bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2430: The expression of BCL6 and ZEB family transcription factors and their correlation in breast cancers
Authors: Zhao Min , Ang Lin , Zheng Li , Wang Jin , Huang Jin , Hu Hongguang , Zou Qiang 
Published: July 2017

Abstract
The proto-oncogene B-cell lymphoma 6 (BCL6) is an evolutionarily conserved zinc finger protein and a potent transcriptional repressor. It is also the master regulator of B-lymphocyte development. Emerging evidence indicates that BCL6 may play an important role in breast cancer progression. In this study, we investigated the expression of BCL6 and tis correlation with the expression of epithelial-mesenchymal transition (EMT)-associated transcription factors zinc finger E-box-binding homeobox 1 (ZEB1) and ZEB2 in invasive breast cancers. The mRNA and protein expression of BCL6, ZEB1 and ZEB2 were examined using in situ hybridization and immunohistochemistry, respectively, in 228 breast cancer patients and 80 patients with breast benign diseases. The association of BCL6, ZEB1 and ZEB2 expression with clinicopathological parameters and patient survival were analyzed. We found that the expression of BCL6, ZEB1 and ZEB2 protein and mRNA were significantly higher in breast cancer tissues than in breast benign disease tissues (P&lt;0.05). The expression levels of BCL6, ZEB1 and ZEB2 were all positively correlated with the tumor size, lymph node metastasis and higher tumor stages (P&lt;0.05). Furthermore, patients with BCL6, ZEB1 and ZEB2 protein-positive primary tumors were associated with a significant lower overall survival (OS) rate (P=0.001, 0.002 and 0.001, respectively) and post-operative relapse-free survival (RFS) rate (P=0.002, 0.001 and 0.003 for the expression of BCL6, ZEB1 and ZEB2, respectively). The mRNA expression of ZEB1 and ZEB2 were positively correlated with BCL6 mRNA expression (rs=0.326, P&lt;0.001; and rs=0.382, P&lt;0.001, respectively); the protein expression of ZEB1 and ZEB2 were also positively correlated with BCL6 protein expression (rs=0.449, P&lt;0.001; and rs=0.669, P&lt;0.001, respectively). These results indicate that BCL6, ZEB1 and ZEB2 may be as potential biomarkers for predicting invasion, metastasis and prognosis of breast cancer and that BCL6 may be a regulator of ZEB family transcription factors (ZEB1 and ZEB2).
Note: This abstract was not presented at the meeting.
Citation Format: Min Zhao, Lin Ang, Li Zheng, Jin Wang, Jin Huang, Hongguang Hu, Qiang Zou. The expression of BCL6 and ZEB family transcription factors and their correlation in breast cancers [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 2430. doi:10.1158/1538-7445.AM2017-2430
Abstract 2431: Single cell gene expression profiling in breast cancer cells with the Her2/neu gene knockout by CRISPR-Cas9
Authors: Wang Xiaoyang , Lomas Chip , Tycon Michael A. , Betts Craig , Weaver Suzanne 
Published: July 2017

Abstract
The Her2/neu gene is amplified and overexpressed in 15%-30% of breast cancers. The overexpression of this oncogene is strongly correlated with decreased survival, increased cancer relapse, and poor prognosis. Although therapy has been successfully developed to target this oncogene, a better understanding of this oncogene will provide further insight for breast cancer biology and future drug development. In recent years, the CRISPR-Cas9 system has emerged as an efficient method for genetic engineering, enabling targeted gene knockout with minimal off-target effects.
In this study, we employed a plasmid-based CRISPR-Cas9 system to knock out the Her2/neu gene in breast cancer cells. Puromycin selected, GFP-positive (two indicators of the incorporation of the CRISPR-Cas9 system), Her2-negative individual cells were index-sorted using a BD FACSMelody™ system into individual wells of a 96-well BD™ Precise plate with sample barcoding and molecular indexing. A whole transcriptome amplification (WTA) assay was performed to obtain a gene expression profile for each of the Her2/neu knockout cells. Her2 gene knockout was performed on two cell lines: T47D, a ductal carcinoma-derived breast cancer cell line with no Her2 amplification that shows low to intermediate Her2/neu expression; and SKBR3, an adenocarcinoma-derived breast cancer cell line known for Her2/neu gene amplification and overexpression. For comparison, WTA assays were also carried out on parental cells without gene editing. Comparison of the gene expression profiles reveals downstream changes in gene expression correlated to the Her2 knockout.
The profiling of gene expression in Her2/neu CRISPR-Cas9 knockout cells on a single cell level promises to provide insight into the mechanisms in these aggressive cancers that could help future drug discovery.
For Research Use Only. Not for use in diagnostic or therapeutic procedures.
23-19341-00
Citation Format: Xiaoyang Wang, Chip Lomas, Michael A. Tycon, Craig Betts, Suzanne Weaver. Single cell gene expression profiling in breast cancer cells with the Her2/neu gene knockout by CRISPR-Cas9 [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 2431. doi:10.1158/1538-7445.AM2017-2431
Abstract 2435: Smoothened a new perspective for uterine leiomyoma treatment
Authors: Garcia Natalia , Anjos Laura Gonzalez , Maffazioli Giovana De Nardo , Bozzini Nilo , Baracat Edmund Chada , Carvalho Katia Candido 
Published: July 2017

Abstract
Background: Uterine leiomyomas (LM) are the most common gynecologic tumors occurring in women of reproductive age. Patients may present clinical complications such as bleeding, pain and infertility. Additionally, some researchers believe that a leiomyosarcoma can arise from a degenerated LM. Efficient treatments for LM are still limited. Identification of gene markers can help to elucidate these tumors pathogenesis and to reveal molecules that can be used as therapeutic targets.
Objective: To assess gene and miRNAs expression, and DNA methylation profiles of genes related to the Sonic Hedgehog (SHH) signaling pathway in uterine leiomyoma samples in order to look for potential therapeutic targets.
Methods: 80 samples of LM and 20 myometrium (MM) were obtained in the Department of Obstetrics and Gynecology at HCFMUSP/Sao Paulo - Brazil. Expression profile of 106 genes and 84 miRNAs sequences related to SHH regulation, and the percentage of methylation in the promoter region of the SHH, PTCH1, SMO, SUFU, GLI and GLI3 genes were performed by quantitative Real Time PCR. Results: Among 106 genes evaluated, 16 showed hyper- and 11 showed hypoexpression in LM samples, compared to MM. Only SMOOTHENED (SMO) was found hyperegulated in LM. miRNAs analysis showed 16 sequences with different regulation profiles between LM and MM. None of them is involved in the regulation of SMO expression. DNA methylation profile showed a higher percentage of methylation in LM samples, but this difference did not exceed 2% of methylation for the PTCH1, SMO, GLI1 and GLI3 genes. Conclusion: Our results suggest an activation of SHH pathway in LMs by hyperexpression of SMO. These results are very interesting because there are SMO specific drugs approved by FDA for other tumors types.
Citation Format: Natalia Garcia, Laura Gonzalez Anjos, Giovana De Nardo Maffazioli, Nilo Bozzini, Edmund Chada Baracat, Katia Candido Carvalho. Smoothened a new perspective for uterine leiomyoma treatment [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 2435. doi:10.1158/1538-7445.AM2017-2435
Abstract 2453: Chromatin remodeling genes are frequently somatically altered in cervical carcinomas
Authors: Ojesina Akinyemi , Sundaresan Aishwarya , Srinivasasainagendra Vinodh , Tiwari Hemant , Huh Warner 
Published: July 2017

Abstract
Introduction: Cervical cancer is responsible for 15% of all deaths due to cancer in women worldwide. There is a need to identify somatic mutations driving this cancer in order to facilitate development of novel therapeutic strategies.
Experimental procedures: We analyzed whole exome sequencing data from 430 cervical carcinomas. The data were derived from a combination of our previously published work (Ojesina et al. Nature 2014; Chung et al, Int J Cancer 2015), and publicly available data generated by the Cancer Genome Atlas (TCGA). The Mutect2.0 and MutSig2CV algorithms were used to identify somatic mutations and significantly mutated genes (SMGs) respectively. Copy number alterations were analyzed using the GISTIC algorithm.
Findings: Based on MutSig2CV false discovery rate threshold of 0.1, we identified MLL3 (19%) and MLL2 (13%) as novel significantly mutated genes (SMGs) in cervical cancer. In addition, other chromatin modifying genes including EP300 (12%) and ARID1A (7%) were confirmed as SMGs. Further investigation of genes that did not meet the threshold revealed that 228 of 430 (53%) of cervical tumors harbored at least one somatic mutation in a chromatin modifying gene. These include genes in the myeloid/lymphoid or mixed-lineage leukemia (MLL) family (28%), lysine (K)-specific demethylase (KDM) family (23%), AT rich interactive domain (ARID) family (13%), SWI/SNF related, matrix associated, actin dependent regulator of chromatin (SMARC) family (8%) and histone cluster 1 (HIST1) family (4%).
Conclusions: We have demonstrated that a majority of cervical cancers harbor somatic mutations in chromatin remodeling genes. This novel finding was facilitated by the larger sample size derived from combining multiple datasets, and may have diagnostic and therapeutic implications in cervical cancer.
Citation Format: Akinyemi Ojesina, Aishwarya Sundaresan, Vinodh Srinivasasainagendra, Hemant Tiwari, Warner Huh. Chromatin remodeling genes are frequently somatically altered in cervical carcinomas [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 2453. doi:10.1158/1538-7445.AM2017-2453
Abstract 2455: Human glioblastoma arises from the distant subventricular zone normal appearing but harboring tumor-initiating mutations
Authors: Lee Joo Ho , Lee Jeong Eun , Kahng Jee Ye , Park Junseong , Yoon Seon Jin , Kim Se Hoon , Chang Jong Hee , Kang Seok-Gu , Lee Jeong Ho 
Published: July 2017

Abstract
Glioblastoma multiforme (GBM) is the most devastating and incurable brain tumor. Although the identification of cells with tumor initiating mutations or their location can provide the fundamental basis for understanding disease progression, the origin of GBM remains controversial due to the lack of direct evidence in human GBM patients. Here, we performed ultra-deep sequencing of triple-matched tissues of i) radiologically and pathologically normal subventricular zone (SVZ), which is distant from tumor, ii) GBM tumor, and iii) blood (or normal cortical tissues) from patients with GBM (IDH-wildtype), compared to those with other type of brain tumors such as GBM (IDH-mutant), meningioma, oligodendrgolioma, metastatic brain tumor, and GBM (IDH-wildtype) with SVZ-invasion. Surprisingly, we found that in 55.5% of IDH-WT GBM patients (5 of 9), normal appearing and distant SVZ already contained the low level of GBM mutations such as TP53, EGFR, RB1, PDGRF or TERT variations observed in the matched tumor. Single cell sequencing of GBM tumors and laser capture microdissection analysis of the SVZ show that mutations are enriched in the astrocyte ribbon area, which clonally evolved from the SVZ to the distant GBM tumor. Furthermore, using CRISPR-Cas9 system in the postnatal mouse brain, we showed that neural stem cells with TP53, PTEN, EGFR mutations migrated away from the mutated SVZ site and then formed the high grade malignant glioma in the distant cortical region. Taken together, this study provides the direct evidence that human glioblastoma arises from the distant SVZ that is normal-appearing but harboring tumor-initiating mutations.
Citation Format: Joo Ho Lee, Jeong Eun Lee, Jee Ye Kahng, Junseong Park, Seon Jin Yoon, Se Hoon Kim, Jong Hee Chang, Seok-Gu Kang, Jeong Ho Lee. Human glioblastoma arises from the distant subventricular zone normal appearing but harboring tumor-initiating mutations [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 2455. doi:10.1158/1538-7445.AM2017-2455
Abstract 2468: Gene aberrations for precision medicine against lung adenocarcinoma
Authors: Saito Motonobu , Kono Koji , Kohno Takashi 
Published: July 2017

Abstract
Lung adenocarcinoma (LADC) is often triggered by an aberration in a driver oncogene. LADC harboring EGFR mutation and ALK fusion can be treated with anti-cancer drugs that target the aberrant gene products. These molecularly targeted drugs showed significant positive effectiveness for the LADC patients with EGFR mutations and ALK fusions. Additional oncogene aberrations, including RET, ROS1, and NRG1 fusions, skipping of exon 14 of MET, and mutations in BRAF, HER2, NF1, and MEK1, were recently added to the list of such “druggable” driver oncogene aberrations, and their responses to targeted therapies are currently being evaluated in several clinical trials. On the other hand, about 30% and 50% of LADCs in patients in Japan and Europe/USA, respectively, lack the driver oncogene aberrations listed above. Therefore, novel therapeutic strategies, such as those that exploit the vulnerabilities of cancer cells with non-oncogene aberrations, are urgently required. In this presentation, we show gene mutation profiles according to driver oncogenes and summarize the frequencies of those aberrations. We also compare driver aberrations between Japan and USA according to smoking status and sex. This will provide the current status of research on precision medicine against LADC and enumerates the research priorities for the near future.
Citation Format: Motonobu Saito, Koji Kono, Takashi Kohno. Gene aberrations for precision medicine against lung adenocarcinoma [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 2468. doi:10.1158/1538-7445.AM2017-2468
Abstract 2474: The mechanistic role of polyamines in DNA double-strand break repair
Authors: Lee Chih-Ying , Su Guan-Chin , Ko Min-Yu , Huang Wen-Yen , Chang Geen-Dong , Lin Sung-Jan , Chi Peter 
Published: July 2017

Abstract
Polyamines are essential organic cations for cell growth, proliferation and tissue remodeling. The rate-limiting step in the biosynthesis of polyamines is catalyzed by ornithine decarboxylase (ODC). The activity of ODC and the level of intracellular polyamines significantly increase in many cancers, indicating the critical role of polyamines in tumorigenesis. Depletion of polyamines sensitizes cells to DNA damage agents that lead to DNA double-strand breaks (DSBs), suggesting that endogenous polyamines may participate in DNA repair process. However, the mechanistic role of polyamines in DSB repair remains largely unknown. Here, we wish to ascertain the role of polyamines in DSBs repair pathway and to delineate the underlying mechanism by combining biochemical analyses, cell-based and animal approaches. Our cell-based experiments demonstrated that polyamines indeed participate in DNA double-strand break repair. Specifically, the level of intracellular polyamines regulates homologous recombination (HR) repair pathway rather than non-homologous end joining (NHEJ). Furthermore, our in vitro reconstitution system and functional analyses demonstrated that polyamines significantly enhance RAD51-mediated DNA strand exchange reaction. Importantly, we reveal that the stimulatory effect of polyamines by RAD51 stems from the enhancement of duplex DNA captures in the DNA exchange reaction. Finally, the physiological role of polyamines in DSBs repair was examined by using mouse hair follicle as a model system. The animal model clearly highlights the significant contribution of polyamines to the DNA repair in vivo. Our findings thus furnish valuable insight into the mechanistic basis of polyamines in DNA repair.
Citation Format: Chih-Ying Lee, Guan-Chin Su, Min-Yu Ko, Wen-Yen Huang, Geen-Dong Chang, Sung-Jan Lin, Peter Chi. The mechanistic role of polyamines in DNA double-strand break repair [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 2474. doi:10.1158/1538-7445.AM2017-2474
Abstract 248: Eicosapentaenoic acid attenuates obesity-related hepatocellular carcinogenesis
Authors: Inoue-Yamauchi Akane , Itagaki Hiroko , Oda Hideaki 
Published: July 2017

Abstract
The population of obesity caused by excess energy intake and insufficient physical activity is increasing worldwide. Excess accumulation of body fat is a risk of health, indeed obesity is associated with the pathogenesis of various disease including type II diabetes, cardiovascular disease and cancer. Among various kinds of cancer, the risk of hepatocellular carcinoma (HCC) is strongly influenced by obesity. Studies using diet-induced obesity mouse models show that obesity enhances tumor development inducing chronic inflammation in liver. In fact, obesity failed to promote HCC formation in the absence of inflammatory cytokines IL-6 and TNF-α. Eicosapentaenoic acid (EPA), an omega-3 polysaturated fatty acid, has been shown its anti-inflammatory properties and could be therapeutically useful to ameliorate inflammatory diseases. However, little is known about the effects of EPA on liver cancer which is linked to obesity-related inflammation. Therefore, we tested the effects of EPA on obesity-induced inflammatory response and following tumor development. We used the hepatic procarcinogen dietylnitrosamine (DEN) to induce HCC formation in mice. Since high-fat diet (HFD) can induce obesity and significantly enhance HCC formation in DEN-injected mice, this model is useful to assess tumor promotion on obesity. Using this model, we examined therapeutic potential of EPA in obesity-related cancer. As a result, we found that tumor growth in mice fed HFD supplemented with EPA was reduced compared to HFD-fed mice, indicating that EPA attenuates obesity-related hepatocarcinogenesis. Interestingly, EPA had no obvious effects on obesity-induced inflammation, instead, inhibited tumor growth by suppression of the protumorigenic transcription factor Stat3 signaling. These data suggest translational implications for the treatment of obesity-related HCC.
Citation Format: Akane Inoue-Yamauchi, Hiroko Itagaki, Hideaki Oda. Eicosapentaenoic acid attenuates obesity-related hepatocellular carcinogenesis [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 248. doi:10.1158/1538-7445.AM2017-248
Abstract 2481: RAD51 and AICDA define a new synthetic lethal interaction that is targetable in multiple tumor types
Authors: Mills Kevin D. , Roche Marly I. , Cyr Amber , Maclay Tyler , Hasham Muneer G. , Lamont Kristin , Branca Jane , Cavallo Francesca , Cavallo Francesca , Jasin Maria , Stern Alvin , Kwon Youngho , Zhao Weixing , Sung Patrick 
Published: July 2017

Abstract
Antigen stimulated B-cells transiently express Activation Induced Cytidine Deaminase (AID) which initiates point mutations and DNA double strand breaks (DSB) in immunoglobulin genes to promote B-cell maturation. However, AID is capable of broadly damaging the B-cell genome. We have shown that AID-induced DSBs require the homologous recombination factor RAD51 for their repair. Using genetic approaches, we discovered that reduced HR function is cytotoxic to AID-expressing B-cells. We subsequently demonstrated the feasibility of small molecule inhibition of RAD51 to sensitize AID-overexpressing tumor cells. Here we build on those observations, finding that AID-RAD51 synthetic lethality occurs via mitotic catastrophe, involving the mTOR pathway. We have now developed potent and selective RAD51 modulatory small molecules that preferentially kill AID-expressing tumor cells. Using mouse models of lymphoma and leukemia we provide in vivo efficacy data demonstrating the potential therapeutic feasibility of RAD51 modulation. These studies provide evidence for a novel “synthetic lethal” approach for treating AID-expressing malignancies, via the induction of mitotic catastrophe.
Citation Format: Kevin D. Mills, Marly I. Roche, Amber Cyr, Tyler Maclay, Muneer G. Hasham, Kristin Lamont, Jane Branca, Francesca Cavallo, Francesca Cavallo, Maria Jasin, Alvin Stern, Youngho Kwon, Weixing Zhao, Patrick Sung. RAD51 and AICDA define a new synthetic lethal interaction that is targetable in multiple tumor types [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 2481. doi:10.1158/1538-7445.AM2017-2481
Abstract 2482: Inhibition of RAD51 with a cell penetrating antibody, 3E10
Authors: Glazer Peter M. , Turchick Audrey 
Published: July 2017

Abstract
Many human malignancies arise in the setting of defective DNA repair pathways, leading to genetic instability, carcinogenesis and tumor progression. However, DNA repair deficiency can provide for a therapeutic window that can be exploited with targeted agents. One such anti-cancer agent is 3E10, a unique cell penetrating, anti-DNA autoantibody. 3E10 by itself is considered non-toxic to normal cells but has been shown to have deleterious effects on cells with DNA repair deficiencies. Specifically, 3E10 has been shown to reduce the efficiency of homologous recombination (HR). This has been attributed to its ability to preferentially binding to ssDNA tails, thereby inhibiting Rad51 mediated strand exchange. Prior work has shown that treatment with 3E10 alone can selectively kill cells with genetic mutations that lead to abnormal DNA repair. For example, 3E10 has been shown to be synthetically lethal in BRCA2 deficient human cancer cells. Additionally, 3E10 sensitizes cells to radiation and other DNA damaging therapies. The goal of this project is to characterize the specific mechanism by which 3E10 inhibits DNA repair pathways. Previously, the mechanism by which 3E10 inhibits HR was attributed to 3E10’s DNA binding ability. Through the biochemical evaluation of 3E10 variants, new evidence now suggests that 3E10 inhibits HR independently of 3E10’s ability to bind DNA. We have found that this HR inhibition is a result of a physical interaction between 3E10 and Rad51. Biochemical analysis revealed that 3E10 binds to the N-terminal domain of Rad51, the domain that plays a role in Rad51 homo-oligomerization and filament formation. This 3E10-Rad51 interaction impairs Rad51’s ability to localize to the nucleus and form repair foci. Taken together, this data suggests that 3E10 inhibits HR by physically interacting with Rad51. Overall, 3E10 holds promise as a novel therapeutic agent for certain subsets of cancer.
Citation Format: Peter M. Glazer, Audrey Turchick. Inhibition of RAD51 with a cell penetrating antibody, 3E10 [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 2482. doi:10.1158/1538-7445.AM2017-2482