bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2162: Loss of ATF3 promotes akt activation and prostate cancer development in a pten knockout mouse model
Authors: Wang Ziyan , Xu Dong , Yan Chunhong 
Published: August 2015

Abstract
Activating transcription factor 3 (ATF3) responds to diverse cellular stresses, and regulates oncogenic activities (e.g., proliferation, survival and migration) through direct transcriptional regulation or protein-protein interactions. Although aberrant ATF3 expression was often found in human cancers, the role of ATF3 in tumorigenesis is poorly understood. Here we demonstrate that ATF3 suppresses the development of prostate cancer induced by knockout of the tumor suppressor Pten in mouse prostates. Whereas oncogenic stress caused by Pten loss induced ATF3 expression in prostate epithelium, we found that ATF3 deficiency increased cell proliferation but inhibited apoptosis, leading to early onset of mouse prostatic intraepithelial neoplasia and the progression of prostate lesions to invasive adenocarcinoma. Importantly, loss of ATF3 appeared to promote activation of the oncogenic AKT signaling evidenced by high levels of phosphorylated AKT and S6 proteins in ATF3-null prostate lesions. In line with these in vivo results, knockdown of ATF3 expression in human prostate cancer cells by sgRNA-mediated targeting activated AKT, elevated NF-KB nuclear translocation and increased expression of a broad of matrix metalloproteinase such as MMP-9, MMP-10. By zymography and q-PCR assays, we found that MMP-9 expression increased in ATF3-knockdown DU145 and PC3 cells. Also from luciferase reporter result, we further confirmed that loss of ATF3 could elevate MMP-9 expression via activating NF-KB. And in vivo immunochemistry results also show increased MMP9 expression and discontinuous a-SMA staining along prostate glands. These results were well anticipated that ATF3 deficiency leads to activated AKT signaling, which further activates IKK-A to increase nuclear translocation of NF-KB, which in turn binds to the MMP-9 promoter and induces MMP-9 expression in ATF3-downregulated prostate cancer cells, then promotes invasion in Pten-lost mouse prostates. Our results thus link ATF3 to the AKT signaling, and provide the first genetic evidence supporting that ATF3 is a tumor suppressor for a subset of prostate cancers harboring dysfunctional Pten.
Citation Format: Ziyan Wang, Dong Xu, Chunhong Yan. Loss of ATF3 promotes akt activation and prostate cancer development in a pten knockout mouse model. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2162. doi:10.1158/1538-7445.AM2015-2162
Abstract 2174: Identification of genetic factors contributing to development of common cancers through tissue-specific protein interaction analysis
Authors: Qian David C. , Byun Jinyoung , Han Younghun , Hunter David J. , Henderson Brian E. , Eeles Rosalind , Haiman Christopher A. , Easton Douglas F. , Hung Rayjean J. , Amos Christopher I. 
Published: August 2015

Abstract
In the genetic study of diseases, pathway based analysis captures more of the variability in risk than single-variant analysis, and also provides a meaningful framework for organizing and interpreting findings. Here, we augment the biologic insights provided by pathway based analysis of GWAS results by incorporating tissue-specific protein interactions. From large GWAS meta-analyses of lung cancer (12,160 cases/16,838 controls), breast cancer (15,748 cases/18,084 controls), and prostate cancer (14,160 cases/12,724 controls), we determined the tissue-specific interactomes of proteins expressed from genes containing independently associated variants. The pathways with statistical overrepresentation of proteins in each network were evaluated across the three cancers. Our results show that pathways implicated in the development of all three cancers or two out of the three cancers tend to be broad, essential cellular processes required for growth and survival. The most significant examples include the nerve growth factor (P = 1.65 × 10^-47), epidermal growth factor (P = 1.22 × 10^-37), and stem cell factor/Kit (P = 4.47 × 10^-35) signaling cascades. However, within these shared pathways, the proteins encoded by genes with risk-conferring variants generally differ from cancer to cancer. Pathways found to be unique for a single cancer focus on more specific cellular functions, such as leptin signaling in breast cancer (P = 1.24 × 10^-6) and platelet sensitization by low-density lipoprotein in prostate cancer (P = 3.80 × 10^-6). Taken together, we demonstrate a new method of pathway based analysis following GWAS that considers tissue-specific protein interactions. For cancers of the lung, breast, and prostate, we validate known susceptibility pathways and identify previously unexplored ones, as well as characterize each cancer by its unique pathways.
Citation Format: David C. Qian, Jinyoung Byun, Younghun Han, David J. Hunter, Brian E. Henderson, Rosalind Eeles, Christopher A. Haiman, Douglas F. Easton, Rayjean J. Hung, Christopher I. Amos. Identification of genetic factors contributing to development of common cancers through tissue-specific protein interaction analysis. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2174. doi:10.1158/1538-7445.AM2015-2174
Abstract 220: New computerized image analyzing technique for analysis of bone marrow microvessel density in multiple myeloma
Authors: Sun-Young Kong , Lee Nuri , Kim Young Jae , Sohn Ji Yeon , Lee Hyewon , Eom Hyeon-Seok , Kim Kwang Gi 
Published: August 2015

Abstract
Background: Angiogenesis is important in proliferation and survival of neoplastic cells in multiple myeloma (MM). Microvessel density (MVD) is a useful angiogenesis marker, which can be detected by anti-CD34 immunohistochemical stain. However, counting the MVD of bone marrow (BM) by light microscopy has a limitation in standardization due to inter-observer differences. Consistent method for MVD assessment has been required to resolve the variation in number. Here we developed the MVD counting method using computerized image analyzer (CIA) and light microscopy.
Methods: A total of 21 patients with primary diagnosed with MM were evaluated. MVD was assessed by screening three hot spots of CD34 positive vessels on BM biopsy section (x40 magnification). MVD was measured by three different ways. First, the number of vessels was counted using light microscope at the time of diagnosis by several hematopathologists (MVD-A). Second, the total count of microvessels per 14435.2 μm2 (1388 × 1040μm) of marrow area was measured by a Zeiss microscope using AxioVison LE Image Analyzer with developed image analyzer program (MVD-B). In addition, manual count of captured image by CIA with one observer was examined (MVD-C). Software was developed using Microsoft visual studio (ver. 2010, Microsoft, USA) and VTK (ver. 5.10.0, Kitware, USA) library. Captured image was labeled via pre-processing for image enhancement and seed region growing algorithm to detect the MVD candidates. Using histogram texture analysis, each candidate was determined to MVD.
Results: The range of MVD was as followings: MVD-A (range 3-52; mean 16.5; SD 12.8), MVD-B (range 4-38; mean 19.6; SD 10.0), and MVD-C (range 5-34; mean 14.8; SD 7.8).There was a significant correlation between theses angiogenesis parameters. Pearson's correlation coefficient of MVD-A with MVD-B was 0.535 (P = 0.01), MVD-A with MVD-C was 0.581 (P &lt; 0.01), and MVD-B with MVD-C was 0.897 (P &lt; 0.01).
Conclusions: We developed the computer aided diagnostic tools to measure MVD more objectively. MVD count using image analyzer was well correlated with manual count and more accurate than MVD count on light microscope. Further studies with continuous upgrades on counting program are now in progress. Finally, we tried to apply this method in practice to predict the prognostic impact on MM patient at the time of diagnosis.
Citation Format: Kong Sun-Young, Nuri Lee, Young Jae Kim, Ji Yeon Sohn, Hyewon Lee, Hyeon-Seok Eom, Kwang Gi Kim. New computerized image analyzing technique for analysis of bone marrow microvessel density in multiple myeloma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 220. doi:10.1158/1538-7445.AM2015-220
Abstract 2216: A novel G-quadruplex formed in the proximal P1 promoter of bcl-2 gene is a gene suppressor
Authors: Onel Buket , Carver Megan , Yang Danzhou 
Published: August 2015

Abstract
Deregulation of bcl-2, an anti-apoptotic protein, is associated with several human diseases such as tumorigenesis, neurodegeneration, and autoimmune deficiencies. DNA G-quadruplex secondary structures that form in the G-rich proximal promoter regions have been found to play an important role in gene transcriptional regulation. We discovered a novel GC-rich sequence in the immediate proximal P1 promoter of the bcl-2 gene (bcl2P1Pu29), which forms a thermodynamically stable, intramolecular G-quadruplex (bcl2P1G4) that represses bcl-2 gene transcription. Dimethyl sulfate footprinting studies indicated that this bcl2 P1 promoter G-rich region forms G-quadruplexes under physiologically relevant ionic conditions. This was shown by clear DMS protection of guanine N7, which is characteristic of G-quadruplex formation. NMR spectroscopic study of bcl2P1Pu29 showed the formation of a well-defined major G-quadruplex structure under physiologically relevant ionic conditions, as evident by sharp peaks in the imino proton region. Interestingly, NMR data also indicated the presence of Watson-Crick base-pairing, suggesting a potential unique loop conformation. Circular dichroism (CD) studies suggested that bcl2P1G4 adopts parallel-stranded folding. Both NMR and CD data indicated a monomeric structure of bcl2P1G4 with high thermo-stability. Using a luciferase assay, we have shown that TMPyP4, a planar cationic G-quadruplex-interactive compound, significantly inhibits the promoter activity through this G-rich bcl-2 P1 promoter region, while TMPyP2, a positional isomer of TMPyP4 which is a poor G-quadruplex-interactive compound, did not show a significant effect. Our results suggest that this novel intramolecular G-quadruplex formed in the bcl-2 proximal promoter region appears to be a suppressor of gene transcription, which could be a potential molecular target for small molecules to modulate bcl-2 gene transcription.
Citation Format: Buket Onel, Megan Carver, Danzhou Yang. A novel G-quadruplex formed in the proximal P1 promoter of bcl-2 gene is a gene suppressor. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2216. doi:10.1158/1538-7445.AM2015-2216
Abstract 2225: c-Myc and Frizzled 8 play a major role in the regulation of cancer stem cells and drug resistance in triple-negative breast cancer
Authors: Yin Shuping , Cheriyan Vino T. , Rishi Arun K. , Reddy Kaladhar B. 
Published: August 2015

Abstract
Triple-negative breast cancer (TNBC) studies have shown that neoadjuvant chemotherapy before surgery was effective in the minority of women, whereas the majority that had a residual tumor had a relatively poor outcome. We have previously shown that cisplatin plus TRAIL treatment was most effective compared to PARP -inhibitors, pacliotaxol, dacelotaxol or cisplatin alone in TNBC cells. To identify the mechanism by which residual cancer cells survive chemotherapy, we initially performed gene expression profiling using the CRL2335 and MDA-MB-468 TNBC cells before and after treatment with cisplatin plus TRAIL. Gene expression prolife revealed that cisplatin plus TRAIL significantly inhibited major signaling pathways related with cancer stem cells (CSCs) such as Notch, Hedgehog, TGFβ and most of the Wnt/β-catenin signaling when compared with untreated control group. However, residual cells after cisplatin plus TRAIL treatment showed a significant increase in the expression of Frizzled 8 (FZD8 -one of the Wnt receptors) and c-Myc. In vivo, animal studies indicate that cisplatin plus TRAIL treatments predominantly eliminated non-cancer stem cells (non-CSCs), as demonstrated by whole-body fluorescent imaging of mice injected with mammosphere-forming CRL2335 cells that were stably transfected with dsRed. This led to CSCs enrichment in residual tumors, as confirmed by immunostaining for CSC markers. Increase in FZD8 and c-Myc expression was also observed in residual tumors following treatment with cisplatin and TRAIL. In this study, we have found that c-Myc overexpression increased FZD8 expression, and its downstream signaling and together protect the cells from drug mediated cell death compared to vector transfected cells. c-Myc over-expressing cells do not show increased mammosphere formation; the numbers of CSCs per mammosphere are much higher compared to vector transfected controls. CDK inhibitor (dinaciclib) enhanced the cell death in c-Myc over expressing non-CSCs with minimal effect on CSCs. Inhibition of c-Myc using siRNA reduced c-Myc, FZD-8 and CSCs and enhanced sensitivity of cells to cisplatin plus TRAIL. Taken together, our findings suggest that c-Myc may play a major role in mediating CSC survival and resistance to chemotherapy, making it a potential target to enhance chemotherapeutic efficacy in patients with TNBC.
Citation Format: Shuping Yin, Vino T. Cheriyan, Arun K. Rishi, Kaladhar B. Reddy. c-Myc and Frizzled 8 play a major role in the regulation of cancer stem cells and drug resistance in triple-negative breast cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2225. doi:10.1158/1538-7445.AM2015-2225
Abstract 2261: DLGAP5, MAT1A, SKA3, and ZMYM5 are novel susceptibility genes for aggressive prostate cancer
Authors: Lee Minnkyong , Williams Kendra A. , Hu Ying , Andreas Jonathan , Patel Shashankkumar J. , Zhang Suiyuan , Crawford Nigel PS 
Published: August 2015

Abstract
Prostate cancer is a common disease with approximately 233,000 men estimated to be diagnosed in the United States alone in 2014. Yet, it is usually an indolent disease with only 13% of patients succumbing to prostate cancer, and the molecular determinants of aggressive prostate cancer remain unclear. Previously, we reported that germline variation influences disease aggressiveness in the C57BL/6-Tg(TRAMP)8247Ng/J (TRAMP) mouse model. These mice develop neuroendocrine prostate tumors similar to a subset of human prostate tumors associated with poor outcomes. Here, we used a multifaceted approach to identify candidate genes for susceptibility to aggressive prostate tumorigenesis and metastasis using the TRAMP mouse model. Candidate prostate cancer metastasis susceptibility genes were identified through quantitative trait locus (QTL) mapping in 201 (TRAMP x PWK/PhJ) F2 males. Two aggressive disease QTLs were identified; one for lymph node metastasis burden on chromosome 12 (LOD = 5.86) and one for distant metastasis-free survival on chromosome 14 (LOD = 4.41). Correlation analysis using microarray data derived from 27 (TRAMP x PWK/PhJ) F2 prostate tumors identified 35 metastasis-associated transcripts within the two loci. The role of these genes in susceptibility to aggressive human prostate cancer was analyzed in two different datasets. First, logistic regression and survival analyses in human prostate cancer gene expression datasets demonstrated that the expression levels of 5 of the 35 candidate genes was associated with both an increased risk of aggressive disease and a poorer disease-free survival. Second, four of these genes - DLGAP5, MAT1A, SKA3, and ZMYM5 - harbored SNPs associated with aggressive tumorigenesis in the PLCO/CGEMS GWAS cohort of 1,172 prostate cancer patients. This approach, novel to the prostate cancer field, demonstrates how mouse models can be used to identify aggressive disease susceptibility genes, and gives new insight into the molecular mechanisms of aggressive disease.
Citation Format: Minnkyong Lee, Kendra A. Williams, Ying Hu, Jonathan Andreas, Shashankkumar J. Patel, Suiyuan Zhang, Nigel PS Crawford. DLGAP5, MAT1A, SKA3, and ZMYM5 are novel susceptibility genes for aggressive prostate cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2261. doi:10.1158/1538-7445.AM2015-2261
Abstract 2321: A hematopoietic stem cell factor drives brain tumor initiating cell genesis through Notch signaling
Authors: Kim Sunghak , Kim Eun-Jung , Cheol Gyu Park , Oh Se-Yeong , Mutsuko Minata , Kim Hyunggee , Nakano Ichiro 
Published: August 2015

Abstract
Glioblastomas (GBMs) maintain their cellular heterogeneity with glioma stem cells (GSCs) producing a variety of tumor cell types. Here, we interrogated the oncogenic roles of Lim domain only 2 (LMO2) in GBM and GSCs in mice and human. High expression of LMO2 was found in human patient-derived GSCs compared to the differentiated progeny cells. LMO2 is required for GSC growth both in vitro and in vivo, as shRNA-mediated LMO2 silencing attenuated tumor growth derived from human GSCs. Further, LMO2 is sufficient to induce stem cell characteristics (stemness) in mouse pre-malignant astrocytes, as forced LMO2 expression facilitated in vitro and in vivo growth of astrocytes derived from Ink4a/Arf null mice and acquisition of GSC phenotypes. A subset of mouse and human GSCs converted into vascular endothelial-like tumor cells both in vitro and in vivo, which phenotype was attenuated by LMO2 silencing and promoted by LMO2 overexpression. Mechanistically, the action of LMO2 for induction of glioma stemness is mediated by transcriptional regulation of Jagged1 resulting in activation of the Notch pathway, whereas LMO2 directly occupies the promoter regions of the VE-cadherin gene for a gain of endothelial cellular phenotype. Subsequently, selective ablation of human GSC-derived VE-cadherin-expressing cells attenuated vascular formation in mouse intracranial tumors, thereby significantly prolonging mouse survival. Clinically, LMO2 expression was elevated in GBM tissues and inversely correlated with prognosis of GBM patients. Taken together, our findings describe novel dual roles of LMO2 to induce tumorigenesis and angiogenesis, and provide potential therapeutic targets in MGs.
Citation Format: Sunghak Kim, Eun-Jung Kim, Park Cheol Gyu, Se-Yeong Oh, Minata Mutsuko, Hyunggee Kim, Ichiro Nakano. A hematopoietic stem cell factor drives brain tumor initiating cell genesis through Notch signaling. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2321. doi:10.1158/1538-7445.AM2015-2321
Abstract 2322: The Hippo signaling pathway mediates BMP inhibition of cancer stem cells
Authors: Chartier Cecile , Ma Shirley , Antic Dragana , Quintana Elsa , Raval Janak , Wang Min , Dee-Hoskins Cristina , Kapoun Ann , Hoey Tim , Lewicki John , Gurney Austin 
Published: August 2015

Abstract
Multiple developmental signaling pathways cooperatively regulate cancer stem cell (CSC) function. Among them, the BMP pathway has been implicated in brain CSC tumorigenicity. To examine whether BMP is a general regulator of CSCs across diverse organ systems we utilized lentivirus-mediated BMP4 expression in patient-derived xenograft models in NOD/SCID mice. The prevention of tumor growth was observed in breast, colon, ovarian, and melanoma models. Similarly, adenovirus-mediated systemic delivery of BMP4 inhibited tumor growth, dramatically affected CSC-specific cell surface markers and decreased CSC frequency. Microarray analysis of BMP4-treated tumors showed that a set of genes encoding for components of the actin cytoskeleton was significantly enriched amongst regulated genes and identified Hippo pathway genes as potential mediators of the BMP4 anti-tumor response with up-regulation of SAV1 and LATS2 and down-regulation of BIRC5. Hippo signaling regulates organ size, stem cell biology and cancer through a protein kinase complex including MST1/2, SAV1, and LATS1/2, which phosphorylates the downstream nuclear effector YAP/TAZ. Phosphorylated YAP/TAZ is unable to induce the expression of cell proliferation and anti-apoptotic genes through interaction with transcriptional co-activators such as TEAD. The Hippo pathway, known to cross-talk with BMP signaling at multiple levels, recently emerged as a cellular sensor of the physical environment through the actin cytoskeleton. We thus asked whether modulating Hippo signaling affected tumor growth. YAP1 overexpression resulted in tumor growth decrease. A deletion variant of YAP, YAP1-291, possessing a deletion of the transactivation domain has been shown to act as a dominant-negative through binding to TEAD. Intriguingly YAP1-291 was also sufficient to strongly attenuate growth of diverse BMP4-sensitive and BMP4-insensitive tumor models suggesting that transactivation through TEAD is not the only route by which YAP modulates tumor growth. YAP anti-proliferative properties were reported before. In order to reconcile the dual function of YAP in cancer, we propose that the transcriptional co-activator's TEAD-mediated oncogenic function may be counter-balanced by its potentiation of SMAD signaling in response to BMP.
Citation Format: Cecile Chartier, Shirley Ma, Dragana Antic, Elsa Quintana, Janak Raval, Min Wang, Cristina Dee-Hoskins, Ann Kapoun, Tim Hoey, John Lewicki, Austin Gurney. The Hippo signaling pathway mediates BMP inhibition of cancer stem cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2322. doi:10.1158/1538-7445.AM2015-2322