bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3459: BRCA1 controls the cell division axis and governs ploidy and phenotype in human mammary cells
Authors: He Zhengcheng , Nemirovsky Oksana , Kannan Nagarajan , Eaves Connie , Maxwell Christopher A. 
Published: July 2017

Abstract
BRCA1 deficiency alters the relative proportions of progenitor cells in preneoplastic mammary tissue, and typically associates with breast cancers characterized by genomic instability and a basal-like cell phenotype. Oriented division of progenitor cells is one mechanism these cells use to maintain tissue homeostasis, and to suppress tumor formation. We now show that shRNA-mediated reduction of BRCA1 levels in non-tumorigenic and immortalized or freshly isolated, normal human mammary cells alters their plane of division with graded consequences that include the induction of aneuploidy in progeny cells, perturbation of polarity in spheroid cultures, and inhibition of clonal growth with favored expression of basal features. We also demonstrate a requirement for BRCA1 in establishing cortical asymmetry of NUMA-dynein complexes. Mutation of a single BRCA1 allele (BRCA1 185delAG/+) altered the division axis of isolated cells but their deficient spindle positioning was supervised by CDH1-positive adherens, which sustained oriented divisions and produced colonies with luminal features. These findings reveal a previously unrecognized consequence of mutant BRCA1 on the cell division axis, post-mitotic integrity and phenotype control in normal human mammary epithelial cells.
Note: This abstract was not presented at the meeting.
Citation Format: Zhengcheng He, Oksana Nemirovsky, Nagarajan Kannan, Connie Eaves, Christopher A. Maxwell. BRCA1 controls the cell division axis and governs ploidy and phenotype in human mammary cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3459. doi:10.1158/1538-7445.AM2017-3459
Abstract 346: Fatty acid synthase is a risk factor for bleomycin-induced lung fibrosis in mice
Authors: Jung Mi-Yeon 
Published: July 2017

Abstract
Pulmonary fibrosis is a significant complication in cancer patients treated with radiation or various chemotherapeutic agents. One such reagent, bleomycin, is used to treat a variety of cancers including, but not limited to, lymphoma, ovarian cancer, and melanoma. Its efficacy, however, is impacted by the incidence of significant pulmonary fibrosis, which often becomes dose limiting. In studies investigating the role(s) of metabolism in the profibrotic actions of transforming growth factor beta, we previously determined that increased fatty acid synthase (FASN) expression was observed in the fibrotic areas of lungs from idiopathic pulmonary fibrosis (IPF) patients compared to healthy controls. In that FASN levels are significantly increased in numerous human tumors including breast, prostate, colorectal, and ovarian, we wished to integrate these findings by examining whether inhibiting FASN activity could reduce pulmonary fibrosis. To that end, the cerulenin-derived FASN inhibitor C75 was tested in a murine treatment model of bleomycin-induced lung fibrosis. Following addition of C75, there was significant diminution in a number of profibrotic targets including collagen 1α1, fibronectin, connective tissue growth factor, and total lung collagen as assessed by hydroxyproline content. Not only was there a C75 dose-dependent decrease in the aforementioned targets, but lung function as assessed by peripheral blood oxygenation (on room air) was also stabilized/improved. Thus, FASN inhibition might reflect a possible target to maintain normal lung physiology in the context of cancer chemotherapy.
This work was supported by Public Health Service grants GM-055816 and GM-054200 from the National Institutes of General Medical Sciences.
Citation Format: Mi-Yeon Jung. Fatty acid synthase is a risk factor for bleomycin-induced lung fibrosis in mice [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 346. doi:10.1158/1538-7445.AM2017-346
Abstract 3463: Mitotic regulation of the tumor suppressor phosphatase PHLPP1
Authors: Grzechnik Agnieszka T. , Newton Alexandra C. 
Published: July 2017

Abstract
The PH domain Leucine-rich repeat Protein Phosphatases (PHLPP) are tumor suppressors originally discovered for their ability to directly dephosphorylate and inactivate the pro-survival kinase Akt, a key transducer of growth factor signaling. In the decade since this discovery, a number of other PHLPP targets have been elucidated, but still little is known about the molecular mechanisms governing the function and regulation of PHLPP itself. Here we report that PHLPP1 is hyperphosphorylated during mitosis and that, additionally, PHLPP1 suppresses the phosphorylation of the mitotic kinase CDK1. Specifically, we show that PHLPP1 undergoes an electrophoretic mobility shift in mitotic cells that is lost when lysates are treated in vitro with lambda phosphatase, suggesting that PHLPP1 is phosphorylated during mitosis. In addition to a cell cycle-dependent change in its post-translational modifications, PHLPP1 suppresses the phosphorylation of the main mitotic cyclin dependent kinase, CDK1, at Tyr15, an inhibitory phosphorylation that must be removed in order for cells to progress through mitosis. First, Tyr15 phosphorylation is increased in phlpp1-/- mouse embryonic fibroblasts (MEFs) compared to wild-type MEFs. Second, pharmacological inhibition of PHLPP1 in wild-type MEFs results in an increase in Tyr15 phosphorylation. Activation of key mitotic kinases, such as CDK1, and inactivation of phosphatases is required for the large increase in protein phosphorylation that occurs during mitosis. As such, reversible protein phosphorylation plays a role in regulating proper progression through mitosis, which is essential as errors in mitosis can result in aneuploidy, a hallmark of cancer. Our data support a previously undescribed role for PHLPP1 in regulating mitotic progression, potentially providing novel insight into how PHLPP suppresses tumorigenesis.
Citation Format: Agnieszka T. Grzechnik, Alexandra C. Newton. Mitotic regulation of the tumor suppressor phosphatase PHLPP1 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3463. doi:10.1158/1538-7445.AM2017-3463
Abstract 3469: Identification of novel human telomerase associated protein by mass spectrometry
Authors: Wang Jing , Bi Xuezhi , Li Shang 
Published: July 2017

Abstract
Telomeres are nucleoprotein structures at the ends of eukaryotic chromosomes that prevent them from degradation, recombination, and end-to-end fusion. Telomere consists of DNA repeats, which in human is of the sequence TTAGGG, and it is bound by a group of proteins called shelterin complex. Telomere is synthesized by telomerase. Telomerase is absent in most human somatic cells while it is up-regulated in 90% of cancer cells, in which telomerase plays an essential role in cancer cells’ replicative immortality. However, telomerase is only present at approximately 250 molecules per cancer cell. To exert its function of elongating telomere, telomerase has to find the end of telomeres which needed to be elongated. However, how telomerase is precisely recruited to telomere ends is not clearly understood. To better understand the recruitment process of telomerase, we initially screened and subsequently identified novel binding proteins of hTERT, the catalytic subunit of telomerase, through a pull-down assay using cancer cell lines with endogenously Flag-tagged hTERT. Using mass spectrometry (MS), we were able to identify a promising interesting protein. Further, direct interaction between TERT and this protein was validated. Then, we found that this protein can also interact with the shelterin component, TRF1 (Telomeric repeat-binding factor 1), which binds to double stranded telomeric DNA. Furthermore, from previous published reports, this protein was shown to interact with single-stranded telomeric DNA binding protein POT1 (Protection of Telomeres 1) in the shelterin complex. Functionally, overexpression of this protein in cancer cell lines can result in the elongation of telomeres, while knock-down or knock-out of the protein results in the shortening of telomere. In conclusion, we identified an hTERT-binding protein that affects telomere maintenance which may be involved in telomerase recruitment process. In the long run, it could serve as a potential therapeutic target for cancers.
Citation Format: Jing Wang, Xuezhi Bi, Shang Li. Identification of novel human telomerase associated protein by mass spectrometry [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3469. doi:10.1158/1538-7445.AM2017-3469
Abstract 3482: SNORD-X in glioblastoma: regulation and functional analysis
Authors: Gupta Shikha , Jha Prerana , Sarkar Chitra , Kulshreshtha Ritu 
Published: July 2017

Abstract
Glioblastoma Multiforme (GBM) is a kind of brain tumor which arises from astrocytes present in the brain. It represents approximately 15% of all primary brain tumor and has been considered as one of the deadliest type of cancer with very poor prognosis. Thus, there is an urgent need to identify novel targets for GBM therapy. Recently, non-coding RNAs (ncRNAs) such as miRNAs and lncRNAs have emerged as one of the promising tools as diagnostic or prognostic biomarkers and as novel targets for therapy. There are recent evidences that small nucleolar RNAs (snoRNAs), a subtype of ncRNAs might also play a key role in various cancers. In this context, we aimed at studying the role of snoRNAs in GBM. For this, we did snoRNA profiling in GBM patients and found that a particular cluster of snoRNA called SNORD-X was highly downregulated in adult as well as pediatric GBM patients. We also found SNORD-X promoter to be methylated and shows maternal imprinting. We next did functional analyses of SNORD-X by generation of an overexpression construct. Our preliminary data suggests that overexpression of SNORD-X in GBM cell lines (U87MG and A172) increases cell proliferation in vitro. It also enhances the colony forming capability of GBM cells. Further, its overexpression causes decrease in apoptosis in a caspase-dependent manner. A target analysis of SNORD-X was done using RNAhybrid software. We found EGR1, DCUN1D3 and BRCA1 to be the direct targets of SNORD-X using a combination of qRT-PCR and wild-type/mutated 3’UTR luciferase analyses. Overall, our work shows for the first time correlation and functional analysis of SNORD-X cluster in GBM.
Citation Format: Shikha Gupta, Prerana Jha, Chitra Sarkar, Ritu Kulshreshtha. SNORD-X in glioblastoma: regulation and functional analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3482. doi:10.1158/1538-7445.AM2017-3482
Abstract 3485: Identification and characterization of circular RNAs in cancer
Authors: Thrue Charlotte A. , Petri Andreas , Løvendorf Marianne B. , Dybkær Karen , Papaioannou Dimitrios , Garzon Ramiro , Kauppinen Sakari 
Published: July 2017

Abstract
Circular RNAs (circRNAs) are an abundant class of non-coding RNAs that are formed by a backsplice event resulting in formation of covalently closed circular RNA molecules. The efficiency of backsplicing is inferior to linear splicing, however, due to their long half-lives circRNAs can accumulate to high levels in cells. Functional characterization of a few circRNAs has shown that they can act as endogenous microRNA sponges and transcriptional regulators; one example is CDR1as/ciRS-7, which has been shown to act as a sponge for miR-7. However, the functions of most circRNAs are still unknown.
To study the potential role of circRNAs in cancer, we identified exonic circRNA candidates by analysing ENCODE RNAseq data from a panel of cancer cell lines. We used chimeric alignment detection implemented in the STAR aligner and subsequent filtering of output files to identify chimeric alignments consistent with circRNA backsplice sites. The circular nature of the identified putative circRNAs was validated by testing their resistance to RNase R digestion, and sequences surrounding the backsplice sites were used as target recognition sequences for designing LNA-modified gapmer antisense oligonucleotides (ASOs) to specifically knock down the circular isoforms of the RNA transcripts.
Data from ongoing studies on knockdown of several abundant circRNAs in cancer cell lines, assessment of the specificity of backsplice-targeting ASOs relative to the linear mRNA counterparts, and analyses to identify biological effects of modulating circRNA levels in cultured cells will be presented.
Citation Format: Charlotte A. Thrue, Andreas Petri, Marianne B. Løvendorf, Karen Dybkær, Dimitrios Papaioannou, Ramiro Garzon, Sakari Kauppinen. Identification and characterization of circular RNAs in cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3485. doi:10.1158/1538-7445.AM2017-3485
Abstract 3493: LncRNA as potential target in drug-resistant melanomas
Authors: Esteve-Puig Rosaura , Sanlorenzo Martina , Vujic Igor , Lai Kevin , Vujic Marin , Mould Dallas , Lin Kevin , Oses-Prieto Juan , Chand Shreya , Posch Christian , Burlingame Alma , Ortiz-Urda Susana 
Published: July 2017

Abstract
Melanoma is the most common lethal form of skin cancer. Activating mutations in BRAF and RAS oncogenes account for over 80% of all melanomas and hyper-activate the MAPK cascade. Despite major advances in targeted melanoma therapies over the past decade, drug resistance limits their efficacy.
Long noncoding RNAs (lncRNAs) are a new class of genes that do not encode proteins, which have been characterized as epigenetic regulatory molecules. LncRNAs have emerged as important players in cancer, potential predictors of therapeutic responses and targets for new treatments; however, their functions and precise molecular mechanisms remains largely unexplored.
Our study aims to find novel potential targets involved in the acquisition of resistance to MAPK inhibitors.
We identified an intergenic lncRNA (lincRNA) highly differentially expressed in drug-resistant melanoma samples, called MAPK Inhibitor Resistance Associated Transcript (MIRAT). We determined that MIRAT is localized mainly in the cytoplasm and plays a role in modulating the signal transduction pathways without regulating the genomic neighborhood. We discovered that MIRAT is upregulated in early drug tolerance to MAPK inhibition. Mechanistically, the gene overexpression and silencing of MIRAT, as well as preliminary RNA-protein interaction results, showed that it modulates the MAPK signal transduction pathway by binding to a downstream target of MEK.
Collectively, these results highlight the relevance of cytoplasmic lincRNA’s and their role in oncogenic signaling pathways, and further suggest that lncRNAs and their protein-binding partners may serve as novel potential targets for overcoming drug resistance in melanoma.
Note: This abstract was not presented at the meeting.
Citation Format: Rosaura Esteve-Puig, Martina Sanlorenzo, Igor Vujic, Kevin Lai, Marin Vujic, Dallas Mould, Kevin Lin, Juan Oses-Prieto, Shreya Chand, Christian Posch, Alma Burlingame, Susana Ortiz-Urda. LncRNA as potential target in drug-resistant melanomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3493. doi:10.1158/1538-7445.AM2017-3493
Abstract 35: The dual inhibition of Met and EGFR by ME22S, a novel Met/EGFR bispecific monoclonal antibody, suppresses the proliferation and invasion of laryngeal cancer
Authors: Lee Bok-Soon , Kim Dae Ho , Kim Yeon Soo , Chang Jae Won , Koo Bon Seok , Won Ho Ryun , Kim Haeng-Jun , Cha Hyun-Young , Lee Ji Min , Kim Kyung-Ah , Kim Chul-Ho 
Published: July 2017

Abstract
Background and purpose: It has been reported that the abnormal activation of receptor tyrosine kinases is associated with the development of many human carcinomas and the high activation of EGFR and Met mediates the tumorigenicity of laryngeal carcinoma. In this study, we have done the therapeutic efficacy of ME22S, a novel EGFR/Met bispecific antibody, in laryngeal carcinoma in vitro and in vivo was thoroughly evaluated.
Methods: The effects of ME22S on cell viability was assessed through MTT assays, then Western blotting and immunocytochemistry were used to determine the expression of EGFR and Met. Also, wound healing and invasion assays were performed to observe the inhibitory effects of ME22S.
Results: We found the ability of ME22S reducing the expression of both EGFR and Met and significantly inhibiting the cell migration, invasion, and proliferation of SNU899 and HN3 in vitro. Also the notably reduced levels of p-Met, p-ERK, and p-AKT were found when the cells were treated with only ME22S alone or with HGF together. Meanwhile, ME22S, interestingly enough, caused caspase-3-dependent apoptotic cell death when HN3 cells were treated with ME22S for 72h, decreased the HGF-induced Slug expression, and also inhibited the tumor growth of HN3 cells in a xenograft model in vivo.
Conclusion: Taken together, our findings suggest that the dual inhibition of EGFR and Met through ME22S largely suppresses the invasion and growth of laryngeal carcinoma both in vitro and in vivo, hence, can be a practical approach as a novel therapeutic strategy for the treatment of laryngeal carcinoma.
Citation Format: Bok-Soon Lee, Dae Ho Kim, Yeon Soo Kim, Jae Won Chang, Bon Seok Koo, Ho Ryun Won, Haeng-Jun Kim, Hyun-Young Cha, Ji Min Lee, Kyung-Ah Kim, Chul-Ho Kim. The dual inhibition of Met and EGFR by ME22S, a novel Met/EGFR bispecific monoclonal antibody, suppresses the proliferation and invasion of laryngeal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 35. doi:10.1158/1538-7445.AM2017-35
Abstract 3502: RNAi screen identified novel long non-coding RNAs involved in cell growth control, migration, and invasion
Authors: Kuo Tse-Chun , Hsu Sheng-Chieh , Chou Hui-Ju , Li Pei-Shan , Wu Szu-Huei , Yu Yen-Ling , Song Jen-Shin , Kung Hsing-Jien 
Published: July 2017

Abstract
Triple-negative breast cancer (TNBC) is a highly aggressive form of breast cancer often associated with poor prognosis. Owing to the lack of therapeutic targets, patients with TNBC tend to rely on standard chemotherapy; however, chemo-resistance often develops in TNBC as a result of deregulated cell death control like in many other tumors. Long non-coding RNAs (lncRNAs) are transcripts longer than 200bp and have little or no protein-coding capacity. Although once considered as transcriptional noise, significant numbers of lncRNAs are now known as modulators of protein expression and functions and are implicated in a range of developmental processes and diseases. As many of them influence oncogenes and tumor suppressors in cancer, they represent excellent biomarkers as well as potential targets for therapy. In order to gain more insight on cell death regulation and to seek potential targets for TNBC, we employed an RNAi screen targeting 2231 lncRNAs in MDA-MB-231 TNBC cells. By using changes in cell metabolic activity (MTT assay) as readouts for primary screen and changes in cell number as confirmation, our unbiased screen identified two novel lncRNAs that drastically reduced cell proliferation when depleted. In addition to cell growth, the two lncRNAs also contribute to cancer cell migration and invasion. Interestingly, our gene profiling analyses and RNA immunoprecipitation studies show the two lncRNAs are involved in signaling cascades known to promote mammary tumorigenesis including EGF and β-catenin. We are now trying to delineate the detailed molecular mechanism(s) by which the two lncRNAs contribute to TNBC tumorigenesis. Together, our current results suggest a possibility for the two novel lncRNAs as drug targets in triple-negative breast cancer.
Citation Format: Tse-Chun Kuo, Sheng-Chieh Hsu, Hui-Ju Chou, Pei-Shan Li, Szu-Huei Wu, Yen-Ling Yu, Jen-Shin Song, Hsing-Jien Kung. RNAi screen identified novel long non-coding RNAs involved in cell growth control, migration, and invasion [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3502. doi:10.1158/1538-7445.AM2017-3502