bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3104: Genome-wide screen for modulators of cell death induced by the NEDD8-activating enzyme inhibitor MLN4924
Authors: Cosmopoulos Kat , Blank Jonathan , Liu Xiaozhen , Bouck David , Garcia Khristofer , Liao Hua , Bernard Hughes , Tayber Olga , Hather Greg , Liu Ray , Lightcap Eric 
Published: August 2012

Abstract
The NEDD8-activating enzyme (NAE) is an E1 involved in the activation of a large family of ubiquitin E3 ligases termed the cullin-RING ligases (CRLs) through conjugation of the cullin proteins with the ubiquitin-like modifier NEDD8. Polyubiquitination of CRL substrate proteins targets them for degradation by the proteasome. In this way, NAE regulates the stability of proteins required for cancer cell growth and survival. MLN4924 is an investigational small molecule that is a potent and selective inhibitor of NAE in Phase I clinical trials. In order to investigate the primary genetic determinants that confer sensitivity of cells to NAE inhibition, we have performed a genome-wide synthetic lethal RNAi screen using MLN4924 in the A375 melanoma cell line. We have also investigated the biological consequences of NAE inhibition by studying the regulation of protein and transcript levels in MLN4924-treated A375 cells using large-scale quantitative proteomics and gene expression profiling, respectively. The RNAi screen has identified 123 genes whose down-regulation modulates MLN4924-induced cell death, and approximately one-third of these interfere with components of the NEDD8 pathway itself, the cell cycle and apoptotic machinery, and DNA damage-response pathways. Of these genes, 99 were subsequently assessed using high throughput FACS analysis for their contribution to the major phenotype induced by MLN4924. The results emphasize replication, p53, BRCA1/BRCA2, and transcription-coupled repair as being particularly important for MLN4924-induced cell death. In addition, the interactions of 80 genes with roles in cell cycle and DNA damage repair were explored with proteasome inhibitors and 12 DNA damaging agents, demonstrating that MLN4924 induces DNA damage by a distinct mechanism.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3104. doi:1538-7445.AM2012-3104
Abstract 3105: Chromosome 18q encodes a chromosomal instability suppressor locus in colorectal cancer
Authors: Burrell Rebecca A. , McClelland Sarah E. , Endesfelder David , Rowan Andrew , Schenk Arne , Sheffer Michal , Shaikh Nadeem , Domingo Enric , Kschischo Maik , Domany Eytan , Downward Julian , Tomlinson Ian , Swanton Charles 
Published: August 2012

Abstract
Identifying molecular mechanisms initiating Chromosomal Instability (CIN) may lead to approaches to limit intratumour heterogeneity and treatment failure in cancer. Here we identify candidate CIN-suppressor genomic loci that are subject to copy number loss in CIN colorectal cancers (CRCs). Genes encoded within CIN-suppressor loci were characterized through an RNA interference screen for induction of chromosome segregation errors in mitosis, revealing 5 CIN-suppressor genes encoded on chromosome 18q. CIN-suppressor gene silencing in chromosomally stable cells generates structurally abnormal chromosomes, which are missegregated during mitosis. A chromosome segregation error spectrum characteristic of structurally abnormal chromosomes is also observed in CIN CRC cell lines. 18q loss occurs in the majority of aneuploid CRCs, and is associated with both structural and numerical instability in colorectal tumours, and with aneuploidy onset in a rare carcinoma-in-adenoma dataset. These data support a role for chromosome 18q in the maintenance of chromosomal structural integrity and mitotic fidelity, and suggest that 18q copy number loss may initiate CIN during CRC development.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3105. doi:1538-7445.AM2012-3105
Abstract 3106: Collagen-mediated chromatin remodeling promotes chemoresistance in pancreatic cancer
Authors: Dangi-Garimella Surabhi Y. , Munshi Hidayatullah G. 
Published: August 2012

Abstract
Pancreatic ductal adenocarcinoma (PDAC), the fourth leading cause of cancer-related deaths in the US, is associated with a pronounced collagen-rich stromal reaction that has been shown to contribute to chemo-resistance. We have previously shown that PDAC cells grown in the collagen microenvironment are resistant to gemcitabine-induced proliferation- and checkpoint-arrest (Dangi-Garimella et al, Cancer Research 2011). The effects were mediated by ERK1/2-dependent expression of high mobility group A2 (HMGA2), a well-known chromatin remodeling protein. We have now found that relative to cells grown on tissue culture plastic, PDAC cells grown in 3D collagen display increased acetylation of lysines K9 and K27 on histone H3 along with a reduction in the levels of the heterochromatin binding protein HP1-α, suggesting that cells in collagen have a more open chromatin state. Decreasing HMGA2 expression or inhibiting ERK1/2 activity attenuates the effect of collagen on K9 and K27 acetylation. 3D collagen also promotes expression of the histone acetyl transferase (HAT) enzymes PCAF and GCN5 through increased HMGA2 expression and ERK1/2 activation. Additionally, human PDAC tumors display higher histone acetylation near fibrotic regions that also have increased HMGA2 expression. Finally, cells in 3D matrix demonstrate increased H2AX and a reduced tailing with the comet assay following gemcitabine treatment, suggesting that there is increased DNA repair associated with the more open chromatin state when cells are in the 3D collagen microenvironment. Downregulation of HATs along with inhibition of ERK1/2 phosphorylation attenuates gemcitabine-induced H2AX detected in 3D collagen. Overall, our results increase our understanding of how growth in 3D collagen contributes to chemo-resistance and identify potential therapeutic targets against this deadly cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3106. doi:1538-7445.AM2012-3106
Abstract 3111: Synthetic lethality in head and neck cancer
Authors: Lajud Shayanne A. , Yamashita Taku , Han Ziying , Zheng Jun , Mouchli Anas , Bezpalko Orysia , O'Malley Bert W. , Li Daqing 
Published: August 2012

Abstract
Current treatment for advanced stage head and neck squamous cell carcinoma (HNSCC) typically include both radiation and chemotherapy, which is associated with significant morbidity. Our main objective was to explore a novel adjuvant molecular therapy approach to minimize the chemoradiation-induced side effects and toxicities, while maintaining therapeutic anti-tumor effects in HNSCC through the mechanism of synthetic lethality that has been already exploited to a limited extent in clinical trials for breast cancer. It has been demonstrated that synthetic lethality is based on the roles of Poly(ADP-ribose)polymerase-1 (PARP-1) in DNA single-stranded break (SSB) repair, and BRCA-1 and -2 in double-stranded break (DSB) repair. By simply inhibiting PARP-1 in tumor cells carrying a mutation in the Brca genes, one would expect complete tumor regression. The MRN complex (Mre11, Rad50, and Nbs-1) is well recognized as a key sensor of DSBs and acts by recruiting and activating DNA damage response proteins. These concepts led us to investigate the concept of introducing a mutation to the MRN complex, in combination with PARP-1 inhibition, thereby creating “dual hits” that would result in synthetic lethality within tumors expressing wild-type Brca genes such as HNSCC. Human HNSCC tumor cell lines and a mouse model with human HNSCC were used in the study. Wild-type MRN and PARP expressions were detected in these tumor cells. In vitro and in vivo studies were performed to evaluate synthetic lethality effects after combining PARP-1 inhibition with adenovirus-mediated Nbs-1 (Ad-Nbs-1) gene transfer treatment, which we had previously shown to impair MRN expression. Telomere length was measured to investigate the potential mechanism of synthetic lethality. Our study demonstrates that significant synthetic lethality was found with combined PARP-1 inhibition and Ad-Nbs-1 treatment in both in vitro and in vivo experiments; it also suggests that the telomere maintenance may play an important role in synthetic lethality. In conclusion, we propose an important novel mechanism responsible for the synthetic lethality of PARP-1 inhibitors and MRN disruption based on their roles on telomere maintenance. Our findings emphasize the potential benefits of our therapeutic approach and deserve further investigation to help obviate the toxicities associated with existing treatment regimens for HNSCC patients.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3111. doi:1538-7445.AM2012-3111
Abstract 3114: Mutational inactivation of STAG2 causes aneuploidy in human cancer
Authors: Solomon David , Kim Taeyon , Diaz-Martinez Laura , Fair Joshlean , Elkahloun Abdel , Harris Brent , Toretsky Jeffrey , Rosenberg Steven , Shukla Neerav , Ladanyi Marc , Samuels Yardena , James C. David , Yu Hongtao , Kim Jung-Sik , Waldman Todd 
Published: August 2012

Abstract
One of the hallmarks of cancer is chromosomal instability, which leads to aneuploidy, translocations, loss of heterozygosity, and other chromosomal aberrations. Chromosomal instability is an early event in cancer pathogenesis and is thought to help generate the large number of genetic lesions required for a cell to undergo malignant transformation. It has been hypothesized that this instability is due to inactivating mutations in genes that control the mitotic checkpoint and chromosome segregation. However, in the vast majority of human tumors the molecular basis of chromosomal instability and the aneuploidy it produces remains unknown. We have recently identified a clue to the mechanistic origins of aneuploidy through integrative genomic analyses of human tumors (Science 333:1039, 2011). A diverse range of tumor types were found to harbor deletions or inactivating mutations of STAG2, a gene encoding a subunit of the cohesin complex, which regulates the separation of sister chromatids during cell division. Because STAG2 is on the X chromosome, its inactivation requires only a single mutational event. Studying a near-diploid human cell line with a stable karyotype, we found that targeted inactivation of STAG2 led to chromatid cohesion defects and aneuploidy, whereas in two aneuploid human glioblastoma cell lines, targeted correction of the endogenous mutant alleles of STAG2 led to enhanced chromosomal stability. Thus, genetic disruption of cohesin is a cause of aneuploidy in human cancer. These findings and additional unpublished observations regarding the role of STAG2 inactivation in aneuploidy will be presented.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3114. doi:1538-7445.AM2012-3114
Abstract 3177: Transcriptome sequencing identifies oncogenic microRNA signatures that interact with NF-kappaB, TP53 and Notch signaling in head and neck squamous cell carcinoma
Authors: Saleh Anthony D. , Si Han , Lu Hai , Yang Xinping Yang , Chen Zhong , Waes Carter Van , Coupar Jamie 
Published: August 2012

Abstract
MicroRNA dysregulation has been shown to be nearly universal in cancer biology, driving oncogenic signaling networks. However, microRNA mediated global regulatory mechanisms underlying malignant phenotypes of head and neck squamous cell carcinoma (HNSCC) remain unclear. In this study, we have performed genome-wide small RNA sequencing on a panel of nine HNSCC cell lines and three normal primary oral keratinocyte cell lines, as well as matched primary tumor and normal tissues using the SOLiD parallel sequencing platform. A panel of microRNAs with altered expression was identified, including several novel oncogenic microRNAs which are upregulated in parallel with altered activation of NF-kB c-REL, TP53 family members ΔNp63α and TAp73, and involved in the down-modulation of p53 and Notch1, two genes most often mutated or inactivated in HNSCC. To examine the hypothesis that these microRNAs could potentially be regulated by NF-κB and p53 pathways, NF-κB inducer TNF-α was used to treat an HNSCC cell line overexpressing mtTP53, ΔNp63α and TAp73. Genome-wide small RNA sequencing revealed significant changes in microRNA expression modulated by TNF-α that overlaps with the panel of constitutively dysregulated microRNAs in HNSCC. Furthermore, genome-wide ChIP-sequencing revealed that TNF-α modulated DNA binding activities of c-REL, ΔNp63α and TAp73 aligned within the regulatory regions of several differentially expressed microRNAs. Modulation of these microRNAs with anti-miR repression reduced proliferation and motility in HNSCC cell lines, which confirmed the oncogenic activity of the microRNAs and their potential for therapeutic targeting.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3177. doi:1538-7445.AM2012-3177
Abstract 319: The mucin MUC16 protects ovarian cancer cells from innate immune responses
Authors: Felder Mildred , Connor Joseph , Rakhmilevich Alexander , Qu Xiaoyi , Kapur Arvinder , Patankar Manish S. 
Published: August 2012

Abstract
Epithelial ovarian cancer cells overexpress the mucin MUC16. The estimated molecular weight of this membrane spanning mucin is ∼5 million Da. CA125, a diagnostic marker used to monitor regression and recurrence of ovarian cancer in patients undergoing treatment for this disease, is a repeating peptide epitope present in MUC16. Recent studies have indicated that MUC16 facilitates metastasis of ovarian cancer cells and likely also plays a pro-oncogenic role. We have demonstrated that MUC16 protects the ovarian cancer cells from natural killer (NK) cell-mediated cytotoxicity. The large molecular weight allows the mucin to act as a barrier around the cancer cells and prevent the formation of activating immune synapses between NK cells and ovarian cancer cells. In addition, MUC16 also inhibits NK cell responses by interacting with the inhibitory receptor Siglec-9. Here, we extend these initial studies to demonstrate that knockdown of MUC16 impairs ovarian cancer cells from forming tumors in SCID mice. Cytotoxicity experiments using splenocytes from SCID mice proved that the residual biologically active macrophages and NK cells from SCID mice are able to more effectively lyse the MUC16 knockdown ovarian cancer cells as compared to control cells expressing this mucin. The higher susceptibility of the MUC16 knockdown cells to immune cell mediated lysis was also observed when assays were conducted with murine effectors that were previously stimulated with anti-CD40 antibody. In addition, our data also demonstrates that humanized anti-EpCAM antibody is unable to overcome the immunesuppression mediated by MUC16. Stimulation of the immune cells with the cytokine huKS-IL2, an immunotherapeutic agent used in ovarian cancer clinical trials, also does not circumvent the immunosuppressive effects of MUC16. The data we have obtained indicates that ovarian cancer cells specifically express MUC16 to protect themselves from immune attack. Modulation of MUC16 expression may therefore serve as a useful strategy to control the progression of ovarian cancer via immunologic therapy.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 319. doi:1538-7445.AM2012-319
Abstract 3267: Mammalian target of rapamycin (mTOR) signaling proteins are highly expressed in mamamry tumors of MMTV-TGF-β mice
Authors: Dogan Soner , Cleary Margot P. 
Published: August 2012

Abstract
Although the roles of many signaling pathways have been investigated to determine their potential role mammary tumor (MT) development the exact molecular mechanisms of mammary tumorigenesis are still not clear. One pathway of interest with respect to cancer development is mTOR signaling which is implicated in cell growth, transcription, translation, migration, differentiation, and survival. In the present study the expression levels of proteins associated with mTOR signaling pathway in MTs and in normal mammary tissues and fat pads were determined in MMTV-TGF-β transgenic mice that develop hormone responsive MTs as they age. Mice were enrolled at 10 wks of age and were ad-libitum-fed AIN-93M diet until 73/74 wks of age. At this time MTs were removed as well as mammary tissue samples from the same location where MT initially grow. Samples were analyzed histopathologically to confirm either MT or normal mammary tissue and mice assigned to MT-positive or MT-negative groups (n=6-8 per group). Protein expression levels were then determined in MT, mammary tissue and as well as mammary fat pads (MFP). Serum insulin, IL-6 and TNF-α levels were also measured. MT- positive mice had 40% higher serum insulin level compared to MT- negative mice. In addition, serum IL-6 levels were 100% higher in MT- positive compared to the MT-negative group. Serum TNFα levels were similar in both groups. Expression levels of mTOR, p70S6K, p4EBP1, and HIF-1 proteins were significantly higher in MT of the MT-positive group compared to the corresponding tissue of MT-negative group, 64%, 106%, 129%, and 43%, respectively. On the other hand, IGF-I receptor (IGF-IR) expression level was significantly lower by 43% in the MT- positive group compared to the MT-negative group. The expression levels of p70S6K, p4EBP1, and HIF-1 proteins were similar in MFP tissues in both groups while mTOR level was lower in MFP taken from MT-positive compared to MT-negative mice. But, IGF-IR level was significantly higher, 187%, in MFP taken from the MT-positive group compared to the MT-negative group. These findings demonstrate that expression levels of the proteins involve in mTOR signaling pathway are higher in MTs compared to normal mammary tissue obtained from the site of MT origin. This supports the potential role of mTOR signaling proteins in breast cancer development and provides targets for cancer prevention. (Support CA101858, The Breast Cancer Research Foundation and The Hormel Foundation).
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3267. doi:1538-7445.AM2012-3267
Abstract 3268: Histological and biological effects of substituted quinolines (gap junction enhancers) in a spontaneous mammary tumor model
Authors: Shishido Stephanie N. , Nguyen Thu Annelise , Delahaye Adelaide 
Published: August 2012

Abstract
Effective use of antineoplastic drugs depends on the ability to balance the killing of tumor cells against the inherent toxicity to the host. Antineoplastic agents that act primarily on rapidly dividing and growing cells produce multiple side effects and are dose limiting. In recent years, there has been the development of biologic response modifiers aimed at enhancing innate anti-tumor defense mechanisms. Previous publications showed that substituted quinolines possess potent inhibitory activities against breast cancer cells through the enhancement of gap junction intercellular communication. These drugs decrease 71% of xenograft breast tumors in nude mice. The objective of this project is to evaluate the effect of substituted quinolines in a spontaneous mouse mammary tumor model (PyVT). PyVT mice were used at three different stages (pre, early and late) to characterize histological and biological changes in the treated animals compared to controls. Substituted quinolines cause a decrease of tumor growth rate by 112%, 77%, and 57% in the pre, early, and late stages of tumor development, respectively. Treatment during the pre and early stages of tumor formation also resulted in a decrease in the total number of tumors. Western blot analysis of the pre stage tumors show that the gap junction protein connexin 43 is more expressed in treated animals compared to control and the contrary for connexin 46. In the early and late stages, connexin 43 is expressed less in treated mice than controls, and vice versa for connexin 46. The expression of these connexins in control tissue suggests that this is due to an overall increase in connexin 43 and a decrease in connexin 46 during tumor development and metastasis. Histology of vital organs showed no significant alteration in treated animals compared to controls. These findings provide evidence that substituted quinolines cause a significant tumor reduction in a spontaneous mammary tumor model with no obvious adverse effects.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3268. doi:1538-7445.AM2012-3268