bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5154: Targeting the histone demethylase KDM4 subfamily as a potential therapeutic strategy in breast cancer
Authors: Holowatyj Andreana , Ye Qin , Zhang Lihong , Wu Jack , Yang Zeng-Quan 
Published: May 2015

Abstract
Epigenetic alterations, including histone modifications, play fundamental roles in breast cancer initiation and progression. We originally identified and cloned the GASC1 (gene amplified in squamous cell carcinoma 1, also known as KDM4C) gene from an amplified region at 9p24 in esophageal cancer cells; and recently demonstrated that KDM4C/GASC1 is amplified and over-expressed in breast cancer, particularly in the aggressive basal subtype. The KDM4C/GASC1 protein belongs to the KDM4 family of histone demethylases, and although KDM4 family members have a high degree of homology, they may play different roles in various types of breast cancer. The goal of this study is to analyze genomic anomalies and expression levels of KDM4 demethylases in breast cancer, and elucidate the fundamental role and mechanism of their dysregulation in promoting breast tumorigenesis.
We conducted a large-scale meta-analysis of KDM4 demethylase expression across multiple available gene expression studies in breast cancer. Next, we examined KDM4 expression in a panel of non-tumorigenic and cancerous breast epithelial cell lines using quantitative RT-PCR and Western blot assays. We also assessed global methylation (H3K4, H3K9, H3K27 and H3K36) levels by Western blot in a panel of breast cancer cell lines. Finally, we tested a novel KDM4 inhibitor in breast cancer.
We found that the KDM4 members show different expression patterns in subtypes of breast cancer. GASC1/KDM4C expression is high in estrogen receptor (ER)-negative, basal type breast cancers. In contrast, KDM4B expression is significantly higher in ER-positive luminal-type breast cancers. Expression levels of homologs KDM4A and D are not significantly different between ER-+/- breast cancers. Our findings suggest that H3 global methylation levels vary among different breast cancer cell lines. Furthermore, we demonstrated that inhibition of KDM4 with a novel small molecule inhibitor increased H3K9 methylation levels and slowed KDM4-overexpressed breast cancer cell growth in vitro.
In summary, our data indicate that the KDM4 histone demethylase family may contribute to the dysregulation of histone methylation status differently in breast cancer subtypes. Moreover, breast cancer cell lines with defined histone methylation levels will provide a useful model for investigating biological and functional roles of KDM4 histone demethylases, and for developing novel anticancer epi-drugs in breast cancer.
Citation Format: Andreana Holowatyj, Qin Ye, Lihong Zhang, Jack Wu, Zeng-Quan Yang. Targeting the histone demethylase KDM4 subfamily as a potential therapeutic strategy in breast cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5154. doi:10.1158/1538-7445.AM2014-5154
Abstract 5172: Whole exome mutation landscape of 70 commonly used colorectal cancer cell lines
Authors: Sieber Oliver , Mouradov Dmitri , Sloggett Clare , Jorissen Robert , Love Chris , Li Shan , Burgess Antony , Arango Diego , Strausberg Robert , Buchanan Daniel , Wormald Samuel , O'Connor Liam , Wilding Jenny , Bicknell David , Tomlinson Ian , Bodmer Walter , Mariadason John 
Published: May 2015

Abstract
Human colorectal cancer (CRC) cell lines are an important model system for studying the biology of this malignancy as well as therapeutic and biomarker discovery. However, data on the degree to which established CRC cell lines reflect the somatic diversity of primary cancers at the genome level are limited. Using whole exome sequencing and SNP microarray analysis we show that the profile of mutations and DNA copy-number alterations in 70 widely-used CRC cell lines closely resembles that of primary colorectal tumors published by The Cancer Genome Atlas Network. We demonstrate presence of at least two hypermutation phenotypes, consistent with defective DNA mismatch repair and DNA polymerase epsilon (POLE) proof-reading deficiency, and similar mutation signatures in the WNT, MAPK, PI3K, TGF-beta and TP53 pathways. Paired cell lines derived from the same tumor are found to exhibit substantial mutation and DNA copy-number differences, with in silico simulations suggesting that these largely reflect pre-existing tumor cell heterogeneity, but these differences do not obscure known driver genes. Our genome level data indicate that CRC cell lines are representative models of the main molecular subtypes of primary tumors, and will facilitate informed selection of molecularly-defined models for preclinical investigations.
Citation Format: Oliver Sieber, Dmitri Mouradov, Clare Sloggett, Robert Jorissen, Chris Love, Shan Li, Antony Burgess, Diego Arango, Robert Strausberg, Daniel Buchanan, Samuel Wormald, Liam O'Connor, Jenny Wilding, David Bicknell, Ian Tomlinson, Walter Bodmer, John Mariadason. Whole exome mutation landscape of 70 commonly used colorectal cancer cell lines. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5172. doi:10.1158/1538-7445.AM2014-5172
Abstract 518: Identification of differentially expressed microRNAs in human hepatocellular adenoma associated with type I glycogen storage disease: a potential utility as biomarkers
Authors: Li Ling-Hui , Chiu Li-Ya , Kishnani Priya S. , Chuang Tzu-Po , Tang Cheng-Yang , Liu Cheng-Yuan , Bali Deeksha , Koeberl Dwight , Austin Stephanie , Boyette Keri , Weinstein David A. , Murphy Elaine , Yao Adam , Chen Yuan-Tsong 
Published: May 2015

Abstract
Background: It is known that malignant transformation to hepatocellular carcinoma (HCC) occurs at a higher frequency in hepatocellular adenoma (HCA) from type I glycogen storage disease (GSD I) compared to HCA from other etiologies. In this study, we aimed to identify differentially expressed miRNAs in GSD Ia HCA as candidates that could serve as putative biomarkers for detection of GSD Ia HCA and/or risk assessment of malignant transformation.
Methods: Utilizing massively parallel sequencing, the miRNA profiling was performed for paired adenomas and normal liver tissues from seven GSD Ia patients. Differentially expressed miRNAs were validated in liver tumor tissues, HCC cell lines and serum using quantitative RT-PCR.
Results: miR-34a, miR-34a*, miR-224, miR-224*, miR-424, miR-452 and miR-455-5p were found to be commonly deregulated in GSD Ia HCA, general population HCA, and HCC cell lines at compatible levels. In comparison with GSD Ia HCA, the upregulation of miR-130b and downregulation of miR-199a-5p, miR-199b-5p, and miR-214 were more significant in HCC cell lines. Furthermore, serum level of miR-130b in GSD Ia patients with HCA was moderately higher than that in either GSD Ia patients without HCA or healthy individuals.
Conclusion: We make the first observation of the distinct miRNA deregulation in HCA associated with GSD Ia. We also provide evidence that miR-130b could serve as a circulating biomarker for detection of GSD Ia HCA. This work provides prominent candidate miRNAs worth evaluating as biomarkers for monitoring the development and progress of liver tumors in GSD Ia patients in the future.
Citation Format: Ling-Hui Li, Li-Ya Chiu, Priya S. Kishnani, Tzu-Po Chuang, Cheng-Yang Tang, Cheng-Yuan Liu, Deeksha Bali, Dwight Koeberl, Stephanie Austin, Keri Boyette, David A. Weinstein, Elaine Murphy, Adam Yao, Yuan-Tsong Chen. Identification of differentially expressed microRNAs in human hepatocellular adenoma associated with type I glycogen storage disease: a potential utility as biomarkers. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 518. doi:10.1158/1538-7445.AM2014-518
Abstract 5185: Redefining the somatic landscape of pancreatic adenocarcinoma
Authors: Brown Andrew M.K. , Notta Faiyaz , Lemire Mathieu , Lungu Ilinca , Denroche Robert E. , Yung Christina , Geras Kristen , Stein Lincoln , Bartlett John M. , Hudson Thomas J. , Roehrl Michael H.A. , Gallinger Steven , McPherson John D. 
Published: May 2015

Abstract
Efforts to catalogue genomic abnormalities in pancreatic ductal adenocarcinoma (PDAC) have been challenging due to low tumor cellularity which requires deep sequencing to obtain adequate coverage of tumor DNA. To make whole genome sequencing (WGS) feasible with PDAC tumors, we have developed protocols for sequencing enriched tumor material by laser capture microdissection (LCM) from frozen samples and by flow sorting when fresh tissue is available. The enriched samples have a median tumor cellularity of 88% compared to a median cellularity of 12% in the bulk samples. Furthermore, the enrichment methods may also provide a source of normal or reference material, non-tumor cells in the case of LCM and CD45+ blood cells in the case of flow sorting, and eliminate the need for matched blood samples to call somatic variation. In conjunction with low quantity DNA input protocols for library construction, high quality next generation sequencing libraries are readily produced without sacrificing library complexity that enables somatic mutation, copy-number and structural variant detection at modest sequencing depths (∼50x). These methods are applicable to all tumor types where significant stromal contamination hinders somatic mutation detection. In addition to redefining the rates of known somatically altered genes in PDAC, such as CDKN2A and SMAD4, the high cellularity data set has also allowed us to evaluate PDAC tumor heterogeneity with the ability to detect sub-clonal variation that is not masked by non-tumor DNA. Moreover, in 50% of the samples sequenced to date, we observe evidence of punctuated evolution suggesting a catastrophic event during mutagenesis, which may be associated with the clinically observed rapid progression of the disease. The result of enhanced somatic mutation detection is a more comprehensive picture of the PDAC genomic landscape.
Citation Format: Andrew M.K. Brown, Faiyaz Notta, Mathieu Lemire, Ilinca Lungu, Robert E. Denroche, Christina Yung, Kristen Geras, Lincoln Stein, John M. Bartlett, Thomas J. Hudson, Michael H.A. Roehrl, Steven Gallinger, John D. McPherson. Redefining the somatic landscape of pancreatic adenocarcinoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5185. doi:10.1158/1538-7445.AM2014-5185
Abstract 5192: Mutational analysis of primary central nervous system lymphoma
Authors: Bruno Aurélie , Boisselier Blandine , Labreche Karim , Marie Yannick , Polivka Marc , Jouvet Anne , Adam Clovis , Figarella-Branger Dominique , Miquel Catherine , Vital Anne , Houillier Caroline , Soussain Carole , Mokhtari Karima , Daveau Romain , Hoang-Xuan Khê 
Published: May 2015

Abstract
Background: Primary central nervous system lymphoma (PCNSL) is a rare extranodal diffuse large B-cell lymphoma (DLBCL). Little is known about the genomic basis of tumorigenesis in PCNSL partly explained by the rarity of biological material available for research studies. PCNSL patients display poor outcomes compared to systemic DLBCL and it is still unclear whether this is linked to the organ-specific microenvironment or reflects a specific, aggressive, intrinsic biological behavior. To our knowledge, the mutational landscape of PCNSL has never been investigated
Experimental design: We analyzed 9 paired tumor and germline DNA samples from PCNSL patients by high throughput exome sequencing. Then, we performed focused sequencing in 28 additional PCNSL tumors to validate somatic genomic alterations and better estimate their incidence. Mutational data were correlated with copy number variations (CNV) identified by SNP and CGH arrays and clinical data.
Results: We identified recurrent somatic mutations in genes involved in key signalling pathways such as NFκB (i.e. MYD88, CD79B, TBL1XR1), B cell differentiation (i.e. ETV6, EBF1, IRF4) and cell cycle control (i.e. BTG1, PIM1). We found somatic mutations on MYD88 (38%), CD79B (30%), TBL1XR1 (22%) or ETV6 (16%) genes and described bi-allelic inactivation of TBL1XR1 and ETV6 genes. Interestingly, the correlation with the outcome showed a significant negative impact of TBL1XR1 mutation on survival in a multivariate analysis.
Conclusions: The present study showed that PCNSLs have high genetic heterogeneity and that their mutational patterns display similarities with extracerebral DLBCL, particularly of the ABC subtype, suggesting shared underlying biological mechanisms. These results provide new insights into the mutational landscape of PCNSL and potential targets for therapeutic strategies. This work benefited from the LOC study group network (réseau national de centres experts des lymphomes primitifs du SNC, INCa).
Citation Format: Aurélie Bruno, Blandine Boisselier, Karim Labreche, Yannick Marie, Marc Polivka, Anne Jouvet, Clovis Adam, Dominique Figarella-Branger, Catherine Miquel, Anne Vital, Caroline Houillier, Carole Soussain, Karima Mokhtari, Romain Daveau, Khê Hoang-Xuan. Mutational analysis of primary central nervous system lymphoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5192. doi:10.1158/1538-7445.AM2014-5192
Abstract 5207: miR-491 and miR-218: Two possible tools to reduce FOXP3 expression in breast carcinomas
Authors: Modica Martina D. , Triulzi Tiziana , Regondi Viola , Iorio Marilena V. , Balsari Andrea , Tagliabue Elda , Casalini Patrizia 
Published: May 2015

Abstract
The Forkhead box P3 (FOXP3) gene is a member of the forkhead/winged-helix family of transcription factors implicated in the regulation of immune system development and function. However, FOXP3 is also expressed in human epithelial cancers, where it has been reported to be associated with poor prognosis and in particular with metastasis. Aim of our work is to identify microRNAs able to regulate FOXP3 expression in breast tumors.
To discover microRNAs able to regulate FOXP3 expression in breast cancer cells, an in silico analysis has been performed. Among microRNAs harboring FOXP3 seed regions, we focused our attention on miR-218 and miR-491, described to have oncosuppressive properties. Indeed, it has been reported that miR-218 expression stimulates activation of tumor suppressor genes and miR-491 expression inversely correlates with migratory potential in HCC cell lines and in vivo with metastatic potential.
We therefore evaluated the ability of these microRNAs to act as oncosuppressors by targeting FOXP3 in a breast cancer model. After transient co-transfection either of miR-218 or miR-491 with FOXP3 in MDA-MB-231 cells, a significant decrease in FOXP3 expression at protein level by WB was found.
To perform functional studies both in vitro and in vivo, we generated a breast cancer cell model by stable transfection of MDA-MB-231 with inducible Tet-off plasmid encoding for FOXP3 encompassing 3′UTR region, thus maintaining microRNA-mediated regulation. We demonstrated that FOXP3 expressing clones display an increased migration capacity as compared with their respective non-induced cells. Also in these stable clones a reduction of FOXP3 expression after transfection of miR-491 and miR-218 has been demonstrated by WB. Moreover, FOXP3 was confirmed to be a direct target of both microRNAs by luciferase reporter assay.
We also found an inverse correlation between miR-491 levels and FOXP3 expression in human breast carcinoma specimens.
Overall, these preliminary results demonstrate that microRNAs can regulate FOXP3 expression, and encourage to further investigate the biological and functional consequences of this targeting, and to exploit microRNAs as a potential therapeutic tool for FOXP3 expressing breast carcinomas.
Citation Format: Martina Di Modica, Tiziana Triulzi, Viola Regondi, Marilena V. Iorio, Andrea Balsari, Elda Tagliabue, Patrizia Casalini. miR-491 and miR-218: Two possible tools to reduce FOXP3 expression in breast carcinomas. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5207. doi:10.1158/1538-7445.AM2014-5207
Abstract 5233: MicroRNA in biofluid as robust biomarkers for cancer
Authors: Blondal Thorarinn , Thomsen Anni , Krummheyer Jörg , Mouritzen Peter , Andreasen Ditte , Theilum Maria , Stenvang Jan , Andersen Claus L. , Nielsen Hans J. , Brünner Nils 
Published: May 2015

Abstract
microRNAs constitute a class of small cellular RNAs (typically 19-23 nt) that function as post-transcriptional regulators of gene expression. Current estimates indicate that more than one third of the human cellular transcriptome is regulated by this small class of RNA (∼2000 miRNA). The study of extracellular microRNAs and their potential as pathophysiological markers has greatly expanded in the last couple of years. microRNAs have been shown to be actively exported from tissues into the circulation through a variety of mechanisms including exosome and microvesicle transport, and complexing with RNA binding proteins or HDL. The high relative stability of microRNAs in common clinical source materials (FFPE blocks, plasma, serum, urine, saliva, etc.) and the ability of microRNA expression profiles to accurately classify discrete tissue types and specific disease states have positioned microRNAs as promising new biomarkers for diagnostic application in cancer. We have applied Exiqons highly sensitive LNA™-based qPCR platform for detection of microRNAs, which has enabled microRNA profiling in biofluids where levels are extremely low. The platform uses a single RT reaction to conduct full miRNome profiling and allows high-throughput profiling of microRNAs without the need for pre-amplification. Thousands of biofluid samples including serum/plasma and urine have been profiled to determine normal reference ranges for circulating microRNAs as well as to identify biomarkers of disease. Extensive data qualification and analysis methods have been developed and are central parameters to secure high quality data from biofluids. The methods can quickly and robustly be applied in biomarker discovery and validation projects. We will present examples from our collaborative cancer diagnostic projects. Also we have developed a new exosome enrichment method and will present a comparison of microRNA profiles obtained with this method to profiles obtained with different commercial available exosome isolation methods and standard profiles of whole plasma and serum.
Citation Format: Thorarinn Blondal, Anni Thomsen, Jörg Krummheyer, Peter Mouritzen, Ditte Andreasen, Maria Theilum, Jan Stenvang, Claus L. Andersen, Hans J. Nielsen, Nils Brünner. MicroRNA in biofluid as robust biomarkers for cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5233. doi:10.1158/1538-7445.AM2014-5233
Abstract 5238: Integrative analysis of functional long noncoding RNAs during prostate cancer progression
Authors: Fei Teng , Chen Yiwen , Du Zhou , Liu Xiaole Shirley , Brown Myles 
Published: May 2015

Abstract
Prostate cancer progression from an androgen-dependent state to an androgen-independent phase, which is also referred to castration-resistant prostate cancer (CRPC), not only results in cancer refractory to androgen deprivation therapy but also marks its lethal prognosis. However, it remains largely unknown that how CRPC develops. As a result, ideal diagnosis and therapeutic tools are still highly in demand and under investigation. Recently, many studies indicate that long non-coding RNA (lncRNA) can be extensively functional rather than just transcriptional noise and lncRNAs are also widely involved in the pathogenesis of different types of cancers. To identify and characterize functional lncRNAs during prostate cancer progression, we firstly developed an integrative computational strategy for predicting lncRNAs that may be functionally important for tumorigenesis or tumor suppression via analysis of lncRNA expression profiles, clinical information and somatic genomic alteration profiles of tumor samples. By applying this approach, we predicted a cohort of lncRNAs that may be clinically important for prostate tumorigenesis and experimentally confirmed two functional lncRNAs - PCAT6 and PCAT7 in prostate cancer cell line model. Work from others and our lab have also shown that both androgen receptor (AR) and polycomb group protein enhancer of zest 2 (EZH2) play pivotal roles during prostate cancer progression to CRPC. In contrast to protein coding genes, little is known about AR or EZH2 regulated lncRNAs during this process. To this purpose, we also performed RNAseq in prostate cancer cell lines and combined ChIPseq data to identify androgen-regulated and AR/EZH2-regulated lncRNAs. These regulated lncRNAs are also intersected with above clinically significant lncRNA list to narrow down interesting hits for follow-up mechanistic studies. Our integrative approach has successfully identified a cohort of potentially functional lncRNAs which hold great potentials to be novel prognostic biomarkers and/or therapeutic targets for treatment of advanced prostate cancer.
Citation Format: Teng Fei, Yiwen Chen, Zhou Du, Xiaole Shirley Liu, Myles Brown. Integrative analysis of functional long noncoding RNAs during prostate cancer progression. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5238. doi:10.1158/1538-7445.AM2014-5238