bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5208: Genome-wide AR enhancer activity in prostate cancer
Authors: Ozturan Dogancan , Huang Flora , Morova Tunc , Saffarzadeh Mohammadali , Lack Nathan A. 
Published: August 2019

Abstract
Prostate cancer (PCa) is one of the most commonly diagnosed forms of cancer with one out of every nine North American men developing the disease in their lifetime. Despite robust early detection methods, new therapeutics, and advancements in surgical operations, PCa is still second leading cause of cancer death in men. An increasing number of studies have shown that non-coding mutations plays a critical role in the development and progression of PCa. These somatic mutations can disrupt regulatory elements such as enhancers and alter the transcriptional landscape of the cancer. Discovering and interpreting the non-coding elements is crucial to understand the nature of this disease.
At all stages of PCa, androgen receptor (AR) signaling is essential to the cancer. Recent work from our laboratory demonstrated that there is a significant increase in somatic mutations at AR binding sites (ARBS). Given the importance of AR-mediated transcription, as well as the recurrent nature of these mutations, we proposed that these somatic mutations could play an important role in PCa development. To stratify the mutations, we conducted a massively multi-parallel enhancer assay to identify those ARBS sites with enhancer activity. With STARR-seq we found that 8% of the ARBS had strong inducible AR enhancer activity (341/4139). Interestingly, the majority of these sites did not contain a canonical androgen response element. With these results we incorporated high-throughput chromosome conformation capture (HiC) to formally define the genes regulated by each of these AR enhancers. Based on these results we have selected and characterized several non-coding ARBS mutations. We believe that the importance of the regulatory role of these regions will play a tremendous role in understanding of the prostate cancer and its progression.
Citation Format: Dogancan Ozturan, Flora Huang, Tunc Morova, Mohammadali Saffarzadeh, Nathan A. Lack. Genome-wide AR enhancer activity in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5208.
Abstract 5212: Ablation of SMAD4 repression on Elf3 promotes the progression of lung cancer in vivo
Authors: Liu Jian , Wang Tianyuan , Wu San-pin , Li Jian-liang , Demayo Francesco J. 
Published: August 2019

Abstract
Lung cancer is the leading cause of cancer death among both men and women in United States. ELF3, a transcription factor, overexpresses in human and mouse lung cancer and plays an oncogenic role in lung cancer cells1,2. Understanding the regulatory mechanisms for ELF3 may help to develop related target therapies. Ablation of Smad4 and Pten in mice results in an increase of Elf3 expression and the development of adeno-squamous carcinoma1. Results from in vivo ChIP-Seq analysis demonstrate SMAD4 occupancy near the Elf3 promoter in the pulmonary epithelium1. Therefore, we hypothesize that this SMAD4 occupancy is required to repress Elf3 expression and subsequently suppresses lung cancer progression. To test this hypothesis, we deleted this SMAD4 binding region in vivo and characterized the phenotypic consequences.
CRISPR/Cas9 was used to ablate the SMAD4 ChIP-Seq binding peak on Elf3 promoter region in mice. This resulted in mice with 12 and 17 nucleotide deletions in the Elf3 promoter region. ChIP-qPCR analysis showed that SMAD4 binding was decreased while H3K27ac bindings were increased in the Elf3 promoter region. The reduction in SMAD4 binding and the epigenetic changes in the Elf3 promoter region resulted in an increased expression of ELF3 in these lungs of these mice. Histological analysis of these mouse lungs showed the presence of pulmonary hyperplasia and the development of lung tumors. In order to identify potential interacting factors with SMAD4 in the Elf3 promoter, motif analysis of the deleted SMAD4 binding peak identified GATA2, ETS1 and OXT2 as potential interacting factors.
In summary, small disruption of Elf3 promoter region bound by SMAD4 leads to the increase of ELF3 expression with the enhanced binding of H3K27ac and the decrease of SMAD4 binding and promotes lung hyperplasia and lung cancer development. SMAD4 may interact with GATA2, ETS2 and OXT2 in the regulation of Elf3expression.
Key references
1. Liu, J. et al. ErbB2 Pathway Activation upon Smad4 Loss Promotes Lung Tumor Growth and Metastasis. Cell Rep, doi:10.1016/j.celrep.2015.02.014 (2015).
2. Wang, H. et al. Overexpression of ELF3 facilitates cell growth and metastasis through PI3K/Akt and ERK signaling pathways in non-small cell lung cancer. Int J Biochem Cell Biol 94, 98-106, doi:10.1016/j.biocel.2017.12.002 (2018).
Note: This abstract was not presented at the meeting.
Citation Format: Jian Liu, Tianyuan Wang, San-pin Wu, Jian-liang Li, Francesco J. Demayo. Ablation of SMAD4 repression on Elf3 promotes the progression of lung cancer in vivo [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5212.
Abstract 5216: Identification of Sox2 regulatory factors in small cell lung cancer
Authors: Wollenzien Hannah , Yousef Mira , Voigt Ellen , Kareta Michael S. 
Published: August 2019

Abstract
Sox2 is one of the core pluripotency genes that has also been implicated to be oncogenic in a multitude of cancers. We have shown that Sox2 is required for the formation of SCLC using mouse models and human cell culture. SCLC predominantly arises from in the lung from pulmonary neuroendocrine cells, which are formed from Sox2-expressing progenitors that are then silenced upon terminal differentiation. However, upon transformation Sox2 becomes highly upregulated in SCLC. One means of repressing Sox2 is the Rb tumor suppressor, which binds to the Sox2 locus and represses transcription by the recruitment of many epigenetically silencing factors. However, there are still some gaps in our knowledge of the repression of Sox2 by Rb, such as which factors are recruiting Rb to Sox2. We describe a novel technique of Cre-mediated Protein-DNA Immunoprecipitation (CrePI) to identify proteins at the Sox2 locus in an unbiased manner to further elucidate the mechanism of Rb repression of Sox2.
Citation Format: Hannah Wollenzien, Mira Yousef, Ellen Voigt, Michael S. Kareta. Identification of Sox2 regulatory factors in small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5216.
Abstract 522: PI3K/Akt signaling in tumor cells promotes immune evasion by limiting infiltration, recognition and killing by T cells
Authors: Sivaram Nithya , McLaughlin Patrick , Jiang Ya-Ping , Ballou Lisa , Pham Kien , Liu Chen , Velden Adrianus van der , Lin Richard 
Published: August 2019

Abstract
The presence of tumor-infiltrating T cells is associated with favorable patient outcomes, yet most pancreatic cancers are immunologically silent and resistant to currently available immunotherapy. In this study, a syngeneic orthotopic implantation model of pancreatic cancer was used to show that PI3K/Akt signaling in tumor cells down-regulate immunogenicity to evade T cell surveillance. Genetic silencing of PI3K catalytic isoform Pik3ca in KrasG12D/Trp53R172H-driven pancreatic tumors leads to infiltration of T cells, complete tumor regression, and 100% survival of immunocompetent host mice. By contrast, Pik3ca-null tumors implanted in T cell-deficient mice progress and kill 100% of the animals. Adoptive transfer of tumor antigen-experienced T cells eliminates Pik3ca-null tumors in immunodeficient mice. Pik3ca silencing or inhibition of its effector, Akt, increases the expression of MHC Class I and CD80 on the surface of murine and human pancreatic cancer cells. Down-regulating MHC Class I and CD80 expression, or increasing Akt activity, in Pik3ca-null tumors increases their susceptibility to T cell-mediated regression in vivo. These results indicate that PI3K/Akt signaling in tumor cells limits T cell recognition and clearance of pancreatic cancer. Strategies that selectively target the PI3K/Akt signaling pathway in tumor cells may improve immunotherapy for pancreatic cancer.
Citation Format: Nithya Sivaram, Patrick McLaughlin, Ya-Ping Jiang, Lisa Ballou, Kien Pham, Chen Liu, Adrianus van der Velden, Richard Lin. PI3K/Akt signaling in tumor cells promotes immune evasion by limiting infiltration, recognition and killing by T cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 522.
Abstract 5227: Chromatin folding disruptions in human cancers
Authors: Akdemir Kadir C. 
Published: August 2019

Abstract
Genomic material within the nucleus is folded into successive layers in order to package and organize the long string of linear DNA. This hierarchical level of folding is closely associated with transcriptional regulation and DNA replication. Genes within the same folding domain demonstrate similar expression and histone-modification profiles. Therefore, boundaries separating different domains have important roles in reinforcing the stability of these domain-wide features. Indeed, domain boundary disruptions in human genetic disorders or human cancers lead to misregulation of certain genes, due to de novo enhancer exposure to promoters. However, the frequency of boundary disruptions in human cancers, and whether there are recurrently affected boundaries in specific cancer types, remains unclear. Here, to understand effects and distributions of somatic structural variations (SVs) across TADs, we utilized 288,457 high-confidence somatic structural variations from 2658 tumor-normal pair high-coverage whole genome sequencing datasets across various cancer types. We comprehensively profiled structural variations effects on the domain boundaries and the regulation of genes in human cancers. Our findings demonstrate that the impact of TAD disruptions are substantially varied across tumor types and these events are reflective of overall SV burden and type. Notably, most of the TAD disruptions could result in appreciable changes in nearby gene expression in cancer cells. In addition, we demonstrated that SVs can lead to fusion of discrete TADs. Notably, complex rearrangements drastically change chromatin folding maps in the cancer genomes.
Note: This abstract was not presented at the meeting.
Citation Format: Kadir C. Akdemir. Chromatin folding disruptions in human cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5227.
Abstract 5231: Regulatory mechanism of carboxylesterase 2 expression and its role in human colorectal cancer
Authors: Ishimine Momoko , Lee Hyeon-Cheol , Nakaoka Hirofumi , Orita Hajime , Kobayashi Toshiyuki , Inoue Ituro , Sato Koichi , Yokomizo Takehiko 
Published: August 2019

Abstract
Irinotecan (camptothecin-11 (CPT-11)) is an anticancer drug that has been used in the treatment of a wide spectrum of cancer, and irinotecan-containing regimens such as FOLFIRI and FOLFOXIRI are standard chemotherapy regimens for advanced colorectal cancer. Irinotecan is a prodrug that is converted to its active metabolite 7-ethyl-10-hydroxycamptothesin (SN-38) by carboxylesterases CES1 and CES2. CES2 has a far higher hydrolytic efficiency against irinotecan than CES1. Since CES2 expression is higher than other CES isozymes in colon tissue, it might contribute to local (i.e., intratumoral) activation of irinotecan. Recent studies have shown that CES2 expression is regulated by p53 in human colon carcinoma cell lines. TP53 is a tumor suppressor gene and the frequency of its mutations in colorectal cancer is approximately 50%. Therefore, TP53 mutation may cause downregulation of CES2 expression and affect the sensitivity of colorectal cancer to irinotecan. In our previous study, we showed that both CES2 expression and carboxylesterase activity were significantly lower in most colorectal cancer specimens than in adjacent normal tissue. Nevertheless, there was no clear relationship between CES2 expression and TP53 gene status. We also found that p21 expression was significantly reduced in the tumors compared with adjacent normal tissue independently of their TP53 mutational status. Notably, there was a strong positive correlation between p21 and CES2 expression even in the tumors with nonfunctional p53. Recent studies have reported that colorectal tumors developed in proximal colon (right side) and distal colon (left side) exhibit different molecular characteristics and histology. Patients with left-sided colorectal tumors respond well to conventional adjuvant chemotherapies, and the prognosis of these patients is better than that of patients with right-sided colorectal tumors. To test whether location of tumor affects CES2 expression, we compared the CES2 expression levels of tumors that arose from proximal colon with those from distal colon. We also tested the potency and the selectivity of a recently reported CES2 inhibitor. Our results provide important insights into the regulatory mechanism of CES2 expression and its role in colorectal cancer.
Citation Format: Momoko Ishimine, Hyeon-Cheol Lee, Hirofumi Nakaoka, Hajime Orita, Toshiyuki Kobayashi, Ituro Inoue, Koichi Sato, Takehiko Yokomizo. Regulatory mechanism of carboxylesterase 2 expression and its role in human colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5231.
Abstract 5237: Development of a gene expression database of renal cell carcinoma cases by NGS-combined HiCEP to identify tumor markers
Authors: Kawaguchi Makoto , Matsuo Hirotaka , Araki Ryoko , Shimizu Seiko , Takao Mikiya , Nakayama Akiyoshi , Kitamura Yosuke , Abe Masumi , Ito Keiichi , Shinomiya Nariyoshi 
Published: August 2019

Abstract
Objectives: High coverage expression profiling (HiCEP) is an AFLP-based comprehensive gene expression analysis technique invented in Japan. HiCEP has two unique characteristics. First, it can detect low amounts of mRNA with high sensitivity and reliability. Second, HiCEP enables highly quantitative and reproducible mRNA expression analyses. However, it requires complicated processes, including TA cloning of isolated transcripts, to obtain sequence information on detected peaks. We performed next-generation sequencing (NGS)-combined HiCEP and tried to establish a gene expression database of renal cell carcinoma (RCC) cases to identify effective tumor markers.
Materials and methods: We collected cancerous and macroscopically non-cancerous regions from 83 RCC cases. Of these, six cases with clear cell RCC were analyzed by HiCEP. Total RNA was extracted from the cancerous and non-cancerous tissues of six clear cell RCC cases, and transcribed to cDNA. The cDNA was synthesized and subjected to digestion with the restriction enzymes MspI or MseI, followed by adapter ligation. Selective PCR by 256 kinds of primer pairs was used to amplify the HiCEP fragments, and products with fluorescently-labeled primer were then analyzed by capillary electrophoresis. HiCEP fragments were sequenced using a next-generation sequencer (ion PGM, Thermo Fisher Scientific). We compared the expression levels of HiCEP peaks in cancerous tissues with those in non-cancerous tissues.
Results: We detected several HiCEP peaks in cancerous tissues that showed five times higher expression than in normal tissues. We determined the sequences of the HiCEP fragments by NGS, and developed the first ever cancerous tissue HiCEP fragment database.
Conclusion: We successfully established an RCC gene expression database by NGS-combined HiCEP. We are now performing replication analyses and further analyses of blood samples from the same RCC cases to be able to identify diagnostic and prognostic markers of RCC.
Citation Format: Makoto Kawaguchi, Hirotaka Matsuo, Ryoko Araki, Seiko Shimizu, Mikiya Takao, Akiyoshi Nakayama, Yosuke Kitamura, Masumi Abe, Keiichi Ito, Nariyoshi Shinomiya. Development of a gene expression database of renal cell carcinoma cases by NGS-combined HiCEP to identify tumor markers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5237.
Abstract 5239: Cisplatin disrupts MDM2-DAXX-HAUSP complex, p53 accumulation, cell cycle regulation, and apoptosis in acute leukemia cells
Authors: Kumar Sanjay , Tchounwou Paul 
Published: August 2019

Abstract
Cisplatin (CDDP) is an antitumor drug successfully used in the treatment of various types of human malignancies. It enhances toxicity of arsenic trioxide (ATO) in head and neck squamous cell carcinoma cell, small cell lung cancer, ovarian cancer cells, and oral squamous cell carcinoma cells (, and chronic myelogenous leukemia cells. CDDP induces cytotoxicity, DNA damage, oxidative stress, and apoptosis in acute promyelocytes leukemia (APL) cells. However, the molecular mechanisms of CDDP-induced P53 activation, cell cycle arrest, and apoptosis in APL cells remain poorly understood. We hypothesized that CDDP inhibits proliferation of APL cells through MDM2-DAXX-HAUSP complex disruption, p53 activation leading to cell cycle arrest and apoptosis. To test hypothesis, we used three APL cell lines and mice model of APL and investigated CDDP effects on cells growth, complex disruption, cell cycle progression, and apoptosis by applying western blotting, IP, gene knockdown techniques, immune/histochemistry, and confocal imaging. We found that CDDP - induced stress signal transmitted by protein kinase (ATM, ATR) and its downstream targets (CHK1 & CHK2) phosphorylation leading to down-regulation of complex molecules expression and accumulation of p53. CDDP-induced p53 expression modulated cell cycle progression and apoptosis in APL cells, and stimulated the formation of more promyelocytes with dense granules through reduction of MDM2 expression in bone marrow cells. CDDP also activated p53 in APL mice liver tissues. This novel mechanism of action of CDDP in APL cells may help in the design of new anti-leukemic drugs for treatment of APL patients.
Acknowledgements: This research was supported by National Institutes of Health NIMHD [grant # G12MD007581], through the RCMI-Center for Environmental Health at Jackson State University.
Citation Format: Sanjay Kumar, Paul Tchounwou. Cisplatin disrupts MDM2-DAXX-HAUSP complex, p53 accumulation, cell cycle regulation, and apoptosis in acute leukemia cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5239.
Abstract 5250: Notch signaling in ER+ breast cancer in response to endocrine therapy agents
Authors: Singleton Ciera S. , Miele Lucio , Crabtree Judy S. 
Published: August 2019

Abstract
Breast cancer is the most frequent cancer in women in the world, and more than 70% of breast cancer cases are estrogen receptor α positive (ER+). Standard treatment for ER+ breast cancers is endocrine therapy that consists of selective estrogen receptor modulators (SERMs) such as tamoxifen in pre-menopausal patients; aromatase inhibitors (AIs); or selective estrogen receptor down-regulators (SERDs); fulvestrant, and treatment is dependent on the menopausal state of the patient. Many luminal tumors acquire resistance to therapy and recur, leading to disease progression and mortality. Resistance may result from the activation of quiescent signaling pathways that drive cancer stem cell (CSC) activity, such as the Notch signaling pathway. Previous studies demonstrate that activation of Notch via the NOTCH1 receptor recruits ERα in the absence of estrogen to facilitate transcription of estrogen responsive genes. However, NOTCH4 is often upregulated in resistant ER+ breast cancers, driving endocrine therapy resistance via breast CSC activity. We hypothesize that NOTCH4 promotes the transcription of estrogen-responsive genes in the absence of estrogen in a selective manner that is unlike NOTCH1. Understanding how NOTCH4 regulates the transcription of estrogen responsive genes upon treatment with endocrine therapy may suggest the need for combination therapy for ER+ breast cancer that includes a Notch targeted therapy. We have measured mRNA expression of classic estrogen responsive genes in ER+ breast cancer cell lines that either overexpress NOTCH1 or NOTCH4. Our data demonstrate differential expression of estrogen-responsive genes between NOTCH1 and NOTCH4 in the presence of tamoxifen. We have also measured Notch contribution to breast cancer stem cell activity through mammosphere formation assays using ER+ breast cancer cell lines in the presence of fulvestrant and Notch signaling inhibitors. The expression of classical estrogen responsive genes from mammospheres was altered in the presence of fulvestrant, Notch signaling inhibitors, or combinations of the two treatments. Further, combination treatment led to the disruption of mammosphere formation suggesting that combination therapy in the clinic may be suitable for the prevention of endocrine resistance by inhibition of BCSC activity through NOTCH4.
Citation Format: Ciera S. Singleton, Lucio Miele, Judy S. Crabtree. Notch signaling in ER+ breast cancer in response to endocrine therapy agents [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5250.