bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5493: The cistrome of estrogen receptor beta in colorectal cancer cells
Authors: Indukuri Rajitha , Wang Jun , Mesmar Fahmi , Williams Cecilia 
Published: July 2017

Abstract
Colorectal cancer (CRC) is the second leading cause of death in the United States and a truly preventive approach still remains to be developed. Men have the highest incidence rate for CRC and pre-menopausal women have a lower incidence of CRC, suggesting hormonal factors mediate protective roles. ERβ is the predominantly expressed estrogen receptor in the colonic epithelium and is lost during CRC progression. In colon cancer cell lines re-expression of ERβ has anti proliferative and anti-inflammatory properties, there is however little understanding of the mechanism whereby ERβ mediates these effects in colon cells. In order to elucidate the mechanism of ERβ in CRC, we re-expressed this receptor using lentivirus in four different CRC cell lines. We optimize chromatin-immunoprecipitation (ChIP) with an antibody thoroughly validated for this purpose and used IgG and input as well as cell lines without ERβ expression as controls. ChIP-seq was performed using Illumina library preparation and next generation sequencing. Alignment of sequence reads against the reference genome of version hg19 was done using Bowtie, and statistically significant peaks (FDR) were identified using MACS. Results were compared to RNA-seq analysis of the same cell lines. Key binding-sites and corresponding gene regulations were confirmed using qPCR. We present for the first time, the cistrome of ERβ in different CRC cell lines. We identify key binding motifs, including ERE and AP-1 sites. Together, our results uncover ERβ as an important determinant for attenuating cancer progression.
Note: This abstract was not presented at the meeting.
Citation Format: Rajitha Indukuri, Jun Wang, Fahmi Mesmar, Cecilia Williams. The cistrome of estrogen receptor beta in colorectal 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 5493. doi:10.1158/1538-7445.AM2017-5493
Abstract 5494: Hypoxia via HIF1alpha can regulate Wnt signaling in human colon cancer cells
Authors: Lyou Yung , Habowski Amber , Sprowl-Tanio Stephanie , Pate Kira , Chen George , Waterman Marian L. 
Published: July 2017

Abstract
Standard-of-care treatment for metastatic colorectal cancer combines chemotherapy with bevacizumab, an angiogenesis inhibitor that depletes nutrients and triggers hypoxia. Unfortunately, this strategy extends patient survival only a few months because tumors acquire adaptive resistance, enabling resumption of angiogenesis. Adaptive resistance arises from reprogrammed metabolism, but the regulatory networks that govern reprogramming are not defined. Our studies have shown that overactive Wnt signaling, which is the most common cause of colon cancer, programs cancer metabolism by promoting glycolysis and angiogenesis. Interestingly, metabolic genes targeted by Wnt are also regulated by the hypoxia transcription factor HIF1alpha suggesting there may be crosstalk between the two pathways. Several studies suggest that HIF1alpha can influence Wnt signaling, but the reported effects are variable ranging from positive to negative. We find that HIF1alpha and LEF/TCF/beta-catenin complexes co-regulate metabolic targets including LEF1 and TCF1 (TCF7) expression. Using luciferase reporters driven by LEF/TCF promoters, we observe significantly increased LEF1/TCF1 but not TCF3(TCF7L1)/TCF4(TCF7L2) promoter activity in hypoxic colon cancer cells. We identified putative hypoxia responsive elements (HREs) in the human LEF1 promoter and deletion of these HREs reduced responsiveness to hypoxia. Furthermore, when colon cancer cells were treated with inhibitors that either inactivate or reduce HIF1alpha protein, there was a significant decrease in Wnt reporter activity. These results suggest that hypoxia and the Wnt pathway crosstalk wherein hypoxia co-regulates metabolism genes and increases Wnt signaling capacity via LEF/TCF expression. Current studies are underway to investigate the mechanisms of crosstalk and joint regulation of metabolic gene programs during adaptive resistance.
Citation Format: Yung Lyou, Amber Habowski, Stephanie Sprowl-Tanio, Kira Pate, George Chen, Marian L. Waterman. Hypoxia via HIF1alpha can regulate Wnt signaling in human colon 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 5494. doi:10.1158/1538-7445.AM2017-5494
Abstract 550: Predictive value of co-expression network consisting of FOXM1 and its neighbor genes in cancers
Authors: Song Bic-Na , Chu In-Sun 
Published: July 2017

Abstract
Purpose: Forkhead box protein M1 (FOXM1) is a key regulator of tumorigenesis. Previous studies demonstrated that FOXM1 expression was strongly correlated with poor prognosis of various cancers. The aim of this study is to define a signature consisting of FOXM1 and its associated genes and assess its prognostic potential in cancers including hepatocellular carcinoma (HCC) and others.
Experimental procedures: We analyzed a gene expression profile of 100 patients with HCC to identify FOXM1-correlated genes (the FOXM1 signature) associated with the prognosis of HCC patients. The validity of the FOXM1 signature was verified in an independent HCC cohort (n = 242). Using the signature, we also analyzed different cancer types including pancreatic adenocarcinoma, lung adenocarcinoma, breast carcinoma, and bladder urothelial carcinoma to verify the association between the FOXM1 signature and prognosis. Various statistical methods were applied to signature finding and validation. Upstream regulator and gene-to-gene network analyses were performed to identify potential key mediators of the FOXM1 signature.
Results: Through a gene expression profiling in 100 patients with HCC, we identified a gene set consisting of FOXM1 and its co-expressed genes for predicting poor prognosis. A predictive value of the signature was validated in an independent cohort containing 242 HCC patients. In multivariate analysis, the FOXM1 signature showed the most significant prognostic value (HR = 1.706, 95% CI = 1.176-2.475, P = 0.005). By directly applying the signature to four data sets in different cancer types, our signature showed a consistent prognostic significance, regardless of tumor types. Finally, upstream regulator and gene-to-gene network analyses found an interconnection of network hubs composed by FOXM1, MYC, and E2F1 that might be common key mediators of patient survival in cancer.
Conclusions: The FOXM1 signature represents a promising common diagnostic tool to identify high-risk cancer patients and may extend treatment options in various cancers.
Note: This abstract was not presented at the meeting.
Citation Format: Bic-Na Song, In-Sun Chu. Predictive value of co-expression network consisting of FOXM1 and its neighbor genes in cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 550. doi:10.1158/1538-7445.AM2017-550
Abstract 5502: Functional evaluation of superenhancers as mediators of epithelial ovarian cancer risk
Authors: Vavra Kevin C. , Coetzee Simon , Lee Janet M. , Pharoah Paul , Hazelett Dennis J. , Lawrenson Kate , Gayther Simon A. 
Published: July 2017

Abstract
Superenhancers are master regulators of genes involved in cellular differentiation and tumorigenesis. While it is now well established that typical enhancers are key mediators of alleles associated with a mild risk of polygenic diseases, including cancer, the role of superenhancers is less understood. We evaluated the role of superenhancers in mediating risk of epithelial ovarian cancer (EOC). Using FunciVar software and superenhancers defined using H3K27ac chromatin immunoprecipitation followed by next generation sequencing, performed in cell lines and tissues, we characterized the superenhancer-risk SNP intersect and identified a series of risk-associated loci where multiple candidate causal alleles overlap with ovarian superenhancers. In particular, locus 3q25, the locus most associated with epithelial ovarian cancer (EOC) risk from GWAS studies, has &gt;70 candidate causal risk SNPs, all of which coincide with superenhancers detected in ovarian cancer precursor cells (ovarian and fallopian tube epithelia) but not in ovarian cancers. We are proposing that the presence of one or more SNPs occurring at this locus leads to a higher expression of one or more genes by modulating activation of the superenhancer region. We tested the effect of decreasing the binding affinity of BRD4, a protein that binds superenhancer regions, using a small molecule inhibitor on the expression of genes in this locus. We identified three candidate genes—LEKR1, SSR3, and TiPARP—that demonstrated a decrease expression level as a result of BRD4 binding inhibition.
Preliminary results show that partial knockdown of either SSR3 or TiPARP decreases normal ovarian and fallopian cell proliferation, and knocking down both SSR3 and TiPARP simultaneously shows an enhanced proliferation decrease compared with knockdown of a single gene. We then created stable knockout (KO) models using the CRISPR-Cas9 system to fully KO one, two or all three of our candidate causal genes: LEKR1, SSR3, and TiPARP. Functional evaluation of these KO models is currently underway to test the hypothesis that risk SNPs may regulate more than one gene at this locus. In all we identify a potential role for superenhancers at a subset of EOC risk loci, and present a functional pipeline for identification of the target gene/genes and evaluation of their role in neoplastic transformation.
Citation Format: Kevin C. Vavra, Simon Coetzee, Janet M. Lee, Paul Pharoah, Dennis J. Hazelett, Kate Lawrenson, Simon A. Gayther. Functional evaluation of superenhancers as mediators of epithelial ovarian cancer risk [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 5502. doi:10.1158/1538-7445.AM2017-5502
Abstract 5508: Histone modifications affect differential regulation of TGF-beta-induced Nox4 by p53
Authors: Boudreau Howard E. , MA Wei Feng , Korzeniowska Agnieszka , Park Jonathan J. , Leto Thomas L. 
Published: July 2017

Abstract
Recent studies suggest p53 plays an important role in TGF-β-mediated cell signaling and migration. Previously, we showed wild-type (WT) and mutant (mt) forms of p53 differentially regulate reactive oxygen species (ROS) generation by NADPH oxidase-4 (NOX4). We found that WT-p53 suppresses TGF-β-induced NOX4, ROS production, and cell migration, whereas tumor-associated p53-mt proteins enhance NOX4 expression and cell migration by TGF-β/SMAD3-dependent mechanisms. In this study, we utilized The Cancer Genome Atlas (TCGA) to perform statistical analysis on gene expression data from primary tumor samples and found a correlation between tumors with p53 “hotspot” mutations and increased NOX4 mRNA expression. Furthermore, we examined the basis of human NOX4 promoter regulation by p53 and SMAD3. By deletion analysis of the NOX4 promoter, we found two critical SMAD3 binding elements (SBE) are also required for p53-dependent promoter activity. Conversely, promoter activity was abolished by dose-dependent heterologous expression of p53-WT. Moreover, expression of active SMAD3 resulted in robust NOX4 promoter activity, which was abolished when co-expressed with p53-WT. Chromatin immunoprecipitation (ChIP) analysis revealed SMAD3 and p53-WT or p53-mt were associated with specific SBEs and p53 response elements (p53-RE) in a TGF-β-dependent manner. Interestingly, the repressive effect by p53-
WT on NOX4 was relieved upon treatment with histone deacetylase (HDAC) inhibitors or mutation of the transactivation domain. Overexpression of p300, a known p53-mt-binding transcriptional co-regulator and histone acetyltranserfase (HAT), enhanced p53-mt-mediated NOX4 promoter activity, whereas the HAT-inactive p300-mt reduced promoter activity. Furthermore, overexpression of p53-mt augmented TGF-β-mediated acetylation of histones associated with the NOX4 promoter. Finally, scratch wound assays demonstrated NOX4 and p300 promote TGF-β/mutant p53-mediated cell migration. Collectively, these data and provide new insight on TGF-β/SMAD3 and mutant p53-mediated NOX4 induction involving epigenetic control of NOX4 in tumor cell migration.
Citation Format: Howard E. Boudreau, Wei Feng MA, Agnieszka Korzeniowska, Jonathan J. Park, Thomas L. Leto. Histone modifications affect differential regulation of TGF-beta-induced Nox4 by p53 [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 5508. doi:10.1158/1538-7445.AM2017-5508
Abstract 5511: Lineage-specific and shared cytokine-sensing genes respond distinctly to the master regulator STAT5
Authors: zeng xianke , Willi Michaela , Shin Ha Youn , Wang Chaochen , Hennighausen Lothar 
Published: July 2017

Abstract
JAK/STAT signaling pathways are critical for cell response to cytokines across multiple tissues, genetic variation in this pathway could associate with neoplastic diseases. STAT5, the most common used STAT family member, differently activates two distinct classes of genes. It activates cell-specific genes up to two orders of magnitude higher than shared genes expressed across different cell types. Socs2 (Suppressors of cytokine signaling 2), a widely expressed STAT5 target gene and a negative regulator of cytokine feedback loops, contains STAT5 response element within its promoter region. In our study, we demonstrated that STAT5 preferentially binds to promoter sequence of shared STAT5 targeted genes and to distal putative enhancers of lineage-specific genes. DNase-seq demonstrated that chromatin accessibility of STAT5-based enhancers was greatly dependent on cytokine exposure, while common STAT5 promoter targets were constitutively accessible. CRIPSR /Cas9 gene editing was used to delete the generic STAT5 binding sites in Socs2 locus in mice. Prolactin induction of Socs2 was abrogated both in liver and mammary gland, and resulted in elevated STAT5 activation and precocious mammary development in mutant mice. Taken together, we demonstrated that promoter-bound STAT5 modulates cytokine responses of universal STAT5 target genes, while enhancer-bound STAT5 is necessary for linage-specific target gene activation. This study provides new insight into the mechanism of used by a generic cytokine response element controlling lineage-specific transcription.
Citation Format: xianke zeng, Michaela Willi, Ha Youn Shin, Chaochen Wang, Lothar Hennighausen. Lineage-specific and shared cytokine-sensing genes respond distinctly to the master regulator STAT5 [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 5511. doi:10.1158/1538-7445.AM2017-5511
Abstract 5518: Rgs8 and Rgs16 are tumor suppressor genes in mouse pancreatic ductal adenocarcinoma
Authors: Choudhuri Shreoshi Pal , Zolghadri Yalda , Mascarenhas Luke , Ocal Ozhan , Wilkie Thomas 
Published: July 2017

Abstract
We have identified regulators of G protein signaling (Rgs8 and Rgs16) as a new class of tumor suppressor genes in a mouse model of pancreatic ductal adenocarcinoma (PDA). PDA is the 3rd leading cause of cancer related deaths in the United States. Kras mutations (e.g. KrasG12D) are associated with over 90% of human PDA and are an early event in the multistep process leading to PDA. Kras can be activated by protein kinase and G-Protein Coupled Receptor (GPCR) signaling. Rgs proteins regulate GPCR signaling by accelerating the GTPase activity of Gq- and Gi class alpha subunits. Activating alleles of Gq that are resistant to Rgs inhibition are associated with PDA in humans. We found Rgs8 and Rgs16 are in vivo reporters of Kras activity in pancreatic intraepithelial neoplasia (PanIN), intraductal papillary mucinous neoplasm (IPMN), and PDA progression (DMM 8, 2015). Rgs8 and Rgs16 are expressed in PanIN and IPMN, precursors of PDA, in KC mice (LSL-KrasG12D; p48::Cre). To test if Rgs8-16 function as tumor suppressor genes, we crossed the Rgs8-16 double knockout into KC (termed KCR8-16) mice. Compared to KC, PDA initiates earlier, is more aggressive, and KCR8-16 mice die earlier. Our study suggests that Rgs8 and Rgs16 control Kras-dependent PDA initiation and progression.
Note: This abstract was not presented at the meeting.
Citation Format: Shreoshi Pal Choudhuri, Yalda Zolghadri, Luke Mascarenhas, Ozhan Ocal, Thomas Wilkie. Rgs8 and Rgs16 are tumor suppressor genes in mouse pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5518. doi:10.1158/1538-7445.AM2017-5518
Abstract 5520: CCN5/WISP-2 is a negative regulator of epithelial to mesenchymal transition and stemness in breast cancer
Authors: Maity Gargi , Das Amlan , Sarkar Sandipto , Banerjee Snigdha , Banerjee Sushanta K. 
Published: July 2017

Abstract
Background and Objective: Breast cancer is the most common cancer in women and a leading cause of cancer mortality in western countries. CCN5 (also known as Wnt-1-induced signaling protein-2 or WISP-2) is a 29-31-kDa matricellular protein that plays as a negative regulator of breast carcinoma. Our previous studies had shown the importance of CCN5/ WISP-2 in the suppression of breast and pancreatic cancer progression through the regulation of the invasive phenotypes. Considering the previous report, our aim is to investigate whether human recombinant CCN5 inhibit pathobiological events like epithelial to mesenchymal transition (EMT), migration and stemness in triple negative breast cancer cells.
Methods: To investigate the negative impact of CCN5 on EMT and stemness of TNBC, we performed several techniques like western blot, clonoogenic assay, soft agar assay, sphere formation assay etc.
Results and Conclusions: The exposure of triple negative human breast cancer cells (TNBC), MDA-MB-231 and HCC-70, to recombinant CCN5 (hrCCN5), resulted in a dose-dependent inhibition of cell-proliferation through the induction of apoptotic cell death. The treatment of hrCCN5 regulates various pathobiological events in breast cancer cells, such as reprogramming the mesenchymal to epithelial transition (MET) followed by reduction of stemness features as confirmed by sphere formation assay and delaying in vitro migration. Finally, treatment with hrCCN5 in TNBC cells significantly inhibited anchorage-dependent and independent growth of TNBC. Collectively, CCN5’s control of cancer cell physiology indicates that hrCCN5 has the potential of being used as a major therapeutic agent against triple negative breast cancer.
Citation Format: Gargi Maity, Amlan Das, Sandipto Sarkar, Snigdha Banerjee, Sushanta K. Banerjee. CCN5/WISP-2 is a negative regulator of epithelial to mesenchymal transition and stemness in breast cancer [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 5520. doi:10.1158/1538-7445.AM2017-5520
Abstract 5523: Loss of RAB25 cooperates with oncogenes in the transformation of human mammary epithelial cells
Authors: Rao Krishna , Joshi Pooja Sridhar 
Published: July 2017

Abstract
The RAB guanosine triphosphates (RAS-related in brain) belong to the Ras superfamily of GTPases, and loss of RAB 25 expression has been reported in a number of breast cancer cases containing H-Ras point mutations, particularly triple negative breast cancers (TNBC), one of the most aggressive subtypes of breast cancer and associated with a poor prognosis. The mechanism involved in the progression of these tumors is poorly understood.
In this study, we are trying to understand if loss of RAB25 expression in Human Mammary Epithelial Cell (HMEC) lines co-operates with H-Ras mutations and contributes to tumorigenesis. HMEC were immortalized by transduction with LXSN CDK4 R24C, a mutant form of cyclin-dependent kinase, followed by transduction with hTERT, catalytic subunit of the telomerase enzyme that permits the cells to exceed the Hayflick Limit and become immortal.
We have found that with loss of RAB25 and over expression of mutant H-Ras61L, immortal HMEC undergo transformation. We have looked into the co-operativity between loss of Rab25 and H-Ras61L mutant by in-vitro studies to show their anchorage independent growth and increased ability to migrate. Furthermore, cells express low CD24, high CD44, and very low levels of Claudin indicating that cells acquire stem-like properties upon transformation. Loss of RAB25 and over-expression of H-ras61L resulted in increased expression of transcription markers Snail and Slug that drive these cells to lose E-cadherin and undergo Epithelial Mesenchymal Transition (EMT). We also intend to carry out nude mice studies to look for the potential of these cells to form tumors and metastasize.
This study shows that loss of RAB25 and over-expression of mutant H-Ras can transform HMEC and give rise to mesenchymal stem-like tumors. Our findings reveal that RAB25 functions as a tumor suppressor gene, and loss of RAB25 could serve as a novel biomarker in the prognosis of Claudin-low type of TNBC.
Citation Format: Krishna Rao, Pooja Sridhar Joshi. Loss of RAB25 cooperates with oncogenes in the transformation of human mammary epithelial 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 5523. doi:10.1158/1538-7445.AM2017-5523