bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1461: Targeting mitotic kinases in breast cancers in Latinas
Authors: Rivera-Rivera Yainyrette , Marina Mihaela , King Jamie , Lee Miyoung , Saavedra Harold I. 
Published: August 2018

Abstract
African Americans and Latino women (Latinas) in the US have higher risks of developing molecular subtypes of breast cancer that associate with poor-prognosis, including hormone receptor-negative (HR-): triple-negative (ER-PR-Her2-), and Her2-positive breast cancer relative to whites. These women also present with higher-stage breast tumors relative to whites. We specifically study Puerto Rican women, a population in which breast cancers are the primary cause of cancer-related death, and who display a higher frequency of HR- breast tumors than other Latinas. We propose that chromosome instability (CIN) is a principal contributor to poor prognosis of breast cancers in African Americans and Latinas, since HR- breast cancers accumulate the highest CIN of all breast cancer subtypes. CIN in cancers correlates with poor clinical outcomes and centrosome amplification (CA) -defined as the presence of 3 or more centrosomes within a cell-, and defective mitosis are two principal drivers of CIN. Albeit CA correlates with invasion, metastasis, poor clinical outcomes, and HR- subtypes, molecular mechanisms responsible for CA in breast cancers are still unknown. We have identified MPS1 and NEK2 as centrosomes/mitotic kinases that drive CA/CIN in HR- breast cancer cells, and that can potentially be targeted to curb the malignant behavior of the most aggressive breast cancer subtypes affecting ethnic minorities. MPS1 and NEK2 are upregulated in HR- breast tumors and are co-overexpressed in several predictive signatures of poor prognosis subtypes and metastasis. Our preliminary data indicated that these kinases are overexpressed in over 60% breast cancers from Puerto Rican women and that they are exclusively co-upregulated in basal breast cancers. Our preliminary data also showed that these two mitotic kinases can significantly influence epithelial-to-mesenchymal transition (EMT) and invasion -activities never described for mitotic kinases. Also, although inactivating NEK2 suppresses S phase, inhibition of MPS1 reduces survival of breast cancer cells. Because inhibitors are available for MPS1 and NEK2, it would be feasible to target these kinases to combat metastatic HR- breast cancers. Our work will allow the identification of pathways influenced by mitotic regulators in breast cancer cells driving invasion and metastasis and will provide potential prognostic markers for high-risk breast tumors in various ethnic/racial groups, including African American and Latinas (including Puerto Rican women).
Citation Format: Yainyrette Rivera-Rivera, Mihaela Marina, Jamie King, Miyoung Lee, Harold I. Saavedra. Targeting mitotic kinases in breast cancers in Latinas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1461.
Abstract 1465: Clinicopathologic characteristics of TZAP mutation and expression in hepatocellular carcinomas
Authors: Lee Jae-Ho , Park Keon Uk 
Published: August 2018

Abstract
The zinc finger protein ZBTB48 is a telomere-associated factor and renamed it as telomeric zinc finger-associated protein (TZAP). It binds preferentially to long telomeres competing with TRF1 and TRF2. However, its expression in cancers has not been performed. Methods: In the present study, we analyzed TZAP mutation and expression in 123 hepatocellular carcinomas (HCC) and its association with telomere length and TERT expression was also investigated. TZAP mutations (c.1272G&gt;A, L424L) was found in 10.6% (13/123) and TZAP expression level was not different between HCC and paired non-cancerous tissues. There was no association between TZAP mutation and TZAP expression (p = 0.53). TZAP mutation did not have any clinical and prognostic values in HCC. However, TZAP expression was positively associated with TERT expression (29.4% vs. 80.0%, P = 0.047). And, TZAP expression tended to induce poorer survival result (overall survival, χ2= 2.83, P = 0.092; disease-free survival, χ2= 3.59, p = 0.058). TCGA data also showed a positive correlation between TZAP and TERT expression levels (r = 0.839, p &lt; 0.001). However, TCGA survival analysis showed no prognostic value of TZAP expression in HCC (p = 0.576). This result suggested that TZAP expression appears to be a possible prognosis marker dependently with TERT expression in HCC.
Citation Format: Jae-Ho Lee, Keon Uk Park. Clinicopathologic characteristics of TZAP mutation and expression in hepatocellular carcinomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1465.
Abstract 1471: Genomic drivers differ across 33 tumor types, but factors regulating hallmarks of cancer are similar
Authors: Plaisier Christopher L. 
Published: August 2018

Abstract
The unique complement of genes expressed in a given cell type modifies the response to a specific somatic mutation. Thus, each tumor type would present with a different set of mutations that modulate the activity of common factors regulating genes which influence the cancer phenotypes (e.g. the hallmarks of cancer). We assessed the validity of this hypothesis by applying the SYstems Genetics Network AnaLysis (SYGNAL) pipeline to the ~10,000 multi-omic profiles across 33 tumor types from The Cancer Genome Atlas (TCGA). The SYGNAL pipeline synthesizes correlative approaches with mechanistic knowledge to construct a gene regulatory network. A basis of the SYGNAL approach is the discovery of biclusters: gene modules that are both co-expressed and co-regulated over subsets of tumors, by specific transcription factors (TFs) and miRNAs. On top of the biclusters we discover potential mechanistic influences of somatic mutations modulating the activity of these regulators. We discovered 284 somatically mutated genes modulating the activity of 187 transcriptional regulators (175 TFs and 12 miRNAs) which regulated 7,786 significantly co-expressed biclusters that were significantly associated with patient survival. The discovery of 1.5 fold more somatic mutations than transcriptional regulators is consistent with our hypothesis that mutations will be unique to tumor types while the regulation of the genes involved in the hallmarks of cancer will be common across tumor types. We also find that only 15% of causal flows (mutation-&gt;regulator-&gt;gene) are observed across multiple tumor types. We observed only four causal flows across three tumor types (NFE2L2-&gt;BCL6B-&gt;HSPG2 for BLCA, ESCA, and HNSC tumor types; TP53-&gt;ERG-&gt;MTX1 for BRCA, LUAD, and STAD tumor types; TP53-&gt;ZNF511-&gt;NAA38 for LUAD, PRAD, and READ tumor types; and TP53-&gt;AEBP2-&gt;THOC6 for COAD, KICH, and READ tumor types). There were no causal flows observed across more than three tumor types. Using our top-down systems approach we are able to catalog the impact of somatic mutations on the transcriptional regulatory network across 33 tumor types. We are working to replicate the co-expression and survival relationships we discovered in independent cohorts for each tumor type. In addition, we are working to identify potential therapeutic targets at both the regulator and gene level. Future studies will use predictive models based on our detailed transcriptional regulatory networks to identify transcriptional regulators driving cancer phenotypes that won't have general toxicity in normal cells.
Citation Format: Christopher L. Plaisier. Genomic drivers differ across 33 tumor types, but factors regulating hallmarks of cancer are similar [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1471.
Abstract 1472: The role of the BAF complex in Wnt signaling-mediated transcriptional regulation in colorectal cancer
Authors: Sen Madhobi , Hamdan Feda H. , Wang Xin , Rapp Jacobe , Johnsen Steven A. 
Published: August 2018

Abstract
Recent genome- and exome-wide sequencing studies have revealed a close association between the epigenome and the pathogenesis of cancer. Not only were chromatin regulators found to be commonly mutated in a wide range of cancers, but a class of these regulators, the ATP-dependent chromatin remodelers, especially subunits of the mammalian BAF complex, were among the most frequently mutated group of genes across cancer types, mutated in over 20% of cancers. Among these subunits, loss of function mutations in ARID1A (AT-rich interactive domain-containing protein 1A) are most frequent across cancer types including 10% of colorectal cancer (CRC). Very interestingly, a recent publication described the pivotal role of the loss of ARID1A in driving CRC wherein its inactivation alone led to the formation of invasive adenocarcinomas in mice. However, surprisingly, in contrast to the expected tumor suppressive role of ARID1A in CRC, we observe that the knockout (KO) of ARID1A in CRC cell lines leads to impaired proliferation. Moreover, subcutaneous xenografts in SCID/SHO mice using ARID1A KO CRC cells did not form more aggressive tumors than their wild type counterparts. One of the most commonly occurring mutations in CRC is in the APC gene, which leads to hyperactive Wnt signaling. Thus CRC progression is typically highly dependent on this pathway. Notably, it is reported that loss of ARID1A in the context of APC mutations results in diminished tumor formation in mice and increased differentiation. This led us to hypothesize that ARID1A is required for Wnt signaling-mediated transcriptional (de)regulation in CRC. To uncover this further, we utilized several publically available ChIP-seq, RNA-seq and ATAC-seq datasets as well as our own ChIP-seq data for ARID1A in the HCT116 cell line. We observe a substantial co-localization of the BAF complex with TCF7L2, a downstream effector of the Wnt signaling pathway, suggesting cooperation between these factors. Further, these sites are also co-occupied by AP1 transcription factors. A crosstalk between the TCF7L2 and AP1 factors has been reported in intestinal tumors. From data available in the ARID1A KO system, we observe a downregulation of potential target genes which are co-occupied at neighboring sites by these factors. Therefore, we suggest that ARID1A plays an important role in the regulation of colorectal cancer relevant genes that are targets of TCF7L2/AP1, thus facilitating a pathway that is most commonly hijacked in colorectal cancer.
Citation Format: Madhobi Sen, Feda H. Hamdan, Xin Wang, Jacobe Rapp, Steven A. Johnsen. The role of the BAF complex in Wnt signaling-mediated transcriptional regulation in colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1472.
Abstract 1473: Role of acetyltransferases CBP and p300 in de novo fatty acid synthesis in colorectal cancer
Authors: Waddell Aaron , Mahmud Iqbal , Liao Daiqing 
Published: August 2018

Abstract
CBP/p300 are two paralogous lysine acetyltransferases that acetylate protein substrates including histones, and serve as transcriptional co-activators for numerous signaling pathways involved in tumorigenesis and cancer progression. Recently, evidence has emerged that p300 regulates the transcription of genes involved in lipogenesis in cancers. Dysregulated lipogenesis and increased de novo production of fatty acids (FA) represent a major metabolic shift in cancer. De novo FA synthesis in cancer is suggested to be a source of lipids for membrane biogenesis, a reservoir of energy, and a source of pro-survival signaling molecules. Therefore, de novo FA synthesis has been linked to survival and increased proliferation of cancer cells, representing a potential area for therapeutic intervention. While emerging evidence indicates CBP/p300 may play a key role in regulating lipogenesis, little is known about the mechanism of how these proteins control lipid production in different cancers. Colorectal cancer (CRC) is a commonly diagnosed human cancer and is a major cause of cancer-related mortality. Key regulators for de novo FA synthesis, such as FASN, have been reported to be elevated in colorectal cancer. We analyzed publically available data sets and report that in colon adenocarcinoma, the mRNA levels of CBP/p300 positively correlate with the expression of genes involved in lipogenesis, such as FASN, SREBP1 and SREBP2. Furthermore, our analysis shows that EP300 expression is negatively correlated with patient survival. Strikingly, our preliminary data suggests that HDAC inhibitors may regulate p300 activity and could serve as a therapeutic approach for suppressing lipogenesis. We are currently utilizing small molecule inhibitors, genetic manipulation of the CREBBP/EP300 genes, and biochemical experiments to investigate the role of CBP/p300 in de novo FA synthesis in colorectal cancer. We hypothesize that inhibition of CBP/p300 could be an attractive therapeutic option for inhibiting tumor growth through downregulating de novo FA synthesis in colorectal cancer. (Supported by grants from James and Esther King Biomedical Research Program and Bankhead-Coly Cancer Research Program, Florida Department of Health.)
Citation Format: Aaron Waddell, Iqbal Mahmud, Daiqing Liao. Role of acetyltransferases CBP and p300 in de novo fatty acid synthesis in colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1473.
Abstract 1474: Identifying novel chromatin binding sites of nucleolin protein in cancer cells
Authors: Wu Guanhui , Onel Buket , Yang Danzhou 
Published: August 2018

Abstract
Nucleolin is an important regulator of cell proliferation and has been reported to play a role in c-Myc transcriptional regulation. Elevated expression levels of nucleolin have been shown in a number of malignant cells, but how nucleolin contributes to cancer development and progression remains unknown. Recently, G-quadruplexes (G4s) have been shown in vivo to form in G-rich sequences with biological importance. Nucleolin has been reported to bind to G-quadruplexes for its biological functions. In particular, G4s have been shown to form in the MYC promoter and inhibit MYC transcription; nucleolin was found to display a remarkable binding affinity to the c-Myc promoter G4 over its best-known RNA target. CX-3543, the first-in-class G-quadruplex-targeting small molecule, was shown to induce nucleolin redistribution from the cell nucleolus to the cell nucleoplasm and apoptosis in cancer cells, which was suggested to act through the c-Myc promoter G-quadruplex. Therefore, unbiased analysis of the genomic binding sites of nucleolin in human chromatin is pivotal in understanding nucleolin's biological functions. Using chromatin immunoprecipitation (ChIP) assay, we demonstrated that nucleolin binds to the c-Myc NHE III1 region in vivo. Using an anti-nucleolin antibody, the isolated DNA from the immunoprecipitated DNA-protein complexes from HeLa cells yielded numerous c-Myc promoter sequences that were determined by real-time PCR, suggesting the direct interaction between nucleolin and the c-Myc promoter G4-forming region in vivo. G4-interactive ligands have been shown to facilitate the formation of G4 structures in cells. To elucidate the association of nucleolin with G-quadruplexes in vivo, we monitored cellular localization of nucleolin before and after G4 ligand treatments and observed a rapid cellular translocation of nucleolin from the cell nucleolus to the cell nucleoplasm. Using ChIP coupled with next-generation sequencing analysis (ChIP-seq), we identified several binding sites of nucleolin in human chromatin. The determined chromatin binding sites of nucleolin will provide insights into the biological functions of nucleolin and its relationship with G-quadruplexes in cancer cells.
Citation Format: Guanhui Wu, Buket Onel, Danzhou Yang. Identifying novel chromatin binding sites of nucleolin protein in cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1474.
Abstract 1476: Landscape of fusion RNAs generated by cis-spliced adjacent genes in cancer and normal physiology
Authors: Qin Fujun 
Published: August 2018

Abstract
The fusion RNA, SLC45A3-ELK4, was found to be a product of cis-splicing between the two adjacent genes (cis-SAGe). Previously, we used LNCaP, a prostate cancer cell line as a model, and identified 16 additional cis-SAGe events by silencing transcription factor CTCF and paired-end RNA sequencing. One out of the 16 fusion RNAs, D2HGDH-GAL3ST2, is more frequently seen in cancer samples, and seems to be enriched in the African American group. It is more frequently detected in late stage cancer, suggesting a role in cancer progression.
By studying the features associated with the 16 fusions, we developed a set of rules: 1) the parental genes are same-strand-neighboring genes, 2) the distance of between the genes is within 30kb; 3) the 5' genes are actively transcribing; and 4) the fusion RNAs tend to have the second-to-last exon in the 5' genes joined to the second exon in the 3' genes. To investigate the cis-SAGe fusion RNAs at global, we first randomly selected 20 neighboring genes in the genome, and detected four fusion events using these rules in prostate cancer and non-cancerous cells.
To further understand the cis-SAGe fusions in human tissues and cells, we then performed, curated and analyzed nearly 300 RNA-seq libraries covering 30 different non-neoplastic human tissues and cells. More than 10,000 fusion transcripts were found. We focused on the neighboring fusions and performed analysis. Appling our cis-SAGe rules, we identified around 1486 cis-SAGe fusion candidates. A few sequence motifs were found enriched close to the fusion junction sites. We performed functional experiments on a few widely expressed fusions, such as ADCK4-NUMBL, CLN6-CAML4, DUS4L-BCAP29, and found that silencing them resulted in dramatic reduction in moral cell growth and /or motility.
Citation Format: Fujun Qin. Landscape of fusion RNAs generated by cis-spliced adjacent genes in cancer and normal physiology [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1476.
Abstract 1480: Overexpression of histone H3.1 induced cell malignant transformation and mutation of H3.1 C96/110A further induced chromatin instability
Authors: Zhu Yusha , Sun Hong , Costa Max 
Published: August 2018

Abstract
Histones are major proteins in chromatin and are important for chromatin structure and gene expression. Canonical histones are defined as a group of replication-dependent histone proteins and are mainly synthesized during S phase of the cell cycle. Their mRNAs are devoid of poly-adenylated tails, but end up with a stem loop structure, which can be targeted by proteins such as stem-loop binding proteins (SLBP) for processing, exportation, and degradation. In our previous studies, arsenic exposure was found to be associated with reduced levels of SLBP and accumulation of poly-adenylated mRNA of canonical histone H3.1, and ultimately led to malignant transformation of cells. Histone H3.1 and H3.2 are canonical histones and they differ by only one amino acid, Ser96 on H3.2 compared with Cys96 on H3.1, and both of them have a Cys110. Histone H3 is the only histone that contains cysteine. Cysteine (C) is a unique amino acid that is rarely used by nature and it has a reactive thiol side chain that can easily form dimers containing disulfide bridge when oxidized. Here it is hypothesized that cysteine is vital for the structure and stability of chromatin. To test this hypothesis, we generated an H3.1 mutant H3.1 C96/110A, where two cysteine residues were replaced by alanine (A). The wild-type H3.1 and H3.1 C96/110A were exogenously expressed in the Beas-2B cells. Interestingly, Beas-2B cells ectopically expressing poly-adenylated H3.1 and H3.1 C96/110A showed decreased proliferation rate with cell cycle arrest at S phase, and cells also acquired cancer cell properties such as increased anchorage-independent growth along with migration and invasion ability. It was confirmed that H3.1 C96/110A could be incorporated into chromatin, resulting in increased chromatin instability and DNA damage. In addition, the RNA-seq assay revealed a total of 678 genes that were oppositely expressed between H3.1 and H3.1 C96/110A ectopically expressed cells. These findings emphasize the importance of a balance among histone variants in the cell and an essential role of cysteines in histone H3.1.
Citation Format: Yusha Zhu, Hong Sun, Max Costa. Overexpression of histone H3.1 induced cell malignant transformation and mutation of H3.1 C96/110A further induced chromatin instability [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1480.
Abstract 1487: Investigation of triple-negative breast cancer tumor conversion through high-content screening approaches
Authors: Gaudeau Albane , Lamamy Véronique , Jaskowiak Anne-Laure , Scerri Xavier , Chanrion Benjamin , Dorval Thierry , Nery Elaine Del , Perez Franck , Camonis Jacques , Stéphan Jean-Philippe 
Published: August 2018

Abstract
Among Breast Cancer (BC) classification, Triple-Negative (TN) form is the most aggressive, lacking efficient and specific treatment. Our project aims at investigating the possibility to convert TNBC tumor cell lines in Estrogen Receptor (ER), Progesterone Receptor (PR) and/or Human Epidermal growth factor Receptor 2 (HER2)-positive cells using various modalities (siRNA, CRISPR-Cas9, small molecules). Our approach consists in optimizing a multi-parametric High-Content Screening (HCS) relying on phenotypic read-outs such as expression of TNBC positive and negative markers, cell behavior and viability. This poster will present our initial results, validation and future plans. This thesis project fits within a context of drug discovery, innovation, comparison of technologies and understanding of key biological processes and pathways, carried out in partnership between Servier Research Institute and Institut Curie.
Citation Format: Albane Gaudeau, Véronique Lamamy, Anne-Laure Jaskowiak, Xavier Scerri, Benjamin Chanrion, Thierry Dorval, Elaine Del Nery, Franck Perez, Jacques Camonis, Jean-Philippe Stéphan. Investigation of triple-negative breast cancer tumor conversion through high-content screening approaches [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1487.