bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2159: Targeting GRB7/ERK/FOXM1 signaling cascade is a promising therapeutic approach in ovarian cancer
Authors: Chan David W. , Ngan Hextan YS 
Published: August 2012

Abstract
Ovarian cancer is a higly mortal disease with poor prognosis and especially in high grade tumor. Emerging evidence has reported that aberrant upregulation and activation of GRB7, ERK as well as FOXM1 are closely associated with aggresivenesss of human cancers. However, the interplay between these factors in the pathogenesis of human cancers remains unclear. In this study, we found that GRB7 (P &lt; 0.0001), phospho-ERK1/2 (P &lt; 0.0001) and FOXM1 (P = 0.001) were overexpressed and associated with high grade ovarian cancers by immunohistochemical analysis. Intriguingly, the expressions of GRB7, phospho-ERK and FOXM1 showed a significant stepwise increase pattern along Grade 1 to Grade 3 ovarian cancer (P &lt; 0.001). Biochemical studies using western blot analysis demonstrated that enforced expression of GRB7 could elevate the expressions of phospho-ERK and FOXM1, while enforced expression of FOXM1 could not alter levels of GRB7 and phospho-ERK. However, inhibition of ERK signaling by U0126 or PD98059 reduced the level of FOXM1 in GRB7-overexpressing ovarian cancer cells, suggesting that GRB7, ERK and FOXM1 are regulated orderly. Moreover, inhibition of ERK activity by U0126 or decreased FOXM1 expression by thiostrepton significantly inhibited cancer cell growth in vitro and in vivo. Collectively, our findings suggest that targeting GRB7/ERK/FOXM1 signaling cascade is a promising molecular therapeutic choice in combating ovarian 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 2159. doi:1538-7445.AM2012-2159
Abstract 2172: Anti-oncogenic role of peroxisome proliferator-activated receptor-α/β (PPARδ/α) involves inhibition of mitosis and regulation of Hras1-induced senescence
Authors: Zhu Bokai , Khozoie Combiz , Ferry Christina H. , Markell Lauren M. , Bility Moses T. , Blazanin Nicholas , Glick Adam B. , Gonzalez Frank J. 
Published: August 2012

Abstract
Ligand activation of PPARδ/α inhibits chemically-induced skin tumorigenesis and Pparα/α-null mice exhibit enhanced chemically-induced skin tumorigenesis compared to wild-type mice. The mechanism that mediates inhibition of skin carcinogenesis by PPARδ/α is still being unraveled and was examined in this study. Ligand activation of PPARδ/α caused a negative selection against cells expressing higher levels of HRAS by inducing a mitotic block. Mitosis-related genes that are predominantly regulated by E2F were induced to a higher level in HRAS-expressing Pparα/α-null keratinocytes as compared to HRAS-expressing wild-type keratinocytes. Ligand activated PPARδ/α repressed expression of these genes by direct binding with p130/p107, facilitating nuclear translocation, and increasing promoter recruitment of p130/p107. In addition, co-treatment with a PPARδ/α ligand and various mitosis inhibitors increases the efficacy of increasing G2/M arrest. PPARδ/α is also required for HRAS-induced senescence and suppression of malignant conversion of benign papillomas. HRAS-expressing Pparα/α-null keratinocytes evade senescence by utilizing the PI3K-AKT rather than the MEK-ERK pathway. PPARδ/α positively regulates MEK-ERK pathway by maintaining RASGRP1 levels and negatively regulating the PI3K-AKT pathway by repressing ILK and PDPK1 expression. Heightened AKT activity increases endoplasmic reticulum (ER) stress in Pparα/α-null keratinocytes, which in turn helps maintain higher AKT activity, leading to evasion of senescence. In addition, enhanced HRAS activity increases the synthesis of endogenous PPARδ/α ligands, thus providing a PPARδ/α-dependent cell-autonomous mechanism to suppress HRAS-induced carcinogenesis. (Supported by CA124533).
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 2172. doi:1538-7445.AM2012-2172
Abstract 2176: Deletion of 3p14 is linked to ERG-fusion positive prostate cancers and harbors the FOXP1 tumor suppressor gene
Authors: Simon Ronald , Krohn Antje , Burkhardt Lia , Bachmann Frederic , Schlomm Thorsten , Steuber Thomas , Gräfen Markus , Sauter Guido , Minner Sarah , Sirma Hüseyin 
Published: August 2012

Abstract
Genetic rearrangements involving 3p14 are frequent alterations in prostate cancer, affecting approximately 15-20% of tumors. Both the clinical significance and the tumor suppressor at 3p14 locus are currently unknown. We performed SNP array analysis of 72 primary prostate cancers and show a commonly deleted region at 3p14 in 14 (19%) of the tumors. Our data indicate the existence of a small, recurrent deletion in a significant fraction of prostate cancers harboring 8 genes only. Ten of 14 tumors with 3p14 deletions detected in our study included the FOXP1 locus. To estimate the prevalence and clinical significance of FOXP1 deletions, we analyzed a tissue microarray containing 4,699 prostate cancers with histopathological and clinical follow-up data. Heterozygous FOXP1 deletions were found in 15% of tumors, and were strongly associated with ERG-fusion positive cancers (p&lt;0.0001). No homozygous deletions were detected. FOXP1 deletions were unrelated to tumor stage or Gleason grade. FOXP1 deletions were linked to early PSA recurrence in ERG-positive cancers (p=0.0576) but not in ERG negative tumors (p=0.5425). To better understand the association between ERG fusion and FOXP1 expression, we performed FOXP1 immunohistochemistry on our TMA. FOXP1 expression was found in virtually all (95%) prostate cancers, and was particularly strong in ERG-fusion positive tumors. This finding argues for an important role of FOXP1 in prostate cancer in general and for ERG fusion positive tumors in particular. Since FOXP1 is a transcriptional repressor, we hypothesized that upregulation might be a consequence of ERG activation in order to control transcription of ERG target genes. However, neither expression of ERG in LNCaP cells, or depletion of ERG in VCaP cells had an effect on FOXP1 mRNA levels, strongly arguing against a direct link between ERG and FOXP1 at least in the tested cell lines. In addition neither the transcription nor the steady state levels of FOXP1 protein were modulated by activation of AR signaling. Finally, colony formation assays in both benign and malignant prostate cell lines revealed that FOXP1 may act as a tumor suppressor. In summary, our study demonstrates that FOXP1 functions as one of the tumor suppressor genes in prostate cancer that is targeted by genomic deletions at 3p14.
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 2176. doi:1538-7445.AM2012-2176
Abstract 2183: Determining the functional roles of the specific isoforms of ARID3B from cellular localizations
Authors: Deneke Victoria E. 
Published: August 2012

Abstract
Ovarian cancer is the leading cause of death from a gynecological malignancy in the United States, yet the genetic mechanisms that contribute to ovarian cancer progression are poorly understood. We have determined that ARID3B, a member of the AT-rich interaction domain (ARID) family of proteins, is overexpressed in ovarian cancer. Therefore, we want to assess if ARID3B plays an important role in ovarian cancer progression. We have demonstrated that there are two ARID3B isoforms: the long form (ARID3BFL at 61kDa) and the short form (ARID3Bsh at 28kDa). We show that the ARID3BFL is mostly found in the nucleus and some is found in the membrane of cells. Furthermore, the short isoform of ARID3B (when overexpressed) is primarily found in cytoplasmic and membrane/mitochondria fractions. Therefore, we hypothesize that by virtue of these unique cellular distributions that ARID3B isoforms elicit different cellular responses. ARID3BFL binds DNA and induces apoptosis in ovarian cancer cell lines while ARID3Bsh does not induce cell death. Further elucidation of the roles of the two ARID3B isoforms will help us understand ovarian cancer progression, cellular response to chemotherapy, and develop prognostic markers and targeted therapies.
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 2183. doi:1538-7445.AM2012-2183
Abstract 2184: Analysis of human polynucleotide phosphorylase function in human melanoma
Authors: Sokhi Upneet K. 
Published: August 2012

Abstract
Human polynucleotide phosphorylase (hPNPaseold-35) is an evolutionarily conserved 3′, 5′ exoribonuclease predominantly involved in mRNA degradation. It is a type I IFN-inducible early response gene that was identified as a gene upregulated in terminally differentiated and senescent fibroblasts. Overexpression of hPNPaseold-35 via a replication incompetent adenovirus (Ad.hPNPaseold-35) arrests multiple cancer cell types in the G1 phase of the cell cycle, with cells eventually undergoing apoptosis. A potential mechanism of this growth inhibition and eventual apoptosis induction is the ability of hPNPaseold-35 to selectively degrade c-myc mRNA. This was further proven by the overexpression of c-myc that partially but significantly protects human melanoma cells from Ad.hPNPaseold-35-mediated growth inhibition, indicating that c-myc down-regulation might directly mediate the growth-inhibitory properties of Ad.hPNPaseold-35. Since the protection offered by c-myc overexpression was incomplete, additional targets of hPNPaseold-35 are likely to exist that may play a role in mediating its growth-inhibitory effects. The goal of the present study was to identify these additional candidate genes that may be directly or indirectly regulated by hPNPaseold-35, which would help us better understand the physiological implications of this interesting enzymatic protein. In order to identify the target genes a whole genome cDNA microarray was performed to assess gene expression changes that occur when hPNPaseold-35 was silenced in HO-1 melanoma cells. The genes that are upregulated in the hPNPaseold-35 knockdown cell line might be potential direct degradation targets of hPNPaseold-35 according to our current hypothesis. Finally, validation of these targets may provide us a unique opportunity for defining specific molecules and pathways that may represent new targets of hPNPaseold-35 contributing to its growth-inhibitory effects, which may be further used for developing approaches to enhance its therapeutic efficacy.
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 2184. doi:1538-7445.AM2012-2184
Abstract 2188: The ubiquitin-specific protease USP2a targets cyclin A1: A potential role in bladder cancer
Authors: Kim Jayoung , Loda Massimo F. , Freeman Michael R. 
Published: August 2012

Abstract
A deubiquitinating enzyme USP2a has shown oncogenic properties in many cancer types by impairing ubiquitination of FASN, MDM2, MDMX, or Aurora-A. Aberrant expression of USP2a has been linked to progression of human tumors, particularly prostate cancer. However, little is known about USP2a's role or mechanism in bladder cancer. Here we provide evidence that USP2a functions as an oncoprotein in bladder cancer cells. Overexpression of USP2a caused enhanced proliferation, invasion, migration, and resistance to several chemotherapeutic reagents, while USP2a loss resulted in slower proliferation, greater chemosensitivity, and reduced migratory/invasive capability, compared to control cells. USP2a, but not a catalytically inactive mutant, enhanced proliferation in immortalized TRT-HU1 normal human bladder epithelial cells. USP2a bound to cyclin A1 and prevented cyclin A1 ubiquitination, leading to accumulation of cyclin A1 by blocking its degradation. Enforced expression of wild type USP2a, but not an inactive USP2a mutant, resulted in cyclin A1 accumulation and increased cell proliferation. Our finding that USP2a impairs ubiquitination and stabilizes the important cell cycle regulator, cyclin A1, raises the possibility of USP2a silencing as a therapeutic strategy against bladder tumors in combination with chemotherapy.
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 2188. doi:1538-7445.AM2012-2188
Abstract 2192: Genomic amplification and drug-resistance roles of the KDM5A histone demethylase gene in breast cancer
Authors: Hou Jinling , Wu Jack , Dombkowski Alan , Boerner Julie L. , Ethier Stephen , Yang Zeng-Quan 
Published: August 2012

Abstract
Interconnected genetic and epigenetic events control both the initiation and progression of cancer. Specifically, genetic alterations, such as amplification, and the subsequent over-expression of genes encoding ‘epigenetic modifying enzymes’ can directly lead to histone code changes that may be critical for cancer progression. KDM5A (lysine (K)-specific demethylase 5A, also known as RBP2 and JARID1A) was originally identified as the retinoblastoma-binding protein (RBP) implicated in the regulation of retinoblastoma target genes. Recently, several groups discovered that KDM5A is a member of a set of newly identified histone demethylases that control the chromatin-mediated regulation of gene expression. Specifically, KDM5A can function as a transcriptional repressor through the demethylation of tri- and dimethylated histone H3 at lysine 4 (H3K4) active marks. In this study, we observed a significant amplification and over-expression of the KDM5A gene in various tumors, including breast cancer. We found that breast cancer cells with KDM5A gene amplification had intrinsic drug resistance properties and knocking down KDM5A with shRNAs improved the efficacy of epidermal growth factor receptor (EGFR) inhibitors against these breast cancer cells. Further, up-regulation of KDM5A modified the histone methylation status and altered the expression of a subset of key genes, including the tumor suppressor p21 and the apoptotic effector BAK1, in breast cancer. Our findings suggest that alteration of the KDM5A gene may have a critical role in the pathogenesis of breast 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 2192. doi:1538-7445.AM2012-2192
Abstract 2195: Smurf2 is a novel tumor suppressor gene that governs chromatin structure and genome integrity through RNF20
Authors: Blank Michael , Zhang Ying E. 
Published: August 2012

Abstract
Cancers are known to harbour alterations in chromatin landscape in addition to allelic mutations. Here, we show that genomic ablation of Smurf2, a HECT-domain E3 ubiquitin ligase, results in dysregulation of global gene expression, altered DNA damage response, and unstable genomes, which culminate to increased susceptibility to various types of cancers in aged mice. We demonstrate that Smurf2 regulates histone H2B monoubiquitination as well as histone H3 tri-methylation at K4 and K79 by targeting RNF20, the major E3 ligase for histone H2B ubiquitination, to proteasomal degradation. We further show that Smurf2 and RNF20 are co-localized at the γ-H2AX foci of double-stranded DNA breaks in the nucleus, and Smurf2 regulates RNF20 stability in human cancer cells. Thus, our data indicate that Smurf2 has a tumor suppression function that normally maintains genomic stability by controlling the epigenetic landscape of histone modifications through RNF20.
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 2195. doi:1538-7445.AM2012-2195
Abstract 2197: Fliz-1 regulation of GATA-3 expression in mammary tumor cells
Authors: Shrestha Eric , Wang TianJiao , Saunders Justin , Knepper Janice E. 
Published: August 2012

Abstract
The GATA-3 transcription factor is a master regulator of cell fate determination in the mammary gland. Mice lacking expression of GATA-3 in the mammary gland fail to develop complete ductal branching or terminal end buds, while depletion of GATA-3 from adult mammary glands leads to loss of markers for luminal cell differentiation and to caspase-mediated death of luminal cells. In human breast cancer, GATA-3 expression is found in highly differentiated, estrogen receptor positive tumors with good prognosis, while loss correlates with highly metastatic tumors resistant to endocrine therapy. Regulation of GATA-3 expression is incompletely understood, though a positive-cross regulatory loop with the estrogen receptor alpha has been defined. The zinc finger protein Fliz-1 represses GATA-3 transcription in the T cell lineage, but its role in mammary cells is unknown. We hypothesize that Fliz-1 also can repress GATA-3 expression in mammary cells, leading to loss of estrogen response. To test this hypothesis, we identified a mouse mammary tumor cell line expressing high levels of Fliz1, and transfected the cells with a Fliz-1 silencing vector or negative control. Successful knockdown was confirmed by RT/PCR. Cells with decreased Fliz-1 expression showed increased expression of GATA-3 and estrogen receptor alpha mRNA relative to controls. The Fliz-1-expressing cells formed tumors that were insensitive to tamoxifen treatment when implanted in syngeneic BALB/c mice, while cells with decreased Fliz-1 expression exhibited decreased tumor growth in response to endocrine therapy. As a reciprocal experiment, we constructed a fusion gene linking Fliz-1 with a C-terminal green fluorescent protein tag. The fusion protein properly localizes to the nucleus of transfected MCF-7 (human breast cancer) and COMMA-D (mouse mammary epithelial) cells. Chromatin immunoprecipitation was used to show that Fliz1-GFP binds to an intronic regulatory region within the GATA-3 gene in COMMA-D cells. These data provide evidence supporting a role for Fliz-1 in control of GATA-3 expression in mammary cells and tumors.
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 2197. doi:1538-7445.AM2012-2197
Abstract 2198: A functional ETS/E2F module in cancers expressing ETS fusion genes
Authors: Schwentner Raphaela , Bilke Sven , Kauer Max , Jug Gunhild , Walker Robert L. , Meltzer Paul S. , Kovar Heinrich 
Published: August 2012

Abstract
Ewing's sarcoma (ESFT) is a highly aggressive pediatric cancer characterized by the chimeric ETS transcription factor EWS-FLI1 as a result of a chromosomal translocation. By whole genome gene expression and ChIP-seq analyses we obtained evidence that EWS-FLI1 directly binds to 50% of E2F target genes in ESFT. Furthermore, several E2F factors were themselves found to be directly regulated by EWS-FLI1. Therefore, we studied the functional interaction of EWS-FLI1 with E2F. Ten arbitrarily chosen EWS-FLI1/E2F candidate targets including E2F3, RAD51, and ATAD2 were chosen for an in-depth promoter activity study by luciferase reporter gene assays in combination with mutation analysis of transcription factor binding motifs. By ChIP-PCR we confirmed direct EWS-FLI1 promoter binding, and observed decreased reporter activity for all ten studied promoters upon knockdown of EWS-FLI1 by RNAi. Furthermore, the study of promoter occupancy by different E2F family members revealed that silencing of EWS-FLI1 results in the exchange of EWS-FLI1 induced, activating E2F3 by constitutively expressed repressive E2F4 on the promoters of there jointly regulated target genes. Importantly, testing E2F3 promoter occupancy on wildtype and ETS motif mutated promoter constructs in ESFT cell lines revealed that binding of E2F3 to its target promoters is dependent on an intact ETS binding site. Mutation of the ETS motif resulted in reduced binding of E2F3. These data are consistent with a model in which EWS-FLI1 actively recruits an activating E2F factor thereby replacing a repressing E2F factor and in which EWS-FLI1 binding is essential for E2F binding. Strikingly, the functional E2F/ETS transcriptional module detected in ESFT for the chimeric ETS factor EWS-FLI1 was found to be also relevant to TMPRSS2-ERG expressing prostate cancer cells, but not active in HeLa cells. Supported by grants from the Austrian Science Fund (P22328-B09), and the European Comission (EU-FP7 STREP 259348). R. Schwentner is a recipient of a DOC-fFORTE-fellowship of the Austrian Academy of Sciences.
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 2198. doi:1538-7445.AM2012-2198
Abstract 2202: HMG box-containing protein 1 (HBP1) is a direct target of transcription factor FOXO1 in invasive oral cancer
Authors: Chou I-Tai , Chan Chien-Yi , Lee Ming-Fen , Huang Chun-Yin 
Published: August 2012

Abstract
Constitutively activated PI3K/Akt signaling with deregulated activity of FOXO factors is often associated with tumorigenesis. Reduced HBP1 expression and/or loss-of-function HBP1 mutants have been observed in several types of cancer. FOXO1 and HBP1 seem to share common biological roles such as cell growth inhibition. We have previously demonstrated that, in oral cancer, reduced HBP1 expression expedited cell proliferation, growth, and migration, while the role of FOXO1 remains unclear. Hence, the objective of the current study is to investigate the reciprocal roles of FOXO1 and HBP1 in oral cancer. In a subset of oral tumor specimen, we found that both FOXO1 and HBP1 expression levels were significantly lower than those of the control tissues. In addition, FOXO1 expression was positively correlated with that of HBP1, and the status of low FOXO1 and HBP1 was associated with invasiveness of oral tumor, indicating a coordinated down-regulation of FOXO1 and HBP1 in invasive oral cancer. To further examine if HBP1 is a transcriptional target of FOXO1, we searched for putative binding sites within a 2-kb HBP1 promoter region, and identified two FOXO1 consensus sites, located −177 to −184 bp and −388 to −395 bp, from the transcription start site. As shown by reporter analysis and in vivo chromatin IP assay, these cis-acting elements and trans-acting FOXO1 factors, with functional DNA-binding domains, were necessary for complete activation. Furthermore, suppression of FOXO1 led to a reduction of HBP1 expression. In a reciprocal manner, FOXO1-mediated inhibition of colony formation, cell growth, and invasion was disrupted upon HBP1 knockdown in invasive oral cancer cells. Taken together, our data provide the significant findings that HBP1 is a novel downstream target of FOXO1 and that the FOXO1-HBP1 pathway might be a prospective means of intervention in invasive oral 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 2202. doi:1538-7445.AM2012-2202