bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3314: Heritable methylation marks associated with prostate and breast cancer risk
Authors: Southey Melissa C. , Joo Jihoon E. , Dowty James G. , Milne Roger L. , Wong EE Ming , Dugué Pierre-Antoine , English Dallas , Hopper John L. , Goldgar David E. , Giles Graham G. 
Published: August 2018

Abstract
While most epigenetic marks are reprogrammed during early embryogenesis, some studies have reported Mendelian-like inheritance of germline DNA methylation in particular in cancer susceptibility genes. For instance, individuals with MLH1 silenced throughout the soma fit the clinical criteria for hereditary nonpolyposis colorectal cancer that is indistinguishable from the syndrome resulting from germline mutations in MLH1. Research using multiple-case breast cancer families has shown that LINE-1 and Sat2 DNA methylation levels are lower in individuals with a strong family history. Family clustering of cancer could therefore be due to epigenetic as well as genetic and shared environmental factors. We have recently identified heritable methylation marks associated with breast and/or prostate cancer susceptibility by conducting a study involving 45 Australian multi-generational families with multiple cases of breast or prostate cancer who are not known to carry genetic mutations in cancer susceptibility genes. We developed and applied a new statistical method to identify heritable methylation marks based on complex segregation analysis and identified 24 and 41 methylation marks significantly associated with breast and prostate cancer risk respectively. Several marks across VTRNA2-1, a gene located in a differentially methylated region that is involved in imprinting and shows allele-specific methylation, were associated with heritable risk of both cancer types. A proportion of all identified marks were found to be associated with cancer risk in independent nested case-control studies (ie outside of the multiple-case family setting). We are expanding these successful studies to include additional families and to estimate HRs and age-specific cumulative risks of cancer associated with these marks to enable the incorporation of this information into clinical tools for risk prediction.
Citation Format: Melissa C. Southey, Jihoon E. Joo, James G. Dowty, Roger L. Milne, EE Ming Wong, Pierre-Antoine Dugué, Dallas English, John L. Hopper, David E. Goldgar, Graham G. Giles. Heritable methylation marks associated with prostate and breast cancer risk [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3314.
Abstract 3319: Epigenetic upregulation of E3 ubiquitin ligase CBLC enhances EGFR dysregulation and signaling
Authors: Hong Shiao-Ya , Kao Yu-Rung , Lee Te-Chang , Wu Cheng-Wen 
Published: August 2018

Abstract
CBLC (CBL proto-oncogene c) belongs to the CBL protein family which has E3 ubiquitin ligase activity towards activated receptor tyrosine kinases. CBLC expression is physiologically restricted to normal epithelial cells but frequently upregulated in non-small cell lung cancer (NSCLC). Compared to its family members, very little is known about the functions of CBLC in tumorigenesis. Here, we demonstrated that CBLC is an epigenetically demethylated target and its expression can be upregulated after treatment with a DNA methylation inhibitor, 5'-azacytidine in NSCLC cells. CBLC depletion significantly inhibited cell viability and clonogenicity in vitro and reduced the tumor growth in a xenograft model. In addition, CBLC silencing further sensitized EGFR-mutated NSCLC cells to tyrosine kinase inhibitors treatment. On the other hand, after ligand stimulation, ectopic expression of CBLC enhanced the activation of EGFR and its downstream ERK1/2 signaling via competing with CBL for EGFR binding. By analyzing the ubiquitin linkages on activated EGFR (aEGFR), we found that CBLC ubiquitinated and positively regulated aEGFR stability through the conjugation of polyubiquitin by K6 and K11 linkages. The CBLC-mediated polyubiquitination promoted aEGFR preferentially recycling back to the plasma membrane or trafficking to the cell nucleus. In summary, we demonstrate a novel mechanism by which aEGFR escape lysosomal degradation in a CBLC/ubiquitin-dependent manner to sustain its activation. Our work identifies CBLC as a potential diagnostic biomarker and also points to its utilization as a novel therapeutic target for NSCLC therapy.
Citation Format: Shiao-Ya Hong, Yu-Rung Kao, Te-Chang Lee, Cheng-Wen Wu. Epigenetic upregulation of E3 ubiquitin ligase CBLC enhances EGFR dysregulation and signaling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3319.
Abstract 333: USP1 is required for replication fork stability in BRCA1-deficient tumors
Authors: Lim Kah Suan , Li Heng , Roberts Emma A. , Gaudiano Emily F. , Clairmont Connor , Ponnienselvan Karthikeyan , Liu Jessica C. , Parmar Kalindi , Zheng Ning , D'Andrea Alan 
Published: August 2018

Abstract
Homologous-recombination (HR) deficient tumors with BRCA1 and BRCA2 mutations exhibit replication fork stability defects. To date, PARP inhibitors are the only targeted therapy available in the clinic against HR deficient tumors, and alternative therapies are needed. In this study, we found a deubiquitinase, USP1, to be significantly upregulated in tumors with mutations in BRCA1. SiRNA mediated silencing or small molecule inhibition of USP1 activity resulted in replication fork destabilization and decreased viability of BRCA1 deficient cells, revealing a synthetic lethal relationship between USP1 and BRCA1. The cofactor of USP1, UAF1, had previously been shown to have DNA-binding activity. We observed that USP1 independently binds to and is stimulated by fork DNA. It is therefore the first known deubiquitinase (DUB) to be directly regulated by DNA binding. A truncated form of USP1, lacking its DNA binding region, was not stimulated by DNA and failed to localize and protect the replication fork. Persistence of monoubiquitinated PCNA at the replication fork was the mechanism of fork destabilization and cell death in the absence of USP1. Loss of monoubiquitinated PCNA, resulting from RAD18 knockdown, rescued the sensitivity and replication fork instability induced by USP1 inhibition. USP1 therefore is the first DUB enzyme exhibiting DNA-mediated activation at the replication fork, and is required for fork protection in BRCA1 deficient cells. We propose small molecule inhibitors against USP1 as a therapeutic option for BRCA1 deficient cancers.
Citation Format: Kah Suan Lim, Heng Li, Emma A. Roberts, Emily F. Gaudiano, Connor Clairmont, Karthikeyan Ponnienselvan, Jessica C. Liu, Kalindi Parmar, Ning Zheng, Alan D'Andrea. USP1 is required for replication fork stability in BRCA1-deficient tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 333.
Abstract 3331: Development of a sensitive method to detect aberrant DNA methylation in cfDNA for pancreas cancer diagnosis
Authors: Shinjo Keiko , Katsushima Keisuke , Suzuki Miho , Nagae Genta , Aburatani Hiroyuki , Yamao Kenji , Kondo Yutaka 
Published: August 2018

Abstract
Pancreatic cancer is a highly lethal malignancy despite recent clinical advances. Since pancreatic cancer is often difficult to diagnose, there is an urgent need to develop noninvasive biomarkers for detection. Epigenetic alterations have been recognized as a common hallmark of many types of human cancers as well as pancreatic cancer. The cell-free DNA (cfDNA) in blood possesses tumor-related genetic alterations as well as epigenetic alterations. Therefore, invention of blood-based DNA methylation biomarkers and their high-sensitive detection system may be a promising diagnostic tool for pancreatic cancer. In order to establish the diagnostic biomarkers, first we performed genome-wide DNA methylation analysis of 38 endoscopic ultrasound-guided fine-needle aspiration specimens of pancreatic cancer using Illumina Infinium HumanMethylation450 BeadChip. We further analyzed the DNA methylation profiles of other types of tumors in the public database TCGA (The Cancer Genome Atlas), and identified five marker genes, which were specifically methylated in pancreatic cancers. Analysis of DNA methylation status of pancreas cancers comparing 10 normal tissues in TCGA data set revealed that 99% of tumors were methylated in at least one of the five markers (sensitivity, 98.9%; specificity, 44%). We next examined the DNA methylation status of these markers in the validation cohort (n=46) by bisulfite pyrosequencing or quantitative methylation-specific PCR and found that 42/46 (91.3%) cases were methylated in at least one marker. Finally, we analyzed methylation status in cfDNA from pancreatic cancer patients. We performed bisulfite sequencing using next-generation sequencer and detected methylation in only 5/13 (38.5%) samples in one of the markers. Since the amount of DNA from cancer tissue is very small, we need to develop more a sensitive technique to detect aberrant DNA methylation to diagnose cancer patients. Now we are developing a new sensitive method to detect DNA methylation in cfDNA.
Citation Format: Keiko Shinjo, Keisuke Katsushima, Miho Suzuki, Genta Nagae, Hiroyuki Aburatani, Kenji Yamao, Yutaka Kondo. Development of a sensitive method to detect aberrant DNA methylation in cfDNA for pancreas cancer diagnosis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3331.
Abstract 3336: ARID5B activates the TAL1-induced core regulatory circuit and the oncogene MYC, thereby promoting T-cell leukemogenesis
Authors: Leong Wei Zhong , Tan Shi Hao , Ngoc Phuong Cao Thi , Amanda Stella , Yam Alice Wei Yee , Liau Wei-Siang , Gong Zhiyuan , Lawton Lee N. , Tenen Daniel G. , Sanda Takaomi 
Published: August 2018

Abstract
The oncogenic transcription factor TAL1/SCL is abnormally expressed in 40-60% cases of T-cell acute lymphoblastic leukemia (T-ALL) cells. It induces an aberrant transcriptional program with its regulatory partners (E-proteins, LMO1/2, GATA3, RUNX1 and MYB) in malignant T cells. However, the critical factors that are directly activated by the TAL1 transcriptional complex and contribute to T-ALL pathogenesis are largely unknown. Here, we identified ARID5B, an AT-rich interactive domain (ARID) family DNA binding protein, as a collaborating oncogenic factor involved in the transcriptional program in T-ALL. Our result indicated that ARID5B expression is downregulated at the CD4, CD8 double negative 2-4 stages in normal thymocytes, while it is activated by the TAL1 complex in human T-ALL cells. The enhancer located approximately 135 kb upstream of the ARID5B gene locus is associated with a super-enhancer in multiple T-ALL samples but not in normal thymus. These data suggested that ARID5B is aberrantly activated in T-ALL cells. Interestingly, ARID5B-bound regions are predominantly associated with active transcription, as shown by the active histone marks (H3K27ac, H3K4me1 and H3K4me3) by ChIP-seq analysis. ARID5B and TAL1 frequently co-occupy target genes and coordinately control their expression. Notably, ARID5B positively regulates the expression of TAL1 and its regulatory partners (GATA3, RUNX1 and MYB). In addition, ARID5B activates the expression of the oncogene MYC. Importantly, ARID5B is required for the survival and growth of T-ALL cells in vitro, and forced expression of ARID5B in immature thymocytes results in thymus retention, radio-resistance and tumor formation in zebrafish. Our results indicate that ARID5B reinforces the oncogenic transcriptional program by positively regulating the core regulatory circuit and the oncogene MYC in T-ALL, thereby contributing to T-cell leukemogenesis.
Citation Format: Wei Zhong Leong, Shi Hao Tan, Phuong Cao Thi Ngoc, Stella Amanda, Alice Wei Yee Yam, Wei-Siang Liau, Zhiyuan Gong, Lee N. Lawton, Daniel G. Tenen, Takaomi Sanda. ARID5B activates the TAL1-induced core regulatory circuit and the oncogene MYC, thereby promoting T-cell leukemogenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3336.
Abstract 3337: Nuclear S1P binds PASB domain of HIFα to facilitate HIFα-HIF1β heterodimer formation in hypoxic TNBC cells
Authors: Hait Nitai C. , Maiti Aparna 
Published: August 2018

Abstract
Triple-negative breast cancers (TNBCs) have increased expression of hypoxia-inducible factor 1α (HIF1α) and HIF-direct genes that associated with decreased overall survival in patients. Previously we have shown that nuclear sphingosine-1-phosphate (S1P), a lipophilic pro-cancer signal mediator, a product of the catalytic reaction by sphingosine kinase 2 (SphK2), directly binds to and inhibits histone deacetylases-1 and -2 (HDAC1 and 2), thus, altered epigenetic landscape in breast cancer cells. SphK2/S1P signaling is essential for metastatic TNBC cell growth and survival. We hypothesize that SphK2/S1P epigenetically regulates HIFα functions in TNBC cells; TNBC subset with elevated SphK2 and HIF1α would be a marker for SphK2-mediated HIFα targeted therapy. METABRIC cohort gene expression analysis revealed that the mRNA expression of HIF1α mRNA and downstream angiogenesis gene, vascular endothelial growth factor B (VEGFB) are associated with overall poor survival for TNBC patients compared to non-TNBC patients. Here, we demonstrate that a subset of TNBC patient tissue samples nuclei has elevated HIF1α and SphK2 protein expressions. SphK2/S1P markedly enhances hypoxia-induced HIFα proximal promoter histone acetylation. SphK2/S1P is found in the nuclear protein complexes with HIFα. Moreover, S1P is docked well at the PASB domain of HIFα and facilitate HIFα-HIF1β heterodimer formation in hypoxia. SphK2/S1P markedly augmented HIF1α direct target gene HIF2α and VEGFA promoter occupancy in hypoxia. Down-regulation of SphK2 with siRNA markedly attenuated transcription of HIFα-direct target genes associated with cancer stem cells, angiogenesis, and metastasis. In agreement with an oncogenic role of SphK2, selective inhibition of SphK2 markedly reduced nuclear histone acetylation, HIF1α expression, and in vivo human TNBC tumor growth in mice. Our data strongly suggested that TNBC subset with elevated SphK2 and HIF1α would be a good candidate for SphK2 targeted therapy. Supported by Health Research, Inc. (HRI) Grant 71-4084-01 (NCH).
Citation Format: Nitai C. Hait, Aparna Maiti. Nuclear S1P binds PASB domain of HIFα to facilitate HIFα-HIF1β heterodimer formation in hypoxic TNBC cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3337.
Abstract 3339: Modulating TAK1 expression through the inhibition of GSK3 impairs YAP/TAZ oncogenic functions in pancreatic cancer
Authors: Santoro Raffaela , Zanotto Marco , Piro Geny , Carbone Carmine , Tortora Giampaolo , Melisi Davide 
Published: August 2018

Abstract
Background: Resistance to chemotherapeutic drugs poses one of the greatest challenges in pancreatic cancer (PC) treatment. TGFβ-activated kinase 1 (TAK1) has been demonstrated to drive chemoresistance in PC through the phosphorylation-dependent activation of the NF-κB transcription factor. The transcriptional regulators Yes Associated Protein (YAP) and transcriptional coactivator with a PDZ binding domain (TAZ) are central determinants of malignancy and have been identified as a critical oncogenic effectors of KRAS in PC. We hypothesized that TAK1 could drive PC aggressiveness by sustaining YAP and TAZ oncogenic activities.
Methods: TAK1 expression was silenced by shRNA in AsPC1, Panc1, and MDA-Panc28 cell lines. GSK3 was targeted by using the small molecule inhibitor LY2090314. The expression of TAK1, YAP/TAZ and their target genes in PC cell lines was studied by both Western blot and qPCR. Cell migration was assessed by transwell assays, and stemness by both spheroid formation and percentage of cancer stem cells (CSC). SRB assays were used to assess the in vitro chemopotentiation of nab-paclitaxel, gemcitabine, oxaliplatin, and SN-38. In vivo activity of LY2090314 alone or in combination with nab-paclitaxel was evaluated in an orthotopic nude mouse model with luciferase-expressing AsPC1 tumors. Expression of YAP/TAZ target genes in tumor samples was measured by both qPCR and IHC.
Results: knockdown of TAK1 resulted in inhibition of K48-linked ubiquitination and proteasomal degradation of YAP and TAZ, which was independent on TAK1 kinase activity. Significant reduction of proliferation, migration and chemoresistance of shTAK1 PC cell lines was also observed. Treatment with LY2090314 induced silencing of TAK1, as well as a remarkable reduction of the expression of both YAP and TAZ and their targets. In combination, the GSK3 inhibitor strongly potentiated the cytotoxic activities of chemotherapeutic agents in all three PC cell lines. In nude mice, i.p. admnistration of LY2090314 plus nab-paclitaxel significantly reduced tumor burden.
Conclusions: Our study identified GSK3 and TAK1 as major modulators of YAP and TAZ stability and oncogenic activities, thus indicating that inhibition of TAK1 expression by modulating GSK3 activity could represent a valid approach to revert in vivo the intrinsic chemoresistance of PC.
Citation Format: Raffaela Santoro, Marco Zanotto, Geny Piro, Carmine Carbone, Giampaolo Tortora, Davide Melisi. Modulating TAK1 expression through the inhibition of GSK3 impairs YAP/TAZ oncogenic functions in pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3339.
Abstract 3345: MAZ is a downstream target of CCN1 and promotes aggressive behavior of pancreatic cancer cells via CRAF-ERK signaling pathway
Authors: Maity Gargi , Haque Inamul , Ghosh Arnab , Dhar Gopal , Gupta Vijayalaxmi , Sarkar Sandipto , Azeem Imaan , McGregor Douglas , Choudhary Abhishek , Campbell Donald R , Banerjee Sushanta K. , Banerjee Snigdha 
Published: August 2018

Abstract
MAZ (Myc-associated zinc-finger protein) is a transcription factor with dual roles in transcription initiation and termination. Deregulation of MAZ expression has been shown to associate with the progression of pancreatic ductal adenocarcinoma cancer (PDAC). However, underlying mechanisms of action of MAZ in PDAC progression are largely unknown. Here we present evidence that MAZ mRNA expression and protein level were increased in human PDAC cell lines, tissue samples, subcutaneous tumor xenograft model in a nude mouse, and spontaneous cancer in the genetically engineered PDAC mouse model. We found that MAZ is predominantly expressed in pancreatic cancer stem cells. Functional analysis demonstrates that the depletion of MAZ in PDAC cells results in inhibition of invasive phenotypes such as phenotypic shift, migration, invasion, and the sphere-forming ability of PDAC cells. Mechanistically, we found no direct effect of MAZ on the expression of K-Ras mutants, but evidently MAZ increases the activity of CRAF-ERK-signaling, which is a downstream signaling target of K-Ras. Activation of CRAF-ERK-signaling by MAZ is mediated via p21-activated protein kinases (PAK) and protein kinase B (AKT/PKB) signaling cascades and promotes invasive phenotypes of PDAC cells. Moreover, a matricellular oncoprotein CCN1 regulates MAZ expression in PDAC cells. Thereby, we proposed that CCN1-induced expression of MAZ promotes invasive phenotypes of PDAC cells is not through direct K-Ras activation as presently thought but instead through the activation of CRAF-ERK signals. Collectively, these studies highlight key players that could help in clinical management, prognosis, and therapeutic strategies.
This project is funded by VA Merit Award grants (SB & SKB).
Citation Format: Gargi Maity, Inamul Haque, Arnab Ghosh, Gopal Dhar, Vijayalaxmi Gupta, Sandipto Sarkar, Imaan Azeem, Douglas McGregor, Abhishek Choudhary, Donald R Campbell, Sushanta K. Banerjee, Snigdha Banerjee. MAZ is a downstream target of CCN1 and promotes aggressive behavior of pancreatic cancer cells via CRAF-ERK signaling pathway [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3345.
Abstract 3348: The role of SOX2 in promoting resistance to AR-targeted therapies in prostate cancer
Authors: Wet Larischa de , Williams Anthony , Gillard Marc , Kregel Steve , Garcia Tzintzuni , McAuley Erin , Brown Ryan , Griend Donald Vander 
Published: August 2018

Abstract
Prostate cancer is the most common type of cancer in men, with approximately 181,000 new cases diagnosed in 2016. Due to the central role of the androgen receptor (AR) in prostate development and more importantly prostate cancer cell survival and proliferation, strategies targeting AR have been the mainstay therapy for over 70 years. However, despite potent inhibition of AR pathway activation, many patients develop castration-resistant prostate cancer (CRPC). Second-line therapies, such as enzalutamide, has increased overall survival in CRPC, but resistance to these therapies inevitably emerges, suggesting that other pathways apart from AR signalling are contributing to the failure of treatments. We have previously demonstrated that SOX2 [SRY (sex determining region Y)-box 2] is an AR-repressed gene that is expressed in a large percentage of high Gleason grade prostate tumours, as well as in most metastases. Additionally, expression of SOX2 within a castration-sensitive cell line is sufficient to enable castration-resistant tumor formation in vivo, and enzalutamide resistance in vitro. In prostate cancer, SOX2 is not found with its normal stem cell co-factors, NANOG and OCT4, leading to the hypothesis that SOX2 is interacting with a novel co-factor in prostate cancer to regulate expression of genes promoting castration-resistance. A chromatin-immunoprecipitation experiment in a castration-resistant prostate cancer cell line was performed to determine if SOX2 binds the same genes and activates similar pathways in prostate cancer as in embryonic stem cells. Approximately half of the SOX2 bound genes in the CRPC cell line were shared with the embryonic stem cell line, and these genes are involved in signalling pathways and maintenance of stem cell pluripotency; the genes bound uniquely in the CRPC cell line are present in pathways involved with metabolic processes. To identify potential binding partners of SOX2, computational analysis of the sites bound by SOX2 in the promoter regions of target genes determined the FOXA1 motif is within close proximity to the SOX2 motif, and the physical interaction of these proteins was confirmed through co-immunoprecipitation. Further understanding of SOX2 target genes and the pathways that SOX2 activates in the presence of enzalutamide will be crucial to identify mechanisms of resistance and enable the development of novel therapies for castration-resistant prostate cancer.
Citation Format: Larischa de Wet, Anthony Williams, Marc Gillard, Steve Kregel, Tzintzuni Garcia, Erin McAuley, Ryan Brown, Donald Vander Griend. The role of SOX2 in promoting resistance to AR-targeted therapies in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3348.