bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract LB-395: STAT3-induced lncRNA HAGLROS overexpression contributes to the malignant progression of gastric cancer cells contributes to the malignant progression of gastric cancer cells
Authors: Chen Jinfei , Yang Fen 
Published: August 2018

Abstract
BACKGROUND: Long noncoding RNAs (lncRNAs) are an important class of functional regulators involved in gastric cancer (GC). Studying aberrantly expressed lncRNAs may provide us with new insights into the occurrence and development of gastric cancer by acting as oncogenes or tumor suppressors. In this study, we aim to examine the expression pattern of lncRNA HAGLROS in GC and its biological role and mechanisms in tumor progression.
METHODS: Bioinformatics analysis and qRT-PCR were performed to detect the relative expression of HAGLROS in GC tissues and cell lines. Gain or loss of function approaches were used to investigate the biological functions of HAGLROS. The effect of HAGLROS on proliferation was evaluated by MTT, colony formation assay and nude mouse xenograft model. Wound healing and Transwell assays were used to study the invasion and migration of GC cells. FISH, RIP, RNA-seq, Luciferase report assays, RNA pulldown and Western blot were fulfilled to measure molecular mechanisms. Results are shown as means ± S.D. and differences were tested for significance using Student's t-test (two-tailed).
RESULTS: We screened out HAGLROS, whose expression was significantly increased and correlated with outcomes of GC patients by publicly available lncRNAs expression profiling and integrating analyses. Exogenous down-regulation of HAGLROS expression significantly suppressed the cell proliferation, invasion and migration. Mechanistic investigations showed that HAGLROS was a direct target of transcriptional factor STAT3. Moreover, HAGLROS knockdown decreased mTOR expression and increased autophagy-related genes ATG9A and ATG9B expression. Further investigation showed that HAGLROS regulated mTOR signals in two manners. In the one hand, HAGLROS competitively sponged miR-100-5p to increase mTOR expression by antagonizing miR-100-5p-mediated mTOR mRNA inhibition. On the other hand, HAGLROS interacted with mTORC1 components to activate mTORC1 signaling pathway which was known to be an important negative signal of autophagy. Here activation of mTORC1 signaling pathway by HAGLROS inhibited autophagy, thereby promoted excessive proliferation and maintained the malignant phenotype of GC cells.
CONCLUSION: The present study demonstrates that HAGLROS overexpression contributes to GC development and poor prognosis and will be a target for GC therapy and further develop as a potential prognostic biomarker.
Citation Format: Jinfei Chen, Fen Yang. STAT3-induced lncRNA HAGLROS overexpression contributes to the malignant progression of gastric cancer cells contributes to the malignant progression of gastric cancer 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 LB-395.
Abstract SY07-02: Epigenetic regulation of T-cell exhaustion: Implications for cancer immunotherapy
Authors: Youngblood Benjamin A. , Ghoniem Hazem , Moustaki Ardiana , Abdelsamed Hossam , Fan Yiping , Thomas Paul , Stewart Elizabeth , Federico Sara 
Published: August 2018

Abstract
Immune checkpoint blockade (ICB)-mediated rejuvenation of CD8 T-cell effector functions has emerged as one of the most promising frontiers for treating cancer and chronic infections. However, antigen-specific T cells that have experienced prolonged antigen exposure are often terminally differentiated, and have a limited capacity to mount an effector response during ICB treatment. Such exhaustion of effector potential is a major impediment of current T cell-based immunotherapy efforts. Using in vivo mouse models of tumor and chronic viral infection, we assessed the role of de novo epigenetic programming in establishing ICB-refractory exhausted T cells. We observed that genetic deletion of the de novo DNA methyltransferase, Dnmt3a, in T cells at the effector stage of an immune response to chronic lymphocytic choriomeningitis virus (LCMV) infection allowed antigen-specific T cells to remain highly functional despite expressing high levels of PD-1 and having prolonged exposure to antigen. Quite strikingly, PD-1 blockade treatment of chronically infected animals resulted in massive expansion of PD-1+ Dnmt3a-deficient antigen-specific T cells. Whole-genome methylation profiling of WT and Dnmt3a-deficient LCMV-specific CD8 T cells identified de novo DNA methylation programs that are coupled to development of ICB-nonresponsive virus and tumor-specific T cells. Building upon these findings, we have identified de novo epigenetic programs acquired in human tumor-associated PD-1hi CD8 T cells. Collectively, these data establish Dnmt3a-mediated de novo DNA methylation programming as a key regulator in establishing ICB-refractory exhausted CD8 T cells and highlight epigenetic reprogramming of T cells as a novel approach to enhance T cell-based cancer therapies.
Citation Format: Benjamin A. Youngblood, Hazem Ghoniem, Ardiana Moustaki, Hossam Abdelsamed, Yiping Fan, Paul Thomas, Elizabeth Stewart, Sara Federico. Epigenetic regulation of T-cell exhaustion: Implications for cancer immunotherapy [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 SY07-02.
Abstract SY22-02: Metabolic vulnerability of PTEN mutant cancer
Authors: Parsons Ramon E. 
Published: August 2018

Abstract
Signaling pathways that act as drivers of cancer cell growth and proliferation activate metabolic pathways required to generate the building blocks required for cell doubling. Loss of PTEN activates PI3K, AKT and mTOR to stimulate glucose and glutamine flux to allow DNA replication. One of the metabolic pathways that is activated after deletion of both alleles of PTEN is the de novo pyrimidine synthesis pathway. PTEN null cells show evidence of increased DNA replication and low levels of damage at replication forks that can be rescued by providing supplementary uridine. Interruption of de novo pyrimidine synthesis with an inhibitor of dihydroorotate dehydrogenase (DHODH) increased DNA damage at replication forks of PTEN null cells that ultimately led to chromosome breaks detected in mitosis and cell death. This cellular vulnerability to inhibition of DHODH was rescued with uridine, demonstrating the specificity of the effect. Exploration of the mechanism that led to vulnerability of PTEN null cells demonstrated that it was due to defective ATR signaling at replication forks that was a consequence of activated AKT, which phosphorylate and attenuate TOPBP1 and CHK1. Complementation of PTEN null cells with mutants of TOPBP1 and CHK1 that cannot be phosphorylated by AKT rescued the cells from DNA damage and cell death due to inhibition of DHODH. Tumor cell lines lacking PTEN tended to be more sensitive to DHODH inhibition than PTEN wild type cells were. In conclusion, the attenuated ATR signaling and increased flux of nucleotides to newly synthesized DNA at replication forks makes PTEN mutant cells vulnerable to disruption of de novo pyrimidine synthesis.
Citation Format: Ramon E. Parsons. Metabolic vulnerability of PTEN mutant 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 SY22-02.
Abstract A03: Circulating CCL2 and CXCL8 chemokine levels and receptor interactions differ in African-Americans and Caucasians with breast cancer
Authors: Jenkins Brittany Denise , Hire Rupali , Martini Rachel N. , Davis Melissa B. 
Published: August 2018

Abstract
In 2013, the breast cancer mortality rate of African-American (AA) women in the U.S. was significantly higher than Caucasian women, even though incidence rates were about equal. Undoubtedly, access to health care and socioeconomic status could contribute to this health disparities gap, but inherent biologic differences may also be a contributing factor. The purpose of this study is to determine if differences in immunobiology, particularly the abundance of two proinflammatory chemokines, differs between AA and Caucasian women with breast cancer. Differences in these signaling molecules can affect the migration of immune cells, in addition to having a significant effect on cancer progression and tumor biology. We are also interested in the interactions between these chemokines and one of their receptors, ACKR1, which harbors ancestry-specific alleles. Generally, those of AA descent express less of this receptor on their tumor cells, producing a yet to be determined immune response when it comes to breast cancer.
Using plasma samples obtained from breast cancer patients pretreatment, in addition to plasma samples from control patients, we were able to determine any differences in chemokine protein levels from these participants using a Luminex immunoassay. Our molecules of interest, CCL2 (MCP-1) and CXCL8 (IL-8), were both chosen due to their ability to influence immune cell migration, in addition to angiogenesis and cancer cell progression. From our analysis, race-specific differences were observed for these particular chemokines between AA and Caucasians with breast cancer. When considering CCL2, it appears that AA had significantly less CCL2 present in circulation when compared to Caucasians. For CXCL8, the median concentration for AA cancer patients was much lower than that of the Caucasian group. The presence or absence of ACKR1 on the tumors of these patients also seems to play a role in circulating chemokine levels, with higher circulating levels being associated with those who have the receptor present on tumor cells. Overall, there appear to be biologic differences in immune response between AA and Caucasians with breast cancer, especially when considering CCL2 and CXCL8, and their interactions with ACKR1. This difference could account for variations in treatment responses, in addition to differences in breast cancer aggressiveness and progression seen within these two groups.
Citation Format: Brittany Denise Jenkins, Rupali Hire, Rachel N. Martini, Melissa B. Davis. Circulating CCL2 and CXCL8 chemokine levels and receptor interactions differ in African-Americans and Caucasians with breast cancer [abstract]. In: Proceedings of the AACR Special Conference: Advances in Breast Cancer Research; 2017 Oct 7-10; Hollywood, CA. Philadelphia (PA): AACR; Mol Cancer Res 2018;16(8_Suppl):Abstract nr A03.
Abstract A08: Epigenetic heterogeneity in triple-negative breast cancer
Authors: Maruyama Reo , Yang Liying , Kumegawa Kohei 
Published: August 2018

Abstract
Triple-negative breast cancer (TNBC) is defined by the absence of estrogen/progesterone receptor (ER/PgR) expression and HER2 amplification. Patients with TNBC have a higher rate of distant recurrence and a poorer prognosis than women with other breast cancer subtypes, since targeted therapy is not available for them. TNBC is a highly heterogeneous group of tumors and the underlying biology of these tumors should be substantially different. Stratification is essential for selection of appropriate therapy. We have previously identified key regulators that define basal-like (ER-/PgR-/HER2-) and luminal (ER+/PgR+ and/or HER2+) breast cancer cell phenotypes by using combined somatic cell genetic and integrative epigenomic approaches (Su et al., Cell Reports 2015). We found that common core epigenetic programs in luminal tumors are defined by FOXA1 super-enhancers; however, apart from displaying extinguished luminal features, the basal-like phenotype is not defined by a specific epigenetic state and displays a high degree of heterogeneity.
In this study, we aimed to identify a key regulator that can classify TNBCs into two groups, so that it could help improve our understanding of biology and explain the epigenetic heterogeneity in TNBC. We first reanalyzed our original multi-omics data of hetero-fusion cells in the previous study and also performed an integrated analysis of genomic, transcriptomic, and epigenomic data obtained from the TCGA project. We finally focused on a transcription factor (TF-X), whose function is currently unknown. TF-X is upregulated in a subset of TNBCs and the expression level of the gene is associated with poor prognosis in TNBC. Knockdown of TF-X decreased cell survival rate and changed cellular morphology of the cells. We are currently doing further functional analysis of TF-X. Our findings seem to imply that TF-X is one of the key regulators that govern cellular property of TNBC.
Note: This abstract was not presented at the conference.
Citation Format: Reo Maruyama, Liying Yang, Kohei Kumegawa. Epigenetic heterogeneity in triple-negative breast cancer [abstract]. In: Proceedings of the AACR Special Conference: Advances in Breast Cancer Research; 2017 Oct 7-10; Hollywood, CA. Philadelphia (PA): AACR; Mol Cancer Res 2018;16(8_Suppl):Abstract nr A08.
Abstract A11: Association of the main variants of the 8q24- rs13281615 and 2q35-rs13387042 with breast cancer risk in Khorasan population
Authors: Pasdar Alireza , Nesay Abolfazl , Tajbaksh Amir , Rivandi Mahdi , Javan Fahime Afzal , Moezzi Atefe , Toroghian Younes , Ghasemi Amirhossein , Soltanian Hossein , Salehi Mahta , Shandiz Fatemeh Homaei 
Published: August 2018

Abstract
Background: Since 2013, the incidence rate of breast cancer has remained as the first rank among female cancers worldwide. Breast cancer is a heterogeneous disease that has different environmental and genetic risk factors. In recent years, advances in molecular techniques resulted in the inaccurate characterization of molecular markers and therefore improvement of diagnostic and treatment methods. GWA studies play a key role in determining low-penetrance variants that influence the susceptibility of breast cancer. Studies have shown the strong association of two markers, rs10995190 and rs10822013, on chromosome 10q21.2, with breast cancer among different populations.
Considering genetic diversity among various populations and the fact that the association of these markers with the risk of developing breast cancer has not been investigated in our population, our study aimed to investigate if these markers are associated with increased risk of breast cancer in the Khorasan province population.
Methods: The current study was conducted on 400 women, including 185 breast cancer patients and 215 healthy controls. Genotyping was performed using ARMS_PCR method.
Results: There was a significant difference in rs10822013 genotype allele frequencies between patient and control groups (P&lt;05). However, there were no significant differences in genotype and allele frequencies between patient and control group (P=0.41) for rs10995190.
Conclusion: Based on the results, rs10822013 may increase the risk of breast cancer in our population, which is in line with the other results in the Asian population.
Citation Format: Alireza Pasdar, Abolfazl Nesay, Amir Tajbaksh, Mahdi Rivandi, Fahime Afzal Javan, Atefe Moezzi, Younes Toroghyan, Amirhossein Ghasemi, Hossein Soltanian, Mahta Salehi, Fatemeh Homaei Shandiz. Association of the main variants of the 8q24- rs13281615 and 2q35-rs13387042 with breast cancer risk in Khorasan population [abstract]. In: Proceedings of the AACR Special Conference: Advances in Breast Cancer Research; 2017 Oct 7-10; Hollywood, CA. Philadelphia (PA): AACR; Mol Cancer Res 2018;16(8_Suppl):Abstract nr A11.
Abstract A12: Characterization of the mitronic tsmiR miR6855-3p as a DNA damage repair regulator in the SLUG-high metastatic breast cancer cells
Authors: Ellison Marshall JD , Misra Smita , Chaudhuri Gautam 
Published: August 2018

Abstract
The precursor of the human microRNA hsa-miR-6855-3p is a 5-tailed mitronic pre-miRNA that is coded by intron #13 of the deubiquitinase USP20 gene. Our preliminary data suggest that the biosynthesis of this miRNA is upregulated by oxidative stress in the SLUG-high metastatic breast cancer cells, promoting DNA double-strand break repair (DSBR) through the indirect enhancement of BRCA2 gene expression. We found that miR-6855-3p favors BRCA2 biosynthesis through the enhancement of the level of an alternately translated form of the BRCA2 gene enhancer protein SPRDX5. We hypothesize that BRCA2 gene silencer acts as a scaffolding to co-recruit SLUG and SPRDX5 and promote SPRDX5-mediated oxidative inactivation of the BRCA2 negative regulator protein SLUG. Here, we present evidence that (a) the expression of miR-6855-3p is essential for the expression of BRCA2 in the SLUG-high metastatic breast cancer cells; (b) knockdown of miR-6855-3p affects DSBR in these cells; and (c) the miR-6855-3p knocked-down cells are susceptible to the synthetic lethality by the PARP inhibitors. Our study reveals a novel mechanism of regulation of BRCA2 gene expression in the aggressive breast cancer cells, offering an alternative strategy to chemically intervene in the progression of hard-to-cure, highly aggressive SLUG-high breast cancer. We propose that the inhibition of miR-6855-3p will induce BRCA2 deficiency in the BLBC cells, thus increasing their susceptibility to standard chemotherapy as well as to PARP inhibitors as has been described for other BRCA2-deficient cells. Supported in part by DOD-CDMRP IDEA Expansion Grant #BC103645 and NIH/NCI grant 1R21CA181920-01 to GC and 1U54RR026140 to SM.
Note: This abstract was not presented at the conference.
Citation Format: Marshall JD Ellison, Smita Misra, Gautam Chaudhuri. Characterization of the mitronic tsmiR miR6855-3p as a DNA damage repair regulator in the SLUG-high metastatic breast cancer cells [abstract]. In: Proceedings of the AACR Special Conference: Advances in Breast Cancer Research; 2017 Oct 7-10; Hollywood, CA. Philadelphia (PA): AACR; Mol Cancer Res 2018;16(8_Suppl):Abstract nr A12.
Abstract A17: Ganoderma lucidum inhibits the DNA damage response in combination with carboplatin in breast cancer cells
Authors: Suárez-Arroyo Ivette , Martínez-Montemayor Michelle 
Published: August 2018

Abstract
Management of triple-negative breast cancer (TNBC) is challenging because of a lack of targeted therapy, aggressive behavior, and poor prognosis. Interest in using platinum agents, such as carboplatin, as a line of treatment emerged from data suggesting frequent DNA repair defects in TNBC. Carboplatin resistance may occur due to multiple factors including increased activation of DNA repair mechanisms. Studies show that Ganoderma lucidum extract (GLE) sensitizes cancer cells to different anticancer therapies. Thus, we aim to investigate the effects of GLE in combination with carboplatin and to elucidate its effects in the DDR signaling. To study whether GLE sensitizes breast cancer cells to carboplatin therapy, we treated SUM-149 and MDA-MB-231 triple-negative breast cancer cell lines with several concentrations of carboplatin, GLE, or both treatments simultaneously for 72h. Our results demonstrate that when carboplatin and GLE are used in combination, the IC50s decreased in both breast cancer cell lines in comparison with treatments alone. Moreover, our data revealed that GLE and/or the combination decrease the expression of 53BP1, p-CHK2, p-CHK1, p-ATR, p-ATM, and p-BRCA1 in SUM-149 and/or in MDA-MB-231 cells. In addition, the phosphorylation of the pro-apoptotic protein p53 was upregulated by the combination. Immunofluorescence studies on DNA repair proteins 53BP1 and phosphorylated γH2AX to detect DNA double-strand breaks suggest that the GLE and/or carboplatin combination impair DDR. Taken together, our results provide evidence of GLE’s potential in chemosensitizing TNBC cells to carboplatin therapy affecting the DDR. These results highlight GLE’s anti-breast cancer therapeutic potential. This work is supported by NIGMS SC3GM111171 (MMM), PRSTT SGRP 2016-2017 (MMM), NIMHD MD007583 (MMM), and Title-V-PPOHA P031M105050 and Title-V-Cooperative P031S130068 from the U.S. Dept. of Education.
Note: This abstract was not presented at the conference.
Citation Format: Ivette Suárez-Arroyo, Michelle Martínez-Montemayor. Ganoderma lucidum inhibits the DNA damage response in combination with carboplatin in breast cancer cells [abstract]. In: Proceedings of the AACR Special Conference: Advances in Breast Cancer Research; 2017 Oct 7-10; Hollywood, CA. Philadelphia (PA): AACR; Mol Cancer Res 2018;16(8_Suppl):Abstract nr A17.
Abstract A25: TEM8 specific CAR T cells induce regression of patient-derived xenograft and metastatic models of triple-negative breast cancer
Authors: Byrd Tiara , Fousek Kristen , Pignata Antonella , Szot Christopher , Samaha Heba , Dobrolecki Lacey , Oo Htoo Zarni , Sorensen Poul , Ellis Matthew , Lewis Michael , Hegde Meenakshi , Fletcher Bradley , Croix Brad St. , Ahmed Nabil 
Published: August 2018

Abstract
Lacking marked expression of human epidermal growth factor receptor 2 (HER2), estrogen receptor (ER), and progesterone receptor (PR), triple-negative breast cancer (TNBC) is a breast cancer subtype in desperate need of targeted therapy options. Tumor endothelial marker 8 (TEM8), initially identified as a tumor endothelium marker in colon cancer, has been shown to be upregulated in TNBC. To confirm this, we stained primary TNBC tissues for TEM8; in all cases TEM8 was expressed with no expression in normal breast tissue. TEM8 is expressed by TNBC cell lines as indicated by flow cytometry and Western blot. We thus engineered chimeric antigen receptor (CAR) T cells to specifically target TEM8 in TNBC. TEM8 CAR T cells distinctly recognized TEM8, secreted immunostimulatory cytokines, and killed TEM8-positive TNBC cells in vitro. In vivo, the adoptive transfer of TEM8 CAR T cells induced regression against orthotopic patient-derived xenograft (PDX) models, including the aggressive claudin-low TNBC PDX, WHIM12. Systemic administration of TEM8 CAR T cells also induced regression against a lung metastasis TNBC model. In all models, treatment with TEM8 CAR T cells resulted in a survival advantage in mice compared to controls. Hence, TEM8 may serve as an attractive targeted immunotherapy of TNBC.
Citation Format: Tiara Byrd, Kristen Fousek, Antonella Pignata, Christopher Szot, Heba Samaha, Lacey Dobrolecki, Htoo Zarni Oo, Poul Sorensen, Matthew Ellis, Michael Lewis, Meenakshi Hegde, Bradley Fletcher, Brad St. Croix, Nabil Ahmed. TEM8 specific CAR T cells induce regression of patient-derived xenograft and metastatic models of triple-negative breast cancer [abstract]. In: Proceedings of the AACR Special Conference: Advances in Breast Cancer Research; 2017 Oct 7-10; Hollywood, CA. Philadelphia (PA): AACR; Mol Cancer Res 2018;16(8_Suppl):Abstract nr A25.