bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5524: Gene 33/Mig6 regulates apoptosis and the DNA damage response through independent mechanisms
Authors: Li Cen , Park Soyoung , Zhang Xiaowen , Eisenberg Leonard , Zhao Hong , Darzynkiewicz Zbigniew , Xu Dazhong 
Published: July 2017

Abstract
Gene 33 (Mig6, ERRFI1) is an inducible adaptor/scaffold protein whose expression can be induced by both stress and mitogenic signals. It contains multiple domains for protein-protein interaction and is involved in a broad spectrum of cellular functions including cell proliferation, cell migration, cell apoptosis, and cell senescence. Many functions of Gene 33 are attributable to its ability to bind to the kinase domain of the EGFR family receptor tyrosine kinases thereby inhibiting their activities. Gene 33 also binds and activates tyrosine kinase c-Abl and is involved in other signing pathways such as NF-κB, HGF, and JNK. Growing evidence at the genetic, cellular, and animal levels indicates that Gene 33 functions as a tumor suppressor in the lung. Gene 33 has been shown to promote apoptosis. A recent study has linked this protein to the DNA damage response induced by hexavalent chromium [Cr(VI)]. In the current study we find that ectopic expression of Gene 33 strongly induces apoptosis by both activating the c-Abl/p73 pathway and inhibiting the EGFR/AKT pathways in BEAS-2B lung epithelial cells and A549 lung carcinoma cells. Surprisingly, ectopic expression of Gene 33 also triggers the DNA damage response in an ATM-dependent fashion and through pathways with and without association with apoptosis. We observed striking presence of Gene 33 in the nucleus and chromatin, which is in contrast with the belief that Gene 33 is an exclusively cytoplasmic protein. Our data show that chromatin localization of Gene 33 is partially dependent on the EBD motif of Gene 33, a domain required for interaction with EGFR and c-Abl. Our data also indicate that Gene 33 may regulate chromatin targeting of c-Abl and EGFR. Furthermore we find that both endogenous and ectopically expressed Gene 33 strongly interact with histone H2AX. Our data have revealed potential nuclear/chromatin-associated mechanisms that underline the function of Gene 33 in apoptosis and the DNA damage response.
Citation Format: Cen Li, Soyoung Park, Xiaowen Zhang, Leonard Eisenberg, Hong Zhao, Zbigniew Darzynkiewicz, Dazhong Xu. Gene 33/Mig6 regulates apoptosis and the DNA damage response through independent mechanisms [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 5524. doi:10.1158/1538-7445.AM2017-5524
Abstract 5526: Tumor suppressive role of BMI-1 through inhibition of JAK-STAT signaling in leukemia
Authors: Lam Yuk Man , Lam Stephen Sze Yuen , Leung Anskar Yu Hung , Ng Ray Kit 
Published: July 2017

Abstract
BMI-1, which is one of the core components of polycomb repressive complex 1, is frequently found deregulated in patients with hematological disorders. In last decades, researchers concordantly agree that BMI-1 mediates tumorigenesis of leukemia stem cells through p16INK4A leukemogenic pathway. However, accumulating evidences contradict the idea that BMI-1 solely plays an oncogenic role in tumorigenesis. It has been shown BMI-1 depletion favors the development of myelofibrosis in mice; whereas high BMI-1 expression suppressed colony forming ability of MLL-ENL-transformed bone marrow and correlated with higher survival in some cancers. In this study, we hypothesized that BMI-1 plays a tumor suppressive role, which is independent of the regulation of INK4A-ARF locus, in human leukemia. BMI-1 was over-expressed in a panel of myeloid and lymphoid lineage leukemia cells, including HL-60, MV4-11, MonoMac-6, SEM, Nalm-20 and RS4;11. We observed no deregulation of p16INK4A and p14ARF genes by BMI-1, suggesting the regulation of INK4A-ARF locus is independent of BMI-1 modulation in leukemia cells. Nevertheless, over-expression of BMI-1 resulted in significant reduction of leukemia cell proliferation. It is noted that constitutively active JAK-STAT signaling pathway is crucial to leukemia cell survival. By modulation of BMI-1 level, we demonstrated suppression of the activated JAK-STAT signaling pathway in most of the leukemia cell lines with the exception of MonoMac-6 and RS4;11. This is in agreement with the high sensitivity to ruxolitinib, a JAK-STAT inhibitor, in all the tested leukemia cell lines except RS4;11. Importantly, we showed that BMI-1 over-expression could sensitize RS4;11 cells to reduce cell proliferation under ruxolitinib treatment. These results suggest that higher efficacy of ruxolitinib treatment could be achieved under a condition of high cellular level of BMI-1. We further demonstrated that ruxolitinib treatment was more effective in a cohort of AML patient samples (n = 25) with a context of higher BMI-1 expression (p &lt; 0.05). Altogether, our results suggest that BMI-1 functions as a tumor suppressor gene via inhibition of the JAK-STAT signaling pathway. The endogenous level of BMI-1 could be served as an indicator for the effective treatment of JAK-STAT-dependent leukemia cells using ruxolitinib.
Citation Format: Yuk Man Lam, Stephen Sze Yuen Lam, Anskar Yu Hung Leung, Ray Kit Ng. Tumor suppressive role of BMI-1 through inhibition of JAK-STAT signaling in leukemia [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 5526. doi:10.1158/1538-7445.AM2017-5526
Abstract 5527: Effects of PTEN localization and phosphatase activity on gene expression profiling of glioblastoma cells
Authors: Wang Yubing , Chan Andrew M. 
Published: July 2017

Abstract
PTEN possesses both protein and lipid phosphatase activities, with its tumor-suppressor function mainly depends on its lipid phosphatase activity through inhibiting the PI3K/AKT signaling pathway at the cell membrane. However, increasing evidence have demonstrated that PTEN also localizes to other intracellular organelles such as the endoplasmic reticulum, the mitochondria, or the nucleus where it plays important roles in multiple cellular processes. To further understand how PTEN localization affects the gene expression profiling in cancer cells, a PTEN null glioblastoma cell line, U87MG, was stably expressing wild-type, nuclear localization signal (NLS)-tagged, nuclear export signal (NES)-tagged and myristoylation (MYR)-tagged PTEN. Ion Torrent based whole transcriptome sequencing was used for gene expression analysis. Gene ontology enrichment analysis showed that the most common cellular component regulated by PTEN over-expression was extracellular factors, which function as growth factor-binding or fibronectin-binding molecules related to cell adhesion or organ system development. In contrast, nuclear PTEN promoted the enrichment of genes in collagen-binding and integrin-binding, which may be related to blood vessel development or cell motility. KEGG pathway enrichment also confirmed that PTEN over-expression upregulated focal adhesion pathway, an important pathway that frequently disrupted in PTEN Hamartoma Tumor Syndrome (PHTS). Moreover, nuclear PTEN differentially regulated genes showed higher enrichment in immune response signaling pathways.
This unique gene expression profiling driven by NLS-PTEN indicated that besides the phosphatase activities, nuclear PTEN may have additional functions than merely inhibiting the PI3K signaling pathway. The transcriptome data showed potential downstream targets of PTEN in different subcellular localizations, which may lead to unique biological functions. More functional studies will be carried out to further validate how intracellular PTEN regulates the expression of these genes, and what are the signaling pathways involved in the regulatory processes.
Funding sources - This work was supported by the Hong Kong PhD Fellowship (PF12-13876) to WY. AC was supported by a General Research Fund grant (#460713), a Collaborative Research Fund grant (C014-14G) from the Hong Kong University Grants Committee, a Lo Kwee-Seong Biomedical Research Seed Fund, and the Brain & Mind Institute.
Note: This abstract was not presented at the meeting.
Citation Format: Yubing Wang, Andrew M. Chan. Effects of PTEN localization and phosphatase activity on gene expression profiling of glioblastoma 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 5527. doi:10.1158/1538-7445.AM2017-5527
Abstract 5528: The protein phosphatase 2A regulatory subunit PR70 is a gonosomal melanoma tumor suppressor gene
Authors: Kempen Léon C.L. Van , Redpath Margaret , Elchebly Mounib , Klein Kathleen Oros , Papadakis Andreas , Willmott James , Scolyer Richard , Edqvist Per-Henrik , Ponten Fredrik , Schadendorf Dirk , Rjk Anke van , Michiels Stefan , Dumay Anne , Helbling-Leclerc Anne , Dessen Philippe , Wouters Jasper , Stass Marguerite , Greenwood Celia , Ghanem G. Elias , Oord Joost van den , Feunteun Jean , Spatz Alan 
Published: July 2017

Abstract
Male gender is independently and significantly associated with poor prognosis in melanoma of all clinical stages. The biological underpinnings of this sex difference remain largely unknown, but we hypothesize that gene expression from gonosomes may play an important role. The current study demonstrates that loss of the inactivated X chromosome in melanomas arising in females is strongly associated with poor distant metastasis-free survival, suggesting a dosage benefit of two X-chromosomes. The gonosomal PPP2R3B gene is located on the pseudo-autosomal region (PAR) of the X-chromosome in females and on the Y-chromosome in males. We observed that despite its location on the PAR that predicts equal dosage across genders, PPP2R3B expression is lower in males than in females, and is independently correlated with poor clinical outcome. PPP2R3B codes for the PR70 protein, a regulatory substrate recognizing subunit of PP2A, that decreases melanoma growth by negatively interfering with DNA replication and cell cycle progression through its role in stabilizing CDC6/CDT1 interaction that delays the firing of origins of DNA replication. As such, PR70 behaves functionally as an X-linked tumor suppressor gene.
Citation Format: Léon C.L. Van Kempen, Margaret Redpath, Mounib Elchebly, Kathleen Oros Klein, Andreas Papadakis, James Willmott, Richard Scolyer, Per-Henrik Edqvist, Fredrik Ponten, Dirk Schadendorf, Anke van Rjk, Stefan Michiels, Anne Dumay, Anne Helbling-Leclerc, Philippe Dessen, Jasper Wouters, Marguerite Stass, Celia Greenwood, G. Elias Ghanem, Joost van den Oord, Jean Feunteun, Alan Spatz. The protein phosphatase 2A regulatory subunit PR70 is a gonosomal melanoma tumor suppressor gene [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 5528. doi:10.1158/1538-7445.AM2017-5528
Abstract 5529: CD177 suppresses breast cancer progression by regulating the canonical WNT β-Catenin pathway
Authors: Kluz Paige N. , Kolb Ryan , Xie Qing , Borcherding Nicholas , Wang Linna , Andrade James P. De , Spanheimer Phillip M. , Li Wei , Gibson-Corley Katherine N. , Tao Andy W. , Sugg Sonia , Weigel Ronald J. , Zhang Weizhou 
Published: July 2017

Abstract
To better treat breast cancer patients, it is imperative to be able to predict breast cancer relapse and metastasis. Here, we identified the cluster of differentiation 177 (CD177) expression is positively correlated with relapse-free and metastasis-free survival of breast cancer patients. CD177 protein is highly expressed in normal breast epithelial cells and is significantly reduced in invasive cancers. Using mouse models, we found that CD177 suppresses breast cancer, primarily by forming a complex with E-Cadherin and b-Catenin at adherens junctions. The physical interaction prevents the activation of b-Catenin-mediated transcription by the canonical WNT signaling as demonstrated by a TOP-flash dual luciferase assay. In conclusion, we have identified CD177 as a novel breast cancer suppressor and uncovered a new regulatory mechanism for the canonical WNT/b-Catenin-mediated oncogenic signaling transduction.
Citation Format: Paige N. Kluz, Ryan Kolb, Qing Xie, Nicholas Borcherding, Linna Wang, James P. De Andrade, Phillip M. Spanheimer, Wei Li, Katherine N. Gibson-Corley, Andy W. Tao, Sonia Sugg, Ronald J. Weigel, Weizhou Zhang. CD177 suppresses breast cancer progression by regulating the canonical WNT β-Catenin pathway [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 5529. doi:10.1158/1538-7445.AM2017-5529
Abstract 553: Microsatellite genotyping enables precision lung cancer risk classification
Authors: Varghese Robin T. , Velmurugan Karthik Raja , Fonville Natalie C. , Garner Harold R. 
Published: July 2017

Abstract
There remains a large discrepancy between the known genetic contributions to cancer and that which can be explained by genomic variants, both inherited and somatic. Recently, understudied repetitive DNA regions called microsatellites have been identified as genetic risk markers for a number of diseases including various cancers (breast, ovarian and brain). In this study we demonstrate an integrated process for identifying and validating microsatellite based risk markers for lung cancer using data from the cancer genome atlas (TCGA) and the 1000 genomes project. Comparing whole exome germline sequencing data from 488 TCGA lung cancer samples to germline exome data from 390 control samples from the 1000 genomes project, we identified 119 potentially informative microsatellite loci. These loci (risk markers) were found to be able to distinguish between cancer and control samples with sensitivity and specificity ratios over 0.8. Then these loci, supplemented with additional loci from other cancers and controls, were evaluated using a custom target enrichment kit and sample-multiplexed nextgen sequencing. Thirteen of the 119 risk markers were validated using high-depth (579x±315) nextgen sequencing of 30 lung cancer and 89 control samples, resulting in sensitivity and specificity ratios were 0.90 and 0.94, respectively. When 8 loci harvested from the bioinformatic analysis of other cancers are added to the classifier, then the sensitivity and specificity rise to 0.93 and 0.97, respectively. Analysis of the genes harboring these loci revealed two genes (ARID1B and REL) and two significantly enriched pathways (chromatin organization and cellular response to stress) which suggest that the process of lung carcinogenesis is linked to chromatin remodeling, inflammation, and tumor microenvironment restructuring. We illustrate that high-depth nextgen sequencing enables a high precision microsatellite-based risk classifier.
Note: This abstract was not presented at the meeting.
Citation Format: Robin T. Varghese, Karthik Raja Velmurugan, Natalie C. Fonville, Harold R. Garner. Microsatellite genotyping enables precision lung cancer risk classification [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 553. doi:10.1158/1538-7445.AM2017-553
Abstract 5534: Runx1 possesses anti-tumor activity and inhibits stemness in breast cancer cells
Authors: Hong Deli , J Andrew , Finstad Fritz, Kristiaan , Fitzgerald Mark P. , Stein Janet L. , Lian Jane , Stein Gary S. 
Published: July 2017

Abstract
Background: Despite advances in detection and therapies, breast cancer is still the most common malignant disease in women worldwide. Cancer stem cells (CSC) play an important role in formation, growth, drug-resistance and recurrence of tumors. Transcription factor Runx1 has received recent attention for its potential tumor suppressor activity in solid tumors. We previously showed that Runx1 represses the epithelial to mesenchymal transition in breast cancer cells. The objective of the present study is to investigate Runx1 functional effects on cellular activities, and its contribution to inhibiting CSC-like properties in breast cancer cells.
Methods: We generated Runx1 overexpression and Runx1 knockdown stable cell lines in both malignant MCF10AT1 and metastatic MCF10CA1a cells. Cells were analyzed for tumorsphere formation, protein (Western) and RNA (RT-qPCR) expression analysis. Cellular activity assays (cell proliferation, migration, and invasion) were performed to measure the tumorigenic potential of the cells. Xenograft studies were used to determine whether Runx1 overexpression in breast cancer cells represses tumor growth in vivo.
Results: Upon overexpressing Runx1, both MCF10AT1 and MCF10CA1a cells reduce their proliferation, migration and invasion, which support the concept that Runx1 acts as a tumor suppressor in breast cancer cells. Notably, overexpressing Runx1 inhibited the formation of tumorspheres and effectively reduced the stem-like population in these two breast cancer cells. These observations are consistent with the results of Runx1 knock-down in early stage ER positive MCF7 breast cancer cells which showed increased tumorsphere formation efficiency. Furthermore, Runx1 tumor suppressor activity was confirmed in mouse xenograft by showing that Runx1 overexpression inhibits tumor growth.
Conclusion: Our studies show that Runx1 inhibits proliferation, migration, and invasion, reflecting its tumor suppressor activity. Runx1 mediated reduction of tumorsphere formation suggests that Runx1 also contributes significantly to inhibit the population of the breast cancer stem cells. Therefore these studies offer Runx1 as a novel bio-therapeutic molecule for breast cancer intervention.
Citation Format: Deli Hong, Andrew J, Fritz, Kristiaan Finstad, Mark P. Fitzgerald, Janet L. Stein, Jane Lian, Gary S. Stein. Runx1 possesses anti-tumor activity and inhibits stemness in breast cancer 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 5534. doi:10.1158/1538-7445.AM2017-5534
Abstract 5539: The phenotypic characterization of Lrig null mouse embryonic fibroblasts
Authors: Herdenberg Carl , Hedman Håkan 
Published: July 2017

Abstract
The LRIG gene family consists of LRIG1, LRIG2 and LRIG3. The most studied of these is LRIG1, which is a tumor suppressor gene. The LRIG1 protein is downregulated in various types of cancer and it negatively regulates receptor tyrosine kinases including the EGF- and PDGF-receptors. Lrig1 also regulates stem cell homeostasis in mouse skin and intestine. The functions of LRIG2 and LRIG3 are less known, but some findings imply that they might antagonize LRIG1. Intriguingly, the sole LRIG homolog in C. elegans, Sma-10, positively regulates BMP signaling. Thus, it is not known to what degree the LRIG proteins have the same, overlapping, or opposing functions, and the molecular mechanisms involved are poorly characterized. To elucidate the functions of the three LRIG proteins we generated a series of wildtype and LRIG-null (Lrig1-/-;Lrig2-/-;Lrig3-/-) mouse embryonic fibroblast (MEF) lines. These cell lines were created from homozygous Lrig1flox/flox;Lrig2flox/flox;Lrig3flox/flox mouse embryos. The FLOXed Lrig genes were then deleted with CRE-recombinase, thereby creating Lrig-null MEFs. ddPCR analysis showed that the Lrig-null MEF lines were contaminated with less than 1% of cells carrying wildtype Lrig3 alleles. Lrig-null MEFs showed a higher proliferation rate and migrated more in trans-well chambers than the wildtype cells. These cell lines will also be useful to investigate the importance of Lrig proteins for other cellular functions such as, signal transduction, lipidomics, transcriptomics, secretomics, metabolomics, and oxidative stress sensitivity. We also transduced the Lrig-null cells with individual inducible Lrig-genes thus creating a powerful system for the examination of the biology of the specific Lrig proteins.
Citation Format: Carl Herdenberg, Håkan Hedman. The phenotypic characterization of Lrig null mouse embryonic fibroblasts [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 5539. doi:10.1158/1538-7445.AM2017-5539
Abstract 5543: Network guided modeling allows tumor type independent prediction of sensitivity to retinoic acid
Authors: Garattini Enrico , Bolis Marco , Fratelli Maddalena , Terao Mineko 
Published: July 2017

Abstract
Background: All-trans retinoic acid (ATRA) is a differentiating agent used in the treatment of acute-promyelocytic-leukemia and it is under-exploited in other malignancies despite its low systemic toxicity. A rational/personalized use of ATRA requires development of predictive tools allowing identification of sensitive cancer types and responsive individuals.
Materials and Methods: RNA-Sequencing data for 10080 patients and 33 different tumor-types were derived from the TCGA and Leucegene datasets and completely re-processed. The study was performed using machine learning methods and network analysis.
Results: We profiled a large panel of breast-cancer cell-lines for in vitro sensitivity to ATRA and exploited the associated basal gene-expression data to initially generate a model predicting ATRA-sensitivity in this disease. Starting from these results and using a network-guided approach, we developed a generalized model (ATRA-21) whose validity extends to tumor-types other than breast cancer. ATRA-21 predictions correlate with experimentally determined sensitivity in a large panel of cell-lines representative of numerous tumor-types. In patients, ATRA-21 correctly identifies APL as the most sensitive acute-myelogenous-leukemia subtype and indicates that uveal-melanoma and low-grade glioma are top-ranking diseases as for average predicted responsiveness to ATRA. There is a consistent number of tumor-types for which higher ATRA-21 predictions are associated with better outcomes.
Conclusions: In summary, we generated a tumor-type independent ATRA-sensitivity predictor which consists of a restricted number of genes and has the potential to be applied in the clinics. Identification of the tumor-types which are likely to be generally sensitive to the action of ATRA paves the way to the design of clinical studies in the context of these diseases. In addition, ATRA-21 may represent an important diagnostic tool for the selection of individual patients who may benefit from ATRA-based therapeutic strategies also in tumors characterized by lower average sensitivity.
Citation Format: Enrico Garattini, Marco Bolis, Maddalena Fratelli, Mineko Terao. Network guided modeling allows tumor type independent prediction of sensitivity to retinoic acid [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 5543. doi:10.1158/1538-7445.AM2017-5543