte, as well as in mouse embryonic epidermis. In addition we identified a number of p63 early target genes that are involved in cell cycle progression and in DNA replication. Among direct p63 targets we identified members of a specific microRNA (miRNA) family that are highly expressed in the epidermis. p63 binds to their genomic regulatory regions thereby directly repressing their expression. Overexpression of these specific miRNA arrests cell proliferation, whereas specific anti-miRNA expression substantially rescues the cell proliferation defect in p63 ablated keratinocytes. We propose that control of this specific miRNA family by p63 may play a role in sustaining cell proliferation in SCC development.
Citation Information: Cancer Res 2009;69(23 Suppl):A56.