bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4429: FOXP3 transcriptional regulation of MicroRNAs in human breast cancer
Authors: Yi Baozhu , Li Ming , Liu Ying , Liu Runhua 
Published: August 2018

Abstract
MicroRNA (miR)-155 has been found to be overexpressed in breast cancer cells, but its transcriptional regulation remains elusive. The role of miR-155 is also not determined in breast cancer development and progression. In this study, we identified a FOXP3-BRCA1-miR155 axis in breast cancer cells. MiR-155 is induced by FOXP3 through a transcriptional repression of BRCA1 in breast cancer cells. Likewise, overexpression of miR-155 was found in patients with early stage or triple negative breast cancer, but not in patients with high stage or metastatic breast cancer. Of note, expression of miR-155 in blood cells was higher in patients with localized but not metastatic tumors. In addition, although miR-155 in tumor cells is induced by FOXP3, free or exosomal miR-155 in culture medium was not changed with induction of FOXP3. There is a transcriptional axis of FOXP3-BRCA1-miR-155 in breast cancer cells. MiR-155 is a potential biomarker for early stage breast cancer. Plasma miR-155 appears to be related to that in blood cells but not in tumor cells.
Citation Format: Baozhu Yi, Ming Li, Ying Liu, Runhua Liu. FOXP3 transcriptional regulation of MicroRNAs in human breast 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 4429.
Abstract 4434: Contribution of heterogenous ribonucleoprotein A18 in prostate cancer progression
Authors: Chang Elizabeth Tsuying , Choi Eun Yong , Parekh Palak R. , Carrier France 
Published: August 2018

Abstract
Prostate cancer is the third leading cause of cancer deaths among men in the United States, with recurrent metastasis being the predominant cause of mortality. In spite of the significant progress made in the past half century with hormonal therapy for metastatic prostate cancer, a majority eventually progresses to a lethal stage of the disease commonly known as castration-resistant prostate cancer. New treatment strategies are therefore needed. Previous work from our lab has identified the RNA-binding protein heterogenous ribonucleoprotein A18 (hnRNP A18) as a new regulator of protein translation in cancer cells. While its localization is predominantly nuclear, hnRNP A18 translocates out to the cytosol in response to cellular stress like hypoxia. Immunohistochemistry data from tissue microarrays reveals increased expression of hnRNP A18 in prostate hyperplasia, and even greater overexpression in prostate adenocarcinoma as compared to the surrounding normal tissue. Furthermore, a greater percentage of hnRNP A18 is seen to shift from the nucleus to the cytosol as the disease progresses. In the cytosol, hnRNP A18 recognizes and binds to a specific 51 nucleotide RNA motif in the 3' untranslated region of targeted transcripts, stabilizing them and enhancing their translation. Transcripts targeted by hnRNP A18 confer tumor growth advantages. The down-regulation of hnRNP A18 was seen to reduce cancer cell proliferation, migration, and invasion. Moreover, down-regulation of hnRNP A18 significantly reduces prostate cancer growth in a mouse tumor xenograft model. Taken together, our data suggests that hnRNP A18 could be a potentially new target to stop or limit prostate cancer progression.
Citation Format: Elizabeth Tsuying Chang, Eun Yong Choi, Palak R. Parekh, France Carrier. Contribution of heterogenous ribonucleoprotein A18 in prostate cancer progression [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 4434.
Abstract 4448: Mutations in the center MATH domain of Speckle Type BTB/POZ Protein lead to enhanced proteinstability in prostate cancer
Authors: Fried Joshua , Khattar Vinayak , Ma Jinlu , Zeng Qinghua , Zhang Wei , Xu Bo 
Published: August 2018

Abstract
The Speckle type Poz Protein (SPOP) is a tumor suppressor that is often mutated in prostate cancer. Mutation of SPOP is linked to genomic instability and it plays a critical role in prostate cancer initiation. SPOP mutations are found to be in the heterozygous state in patients. The relevance of these mutations on its protein expression has not been systematically investigated. Here we report that mutations in the center MATH domain of SPOP lead to enhanced protein stability in prostate cancer. Among the mutations, F102C, S119N, F125V and WI31G showed increased protein stability. Further we show that these mutations in the MATH domain increase half-life of SPOP protein. Interestingly, the mutant SPOPs enhanced the endogenous wild-type SPOP level. We further explored the structural insights of these SPOP mutants. We present a computational
model to predict how SPOP mutations potentially lead to conformational changes within the protein, promoting its stability. Finally, immunohistochemistry in clinical samples of prostate cancer augment our findings. Together, we highlight a subset of clinically relevant SPOP mutations that have impact on endogenous SPOP protein stability, allowing to further understand its role in prostate cancer initiation and evaluating of potentially altered therapeutic response in patients harboring these mutations.
Citation Format: Joshua Fried, Vinayak Khattar, Jinlu Ma, Qinghua Zeng, Wei Zhang, Bo Xu. Mutations in the center MATH domain of Speckle Type BTB/POZ Protein lead to enhanced proteinstability 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 4448.
Abstract 4453: Osteopontin-c mediated drug resistance in breast and ovarian carcinoma cells
Authors: Brum Mariana C. , Guimaräes Isabella S. , Ferreira Luciana Bueno , Rangel Letícia B. , Maia Raquel C. , Moraes Gabriela N. de , Gimba Etel R. 
Published: August 2018

Abstract
Osteopontin (OPN) has been described as an important gene product mediating resistance to chemotherapeutic drugs. However, the specific roles of each OPN splice variant in mediating chemoresistance should be further investigated. This work aimed to evaluate OPNc expression patterns and its correlations with resistance to doxorubicin (DOX) and cisplatin (CIS) in breast and ovarian tumor cell lines, respectively. We used one breast cancer cell line resistant to DOX (MCF-7 DoxR), and one ovarian cancer cell line resistant to CIS (ACRP) and their corresponding parental cell lines (MCF-7 and A2780). Knockdown of OPNc expression levels has been achieved by transfecting cell lines with specific anti-OPNc phosphothiotate modified DNA oligomers. Cytotoxicity assays have been carried out using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), crystal violet and clonogenic assays. Gene expression has been assessed by quantitative real time PCR. Our results showed that drug-resistant cells overexpress OPNc and P-glycoprotein (P-gp), when compared to their age matched parental cell lines. After transfecting both MCF-7 DoxR and ACRP resistant cell lines with the anti-OPNc oligomers, we found a significant knockdown of OPNc isoform expression, as well as the expression of P-gp. Moreover, these cells exhibited a significantly increased sensitivity to DOX and CIS, and inhibited cell growth and colony formation (p&lt;0,05). Additionally, the epithelial-plasticity phenotype of both MCF-7 DoxR and ACRP resistant cell lines has been reversed, as well the expression of epithelial-mesenchymal transition (EMT)-related interleukins. Altogether, these data evidence that OPNc overexpression can mediate resistance to these chemotherapeutic drugs, possibly by modulating the expression of P-gp and the EMT phenotype. In summary, our data provide early insights on the role of OPNc isoform as a potential molecular target in cancer. Therapeutic strategies aiming to interfere with this isoform expression are likely to overcome resistance to chemotherapeutic agents.
Citation Format: Mariana C. Brum, Isabella S. Guimaräes, Luciana Bueno Ferreira, Letícia B. Rangel, Raquel C. Maia, Gabriela N. de Moraes, Etel R. Gimba. Osteopontin-c mediated drug resistance in breast and ovarian carcinoma 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 4453.
Abstract 4457: Determining the role of novel GLI1 splice variants in breast cancer
Authors: Dixon Maria S. , Chdid Lhoucine , Lamson David , Tarpley Michael , Fleming Jodie M. , Freedman Jennifer A. , Devi Gayathri R. , Williams Kevin P. 
Published: August 2018

Abstract
The purpose of this study is to investigate the biological significance of novel GLI1 splice variants in breast cancer. 15-20% of breast cancers are triple negative/basal-like, are associated with poor clinical outcomes and show disproportionately higher prevalence in younger women of African descent. The Hedgehog (Hh)/GLI1 developmental pathway has emerged as a therapeutic target in many cancers including studies on breast cancer such as those from our lab. Overexpression of the main Hh transcriptional mediator GLI1 correlates with poor patient prognosis and relapse. The human GLI1 transcript undergoes alternative splicing producing two shorter isoforms, an N-terminal deletion variant (GLI1ΔN) and a truncated GLI1 (tGLI1) which have been reported to have different patterns of tissue expression and function. tGLI1 has been identified as being highly expressed in several cancers, including in breast cancer. We undertook an in silico analysis of the NCBI database for evidence of additional human GLI1 transcripts and have identified novel GLI1 splice variants that we have subsequently shown to be highly expressed in breast cancer cell lines. Our objectives were to examine expression differences between GLI1 splice variants in basal-like and luminal breast cancer cell models, AA and White patient samples and to investigate the biological function of GLI1 splice variants in breast cancer. In our studies, we have utilized phenotypic and functional assays to examine the functional impact of these novel isoforms. Our preliminary data suggest that these newly identified GLI1 isoforms are expressed in basal-like breast cancers at substantially higher levels than GLI1, tGLI1 or GLI1ΔN. Previous studies assessing GLI1 expression have not considered these new isoforms and the relative contribution of each to breast cancer aggressiveness and require further investigation.
Citation Format: Maria S. Dixon, Lhoucine Chdid, David Lamson, Michael Tarpley, Jodie M. Fleming, Jennifer A. Freedman, Gayathri R. Devi, Kevin P. Williams. Determining the role of novel GLI1 splice variants in breast 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 4457.
Abstract 4460: BRCA1-associated R-loop accumulation at noncoding putative ERα enhancer area regulates expression of adjacent genes
Authors: Chiang Huai-Chin , Zhang Xiaowen , Zhang Chi , Zhao Xiayan , Li Jingwei , Hu Yanfen , Li Rong 
Published: August 2018

Abstract
Most BRCA1-associated breast tumors are basal-like yet originate from luminal progenitor cells. BRCA1 is best known for its functions in double strand break (DSB) repair and resolution of DNA replication stress. However, it is unclear whether loss of these ubiquitously important functions of BRCA1 fully explains the cell lineage-specific increase in breast tumor development. By sorting and profiling lineage-specific cells from precancerous human breast tissue, I found that BRCA1 mutation carriers tend to have a luminal cell-specific accumulation of R-loop, a transcriptional byproduct of DNA-RNA hybrid structure important for transcriptional regulation and genomic instability. R-loops accumulate preferentially at enhancers and transcription start sites (TSS) of luminal fate-related genes. Using CRISPR-Cas9 system, I've deleted an ERα enhancer area with BRCA1-associated R-loops accumulation in MCF7 cells. The deletion of this non-coding putative ESR1 enhancer area reduced the gene expression level of the neighboring genes of the deleted region, including ERα, RMND1, and CCDC170. In addition, compare to the reduced expression level of ERα, RMND1, and CCDC170 in BRCA1 knockdown of the parental MCF7, knocking down BRCA1 in these deletion clones showed less reduction of these genes. On the other hand, overexpression RNASEH1, an enzyme that specifically removes R-loop, had little effect in these genes after BRCA1 knockdown. These results indicate BRCA1-associated R-loop accumulation at least partially affect gene transcription at these loci. To investigate whether BRCA1-assocaited R-loop accumulation directly contributes to luminal differentiation blockage, I overexpressed RNASEH1 in breast epithelial cells freshly isolated from BRCA1 mutation carriers, flow cytometry comparing different breast lineage reveal a luminal population shift toward more mature luminal. All in all, the results infer that BRCA1 promotes luminal epithelial differentiation by alleviating R-loop accumulation at enhancer of ERα. Aberration in luminal transcription could contribute to lineage-specific BRCA1-associated tumorigenesis.
Citation Format: Huai-Chin Chiang, Xiaowen Zhang, Chi Zhang, Xiayan Zhao, Jingwei Li, Yanfen Hu, Rong Li. BRCA1-associated R-loop accumulation at noncoding putative ERα enhancer area regulates expression of adjacent genes [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 4460.
Abstract 4465: Variants of uncertain significance of the cancer-predisposing genes in two thousand Japanese whole-genome sequencing data
Authors: Yasuda Jun , Iida Keita , Kumada Kazuki , Ogishima Soichi , Shibuya Yusuke , Tokunaga Hideki , Yaegashi Nobuo 
Published: August 2018

Abstract
Many of the cancer predisposing genes are known to be associated with juvenile cancer syndromes such as Li Fraumeni syndrome. The responsible variants of the juvenile cancer syndromes are usually very deleterious and show strong biological effects on the gene functions. It is not so easy to estimate the clinical significance of the moderately deleterious variants in those genes that may have intermediate effects on the hosts' cancer predisposition and these moderately deleterious (or hypomorphic) variants are now classified as variants of uncertain significance (VUSs). The insight that VUSs may have moderate but clinically significant effects on cancer susceptibility now attracts cancer geneticists. To elucidate the state of VUSs of 135 cancer predisposing genes in general population, we functionally annotate the single nucleotide variants (SNVs) in the genes from a 2049 whole genome sequence high confident dataset (2KJPN-HC) obtained from participants in a genome cohort by Tohoku Medical Megabank Organization. Frequency spectrum of the Combined Annotation-Dependent Depletion (CADD) scores of the 135 genes showed very similar pattern to the whole 2KJPN-HC and a weak negative correlation (r = -0.0579) is observed between allele frequencies and CADD scores for each SNV. Among the variants found in 2KJPN, some of the variants are considered as responsible for hereditary cancer syndromes. We used the CADD and Eigen, other scoring system for estimation of impact of the variants, for the known damaging variants in the BRCA1 and BRCA2 genes to narrow down the candidate VUSs that may have moderate risks for cancer predisposition and found one VUS that is identified as a moderate risk SNP for breast cancer in the other studies. Combination of CADD and Eigen will be useful to narrow down the candidate deleterious SNVs for cancer predisposition.
Citation Format: Jun Yasuda, Keita Iida, Kazuki Kumada, Soichi Ogishima, Yusuke Shibuya, Hideki Tokunaga, Nobuo Yaegashi. Variants of uncertain significance of the cancer-predisposing genes in two thousand Japanese whole-genome sequencing data [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 4465.
Abstract 4473: Tumorigenesis by deregulation of CRAD-controlled cytoskeleton dynamics
Authors: Jung Youn-Sang , Wang Wenqi , Jun Sohee , Zhang Jie , Srivastava Mrianl , Kim Moon Jong , Lien Esther M. , Shang Joan , McCrea Pierre D. , Zhang Songlin , Chen Junjie , Park Jae-Il 
Published: August 2018

Abstract
Epithelial cell behavior and homeostasis are mainly modulated by the cytoskeleton and cell adhesion. However, much concerning epithelial cell deregulation in cancer remains unknown. We identified Cancer-related Regulator of Actin Dynamics (CRAD) as frequently mutated or transcriptionally downregulated in colorectal cancer. We found that CRAD is a capping protein inhibitor and stabilizes the cadherin-catenin-actin (CCA) complex. CRAD inactivation disrupts the CCA complex via inhibiting actin polymerization, liberating β-catenin and aberrantly activating Wnt pathway. In mice, CRAD knockout induces the loss of epithelial cell integrity and hyperactivates Wnt signaling, resulting in intestinal adenoma development. With APC mutation, CRAD knockout induces and accelerates mucinous and invasive adenoma development in the colorectum. These results define CRAD as a new tumor suppressor, of which inactivation deregulates the cytoskeleton and hyperactivates Wnt signaling, initiating mucinous intestinal tumorigenesis. Our study reveals the unexpected roles of an actin cytoskeletal regulator in maintaining epithelial cell integrity.
Citation Format: Youn-Sang Jung, Wenqi Wang, Sohee Jun, Jie Zhang, Mrianl Srivastava, Moon Jong Kim, Esther M. Lien, Joan Shang, Pierre D. McCrea, Songlin Zhang, Junjie Chen, Jae-Il Park. Tumorigenesis by deregulation of CRAD-controlled cytoskeleton dynamics [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 4473.
Abstract 4476: Role of MAP-Kinase suppressor in IBD
Authors: Khare Sharad , Zhang Qiong 
Published: August 2018

Abstract
BACKGROUND & AIMS: Endogenous suppressor of Mitogen Activated Kinase Pathway (MAPK) are considered cancer suppressors. In this regard , Sprouty (SPRY) proteins that are endogenous suppressor of receptor tyrosine kinase signaling are reported to be tumor suppressors in various cancers, whereas we discovered that SPRY2 augments Epithelial Mesenchymal Transition (EMT) in colorectal cancer (CRC) [Oncogene, 2016 Jun 16; 35(24): 3151-62]. Significance of SPRY proteins in Inflammatory Bowel Disease (IBD) is not clearly understood.
MATERIALS & METHODS: Biopsies from Crohn's Colitis patients were assessed for SPRY, Beta-catenin, Occludin and ZO1 expression. Tight junction profiler was employed to assess expression of integrin proteins in CaCO2 colon cancer cell line. SPRY was suppressed in colon cancer cells by siRNA and CRISPR/Cas9 technology and changes were assessed by immunoblotting, real time PCR, phase-contrast and confocal microscopy. Spry1 and Spry2 floxed mice were utilized to dissect SPRY functions in mesenchymal cells.
RESULTS: SPRY, E-cadherin, Beta-catenin and Occludin mRNA transcripts were significantly different in IBD patients (p&lt;0.05). No significant changes in ZO1 mRNA transcripts were noted. Suppression of SPRY significantly decreased expression of several integrins in CaCO2 cells (p&lt;0.05) . Treatment of CaCO2 cells with Dextran Sodium Sulfate (DSS) significantly altered SPRY, Beta-catenin, Occludin and ZO1 expressions that was reversed by SPRY suppression. Spry1-/- and Spry2-/- double mutant murine embryonic fibroblasts (MEFs) demonstrated restoration of several epithelial markers which protected cells from DSS-induced changes.
CONCLUSIONS: SPRY expression in colonic epithelium regulates IBD. SPRY has prognostic value in IBD.
Citation Format: Sharad Khare, Qiong Zhang. Role of MAP-Kinase suppressor in IBD [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 4476.
Abstract 4479: Protein arginine methyltransferase PRMT6 regulates cancer stemness through CRAF methylation in hepatocellular carcinoma
Authors: Chan LH , Zhou L , Ng Kai Yu , Wong TL , Lee TK , Ching YP , Yuan YF , Xie D , Richard S , Huen MS , Guan XY , Ma S 
Published: August 2018

Abstract
Arginine methylation is a post-translational modification that plays pivotal roles in signal transduction and gene transcription during cell fate determination. We found protein methyltransferase 6 (PRMT6) to be frequently down-regulated in hepatocellular carcinoma (HCC) cells and its expression to negatively correlate with aggressive cancer features in HCC patients. Silencing of PRMT6 promoted the tumor-initiating, metastasis and therapy resistance potential of HCC cells. Consistently, loss of PRMT6 expression aggravated liver tumorigenesis in a DEN+CCL4 HCC induced PRMT6-/- mouse model. Integrated transcriptome and protein-protein interaction studies revealed an enrichment of genes implicated in RAS signaling and that PRMT6 interacted with CRAF, and likely other RAF family members, and their methylation at conserved arginine 100, negatively regulating its activity, and as a consequence resulting in enhanced MEK/ERK signaling. Our work uncovered a critical repressive function for PRMT6 in maintenance of HCC cells by regulating the MEK/ERK pathway via arginine methylation of RAF, providing a new avenue of molecular mechanism by which ERK mediated stemness in HCC cells are developed.
Citation Format: LH Chan, L Zhou, Kai Yu Ng, TL Wong, TK Lee, YP Ching, YF Yuan, D Xie, S Richard, MS Huen, XY Guan, S Ma. Protein arginine methyltransferase PRMT6 regulates cancer stemness through CRAF methylation in hepatocellular carcinoma [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 4479.