bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1427: Investigating role of RECQ1 in response to gemcitabine treatment in triple negative breast cancer
Authors: Parvathaneni Swetha , Lu Xing , Sharma Sudha 
Published: July 2017

Abstract
The response of cancer cells to therapeutic drugs aimed at causing DNA damage is dependent on proteins that play roles in DNA repair. Single nucleotide polymorphism in RECQ1 (also known as RECQL or RECQL1), a DNA helicase involved in DNA damage and replication stress response, is reported to influence patient’s response to gemcitabine in pancreatic cancer leading to poor survival. Gemcitabine is also used as a chemotherapeutic against triple negative breast cancer; however resistance to gemcitabine is reported. The mechanism by which gemcitabine chemoresistance is obtained is poorly understood. Given the importance of RECQ1 in replication fork restart and it being categorized as a breast cancer susceptibility gene, we wish to investigate the role of RECQ1 in modulating cellular response to gemcitabine in triple negative breast cancer cells. To study RECQ1 functions, we developed isogenic pairs of RECQ1-proficient and RECQ1-deficient cells by CRISPR-Cas9-mediated targeted inactivation of RECQ1 in breast cancer cell lines as in vitro model system. RECQ1-knockout MDA-MB-231 cells displayed reduced cell growth and proliferation, and increased DNA damage as compared to the MDA-MB-231 cells expressing wild type RECQ1. As compared to RECQ1-proficient MDA-MB-231 cells, RECQ1-deficient cells were more sensitive to gemcitabine treatment, incurred significantly greater load of double strand breaks upon gemcitabine treatment, and displayed aberrant cell cycle progression following recovery from gemcitabine treatment. Our ongoing experiments are investigating the detailed mechanism of RECQ1’s role in response to gemcitabine and its implications in therapeutic response.
Funding: This work was funded by the NIGMS/NIH grant SC1GM093999 to Sudha Sharma. We also acknowledge support from the NIMHD/NIH award number G12MD007597 and NIA/NIH award number 1R25 AG047843-02. We thank Drs. Ritu Chaudhary, Xiaoling Li and Ashish Lal (NCI) for their help and support.
Citation Format: Swetha Parvathaneni, Xing Lu, Sudha Sharma. Investigating role of RECQ1 in response to gemcitabine treatment in triple negative 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 1427. doi:10.1158/1538-7445.AM2017-1427
Abstract 1436: Identification of novel tumor suppressor candidates in familial cholangiocarcinoma using sequencing-based Megabase-scale haplotypes from germline and cancer genomes
Authors: Greer Stephanie , Nadauld Lincoln , Lau Billy , Miotke Laura , Hopmans Erik , Wood Christina M. , Bell John M. , Jones David A. , Ji Hanlee P. 
Published: July 2017

Abstract
Cholangiocarcinoma (bile duct cancer) is a rare epithelial malignancy with an extremely poor prognosis characterized by a 5-year survival of less than 10%. While this tumor type can be amenable to specific combination chemotherapy regimens, it is typically diagnosed at an advanced stage and inevitably progresses towards distant metastasis. We identified a family with a predisposition to cholangiocarcinoma, having multiple affected family members, and sought to identify the underlying germline mutation(s).
We employed linked-read sequencing, a microfluidic technology where high-molecular weight DNA molecules (&gt;20 kb) are partitioned into droplets and labeled with unique barcodes, enabling computational reconstruction of the original large molecules following traditional short-read sequencing, to identify entire megabase-scale regions of the genome that segregate with the disease. We applied this technology to an entire generation of a family predisposed to cholangiocarcinoma, including a mix of 8 affected and unaffected siblings. We additionally utilized each affected individual’s cancer genome to search for a common second hit that would serve as further confirmation. Our analysis yielded a small set of four candidate pathogenic variants. Functional validation of the candidate genes in a zebrafish model, using morpholino-based gene silencing, identified one candidate whose silencing led to a reproducible phenotype consistent with known aspects of the candidate gene’s function. The candidate variant occurs in a TGF family-interacting domain, and has not been extensively characterized in other cancers. Cross-validation with TCGA datasets showed the gene was altered in 5% of cholangiocarcinomas, all of which displayed homozygous deletions. This identification of a germline allele associated with familial cholangiocarcinoma represents a unique discovery with clinical implications for the described family and warrants further investigation in other patients who display features of an inherited cholagniocarcinoma. This finding also raises the possibility of TGF pathway targeting as a therapeutic strategy in select cholangiocarcinomas, and highlights the power of whole-genome phasing to discover novel inherited tumor suppressor variants.
Citation Format: Stephanie Greer, Lincoln Nadauld, Billy Lau, Laura Miotke, Erik Hopmans, Christina M. Wood, John M. Bell, David A. Jones, Hanlee P. Ji. Identification of novel tumor suppressor candidates in familial cholangiocarcinoma using sequencing-based Megabase-scale haplotypes from germline and cancer genomes [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 1436. doi:10.1158/1538-7445.AM2017-1436
Abstract 1447: Identification of an oncogenic germline KRAS truncating mutation in hereditary cancers
Authors: Goswami Moloy T. , Hovelson Daniel H. , Johnson Anna , Tomlins Scott A. , Wang Lucy , Zhulke Kimberly , Singh Bhavneet , Anand Sharath Kumar , Cani Andi , Liu Albert , Kamberov Steven , Wu Yi-Mi , Robinson Dan , Chinnaiyan Arul , Cooney Kathleen A. 
Published: July 2017

Abstract
Somatic strongly activating KRAS mutations play an oncogenic role across numerous human cancers, while less activating germline KRAS mutations are associated with developmental disorders. KRAS encodes two splice variant products—KRAS-4A and KRAS-4B—differing in their C-terminus through alternative fourth coding exons. Though KRAS-4A is homologous to the original transforming transcript identified in Kirsten rat sarcoma virus, its role in human cancer is less characterized compared to KRAS-4B. Here, through genetic analyses of three cohorts of patients with hereditary and/or aggressive cancers, we identified a rare KRAS-4A specific C-terminal truncating germline mutation (KRAS-4A C180X; rs373169526) in affected men of three families with hereditary prostate cancer and a patient with hereditary melanoma (minor allele frequency [MAF] of 0.0014 in these combined cancer cohorts assessed vs. 0.000056 in the ExAC population database, odds ratio 24.6 [95% confidence interval 5.1-103.5], two sided Fisher’s exact test p = 9.0E-5). The KRAS-4A C180X mutation truncates the C-terminus, removing the polybasic region and -CAAX motifs previously demonstrated to be necessary for Ras family member membrane association, MAP kinase signaling activation and transformation, suggesting a loss of function phenotype. However, in silico assessment of reported human variation demonstrates truncating germline variants only in KRAS-4A and not KRAS-4B, consistent with tolerance. Expression of KRAS-4A protein in NIH3T3 and MDCK leads to loss of exclusive membrane association and inhibits GTP loading, as expected, but paradoxically resulted in modest but significantly increased proliferation and soft agar colony growth compared to control or wildtype KRAS expressing cells. Pro-oncogenic phenotypes were not dependent on MAPK signaling, but showed sensitivity to AKT inhibition. In summary, we identified a germline truncating KRAS-4A mutation over-represented in hereditary cancers that defines a novel mechanism of KRAS activation not dependent on the C-terminal polybasic and -CAAX motifs.
Citation Format: Moloy T. Goswami, Daniel H. Hovelson, Anna Johnson, Scott A. Tomlins, Lucy Wang, Kimberly Zhulke, Bhavneet Singh, Sharath Kumar Anand, Andi Cani, Albert Liu, Steven Kamberov, Yi-Mi Wu, Dan Robinson, Arul Chinnaiyan, Kathleen A. Cooney. Identification of an oncogenic germline KRAS truncating mutation in hereditary 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 1447. doi:10.1158/1538-7445.AM2017-1447
Abstract 1455: Vitamin D receptor (VDR) gene polymorphisms among Sudanese females with breast cancer attending Radio and Isotope Center of Khartoum
Authors: Yousif Sara O. , Ismail Amar M. , Mohamed Abdelrahim O. , Mohamed Abdelrahim O. 
Published: July 2017

Abstract
Background: Vitamin D Receptor (VDR) gene polymorphisms has been reported to
be associated with different cancers, including breast cancer. geographical and
environmental factors have an impact on vitamin D (VD) metabolism. This study
aims to evaluate VDR-gene polymorphisms (Fok1, Bsm1, Taq1, Apa1) and its
association with breast cancer risk among Sudanese females.
Materials and Methods: this is a case control study done in the Radio and Isotope
Center in Khartoum, Sudan. Hundred thirty seven patients and 69 healthy controls
were enrolled after informed consent. Blood genomic DNA was extracted using
quinidine chloroform method, and single nucleotide polymorphisms (SNPs) Fok1
(T/C) [rs2228570], Bsm1 (G/A) [rs1544410], Taq1 (C/T) [rs731236] and Apa1 (C/A)
[(rs7975232] in VDR-gene were detected by PCR and restriction fragment length
polymorphism (PCR-RFLP) analysis.
Results: VDR-SNPs rs731236 correlated significantly with low risk of breast cancer
(OR=0.5, p= 0.002). There was no significant association observed with rs1544410
and rs7975232. Although our study did not show an overall statistically significant
association of VDR-SNPs rs2228570 with the risk of breast cancer, we found a 1.3
fold increased risk of breast cancer (OR= 1.3) among females with FF genotype when
compared with ff genotype, suggesting that females homozygous for F allele, might be
at more risk than females carrying homozygous f allele.
Conclusions: These results suggested that, VDR-SNPs rs2228570 may be related to
higher risk of breast cancer and VDR-SNPs rs731236 associated with lower risk of
breast cancer in Sudanese females.
Key words: Breast Cancer, VDR, Polymorphisms, SNPs
Citation Format: Sara O. Yousif, Amar M. Ismail, Abdelrahim O. Mohamed, Abdelrahim O. Mohamed. Vitamin D receptor (VDR) gene polymorphisms among Sudanese females with breast cancer attending Radio and Isotope Center of Khartoum [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 1455. doi:10.1158/1538-7445.AM2017-1455
Abstract 1460: miRNome analyses reveal that activity of CAF expressed podoplanin in tumor microenvironment is modulated by exosome miRNAs involved in the PTEN-PI3K-AKT-mTOR signaling
Authors: Tejchman Anna , Mennesson Eric , Fixe Isabelle , Foucher Alexandra , Perera Simon , Artigas Laura , Mas Jose Manuel , Grillon Catherine , Ugorski Maciej , Normand Nadia , Kieda Claudine 
Published: July 2017

Abstract
In breast cancer, cancer associated fibroblasts (CAF) express podoplanin but little is known about its mechanism of expression and modulation. This might be crucial for cancer cell movements and for the ability to escape from the tumor site. Podoplanin showed anti-adhesive activity towards tumor and immune cells. A key control of tumor microenvironment is exerted by microRNAs on gene expression. Therefore miRNAs profiling was performed with 3D-Gene microarray technology on a breast CAF model, on cell lysates and on secreted exosomes, in hypoxia versus normoxia culture conditions.
Systems biology enrichment analyses were carried out through bioinformatics using mathematical models that simulate in silico the behaviour of human physiology. Targets linked to the set of differential miRNAs, both up-regulated and down-regulated, have been analyzed with various methods including a hypergeometric distribution method. Processes linked to hypoxia, glycosylation, angiogenesis, extracellular matrix and pathways associated with PI3K-AKT, mTOR, P53 and chemokines signaling were studied.
We showed that podoplanin expression strongly affected miRNAs involved in these processes. Hypoxia increased expression of miR-210, miR-21 and miR-29b in cells over-expressing podoplanin. miR-21 is an oncogenic regulator in most cancer cells through its downstream target proteins among which stands the tumor suppressor PTEN, a candidate to alleviate hypoxia in tumors, regulating tumor angiogenesis and modulating tumor hypoxia. miR-29b is a tumor suppressor, it also correlates with PTEN repression.
We highlighted miRNA regulation of podoplanin expression through downregulation of upstream genes for tumor suppressor PTEN. The combination of miRNome analysis and systems biology bioinformatics uncovered potential miRNAs involved in the regulation of podoplanin activity in CAF. Such data analysis may be applied to protein and mRNA biomarkers and extended to other pathology pathways.
Citation Format: Anna Tejchman, Eric Mennesson, Isabelle Fixe, Alexandra Foucher, Simon Perera, Laura Artigas, Jose Manuel Mas, Catherine Grillon, Maciej Ugorski, Nadia Normand, Claudine Kieda. miRNome analyses reveal that activity of CAF expressed podoplanin in tumor microenvironment is modulated by exosome miRNAs involved in the PTEN-PI3K-AKT-mTOR signaling [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 1460. doi:10.1158/1538-7445.AM2017-1460
Abstract 1464: miR-6734 induces cell cycle arrest and apoptosis via up-regulation of p21 expression in colon cancer cells
Authors: Kang Jong Soon , Kang Moo Rim 
Published: July 2017

Abstract
Recently, microRNAs have been implicated in the regulation of gene expression in terms of both gene silencing and gene activation. Here, we investigated the effects of miR-6734, which has a sequence homology with a specific region of p21WAF1/CIP1 (p21) promoter, on cancer cell growth and the mechanisms involved in this effect. miR-6734 up-regulated p21 expression at both mRNA and protein levels and chromatin immunoprecipitation analysis using biotin-labeled miR-6734 confirmed the association of miR-6734 with p21 promoter. Moreover, miR-6734 inhibited cancer cell growth and induced cell cycle arrest and apoptosis in HCT-116 cells, which was abolished by knockdown of p21. The phosphorylation of Rb and the cleavage of caspase 3 and PARP were suppressed by miR-6734 transfection in HCT-116 cells and these effects were also reversed by p21 knockdown. In addition, miR-6734 transfection caused prolonged induction of p21 gene and modification of histones in p21 promoter, which are typical aspects of a phenomenon referred to as RNA activation (RNAa). Collectively, our results demonstrated that miR-6734 inhibits the growth of colon cancer cells by up-regulating p21 gene expression and subsequent induction of cell cycle arrest and apoptosis, suggesting its role as an important endogenous regulator of cancer cell proliferation and survival.
Citation Format: Jong Soon Kang, Moo Rim Kang. miR-6734 induces cell cycle arrest and apoptosis via up-regulation of p21 expression in 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 1464. doi:10.1158/1538-7445.AM2017-1464
Abstract 1470: Fine-tuning the expression of heterogeneous network of genes involved in androgen signaling, aerobic glycolysis, apoptosis and epithelial-mesenchymal transition by microRNA-644a in prostate cancer potentiation of AR signaling therapy by miR-644a: Selective manipulation of the prostate cancer transcriptome by miR-644a
Authors: Ebron Jey Sabith , Singh Jagjit , Shankar Eswar , Weyman Crystal , Gupta Sanjay , Lindner Daniel J. , Shukla Girish C. 
Published: July 2017

Abstract
Intratumoral Prostate cancer (PCa) heterogeneity is characterized by multiple intrinsic mechanisms including Androgen signaling, aerobic glycolysis, aberrant transcriptional activation of c-Myc and dysregulation of miRNAs. The ability of prostate cancer cells to alter growth and metabolism in a manner distinct from benign cells is a major concern in the treatment of castration-resistant prostate cancer. Therefore, targeting the diverse oncogenesis promoting pathways involved in PCa progression and resistance at the posttranscriptional level using micro RNAs (miRNAs) offers a novel therapeutic option. Using a miRNA mimic screen, we identified a human-specific miRNA miR-644a, which modulates expression of a diverse set of oncogenic pathways in PCa including androgen signaling, AKT/IGF-1R signaling, c-myc mediated signaling and EMT pathways. We have also demonstrated a potent tumor suppressive function of miR-644a in mouse prostate cancer xenograft model. miR-644a also sensitizes the PCa tumors to current therapeutic options including AR antagonist Enzalutamide by regulating the key modulators in development of drug resistance. In conclusion, our study demonstrates that miR-644a is a novel tumor suppressor miRNA regulating key prostate carcinogenesis promoting pathways.
Citation Format: Jey Sabith Ebron, Jagjit Singh, Eswar Shankar, Crystal Weyman, Sanjay Gupta, Daniel J. Lindner, Girish C. Shukla. Fine-tuning the expression of heterogeneous network of genes involved in androgen signaling, aerobic glycolysis, apoptosis and epithelial-mesenchymal transition by microRNA-644a in prostate cancer potentiation of AR signaling therapy by miR-644a: Selective manipulation of the prostate cancer transcriptome by miR-644a [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 1470. doi:10.1158/1538-7445.AM2017-1470
Abstract 1473: miR-1207-3p regulates c-Myc in aggressive prostate cancer
Authors: Das Dibash K. , Ogunwobi Olorunseun O. 
Published: July 2017

Abstract
Prostate cancer (PCa) is the most common non-skin cancer and the second leading cause of cancer-related death for men in the U.S. A major challenge is understanding the molecular mechanisms involved in the progression from the asymptomatic androgen-dependent PCa to the lethal castration resistant prostate cancer (CRPC). The chromosomal region 8q24 is associated with aggressive PCa and variants of this region have been identified to interact with the PVT1 non-coding gene in PCa. In previous work we demonstrated that microRNA-1207-3p (miR-1207-3p) has prognostic value in PCa, and directly binds to the 3’ UTR of Fibronectin type III domain containing 1 (FNDC1) to regulate a novel FNDC1/fibronectin (FN1)/androgen receptor (AR) pathway upregulated in metastatic PCa. miR-1207-3p is encoded at the PVT1 gene locus, which is located downstream of c-Myc on the 8q24 human chromosomal region. Studies have suggested amplification at the 8q24 human chromosomal region, which includes C-Myc, as a possible prognostic factor for CRPC. c-Myc is a well-established proto-oncogene that is commonly found to be amplified in up to 72% of CRPCs significant amplication of c-myc has been a consequence of antiandrogen treatment, and c-Myc is downstream of AR in some PCa. miRNAs have also been implicated in the regulation of c-Myc. Nevertheless, the mechanisms regulating c-Myc remain unclear in PCa. Using a panel of five PCa cell lines we discovered that c-Myc expression is higher in aggressive CRPC cell lines compared to non-aggressive CRPC and androgen-dependent prostate cancer cell lines. Furthermore, our data reveals that c-Myc expression is higher in the aggressive E006AA-hT PCa cell line when compared to the indolent E006AA PCa cell line. This suggests that c-Myc is associated with aggressive PCa. Moreover, overexpression of miR-1207-3p suppresses the expression of c-Myc in E006AA-hT PCa cells but not E006AA PCa cell line in which c-Myc is underexpressed compared to the normal prostate epithelial cell line, RWPE-1. Next, using a synthetic biotinylated miR-1207-3p duplex, we discovered that overexpression of miR-1207-3p more effictively inhibited migration, inhibited proliferation and increased apoptosis in the aggressive E006AA-hT PCa cell line with increased c-Myc expression when compared to the indolent E006AA PCa cell line with decreased c-Myc expression. These data demonstrate that the miR-1207-3p/FNDC1/FN1/AR pathway may regulate c-Myc in aggressive PCa.
Citation Format: Dibash K. Das, Olorunseun O. Ogunwobi. miR-1207-3p regulates c-Myc in aggressive prostate 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 1473. doi:10.1158/1538-7445.AM2017-1473
Abstract 1480: Mir-182 is involved in sulindac anticancer activity in colon cancer
Authors: Zhao Hongyou , Yi Bin , Liang Zhipin , Ma Ruixia , Xi Yaguang 
Published: July 2017

Abstract
Nonsteroidal anti-inflammatory drugs (NSAIDs) display promising antineoplastic activity in many human solid tumors including colorectal cancer. Previous studies reported that sulindac sulfide (SS) can inhibit the growth of tumor cells through cyclooxygenase-2 (COX-2) dependent or independent pathways. Obviously, COX-2 independent pathway involves a low toxic property to support the clinical potential for using sulindac as a chemoprevention drug. However, the molecular mechanisms responsible for COX-2 independent pathway have not been completely elucidated. In this project, we employed two human colon cancer cell lines, referred to HCT116 and HT29. HCT116 cells are characterized for low COX-2 expression, while HT29 cells show relatively high COX-2 expression. We found that SS could unbiasedly inhibit the growth of HCT116 and HT29 cells by arresting cells in G1/G2 phases. CyclinG2 was found to be upregulated in response to SS treatment. FOXO3a has been reported to regulate CyclinG2 expression at the transcriptional level. Our results demonstrate that SS could also upregulate FOXO3a. By using the loss-of-function strategy, we found that SS could not efficiently upregulate CyclinG2 and lead to cell cycle arrest in cells with FOXO3a knockdown. In addition, we studied the mechanism that could be involved in SS regulation of FOXO3a. Our previous studies reported that a panel of miRNAs could be altered by SS treatment in both colon and breast cancer cells. In the downregulated miRNA list, we found that miR-182 could potentially target FOXO3a. By using luciferase assay, we validated the direct regulation of miR-182 on the expression of FOXO3a. When miR-182 was downregulated, SS could neither efficiently upregulate the expression of FOXO3a nor inhibit cell growth as it did in control cells. We gained highly consistent results in HT29 and HT29 cells with COX-2 knockdown. Therefore, our study demonstrates a pathway consisting of miR-182/ FOXO3a/ CyclinG2 as a novel mechanism responsible for SS anticancer activity in colon cancer, which may imply a COX-2 independent pathway.
Citation Format: Hongyou Zhao, Bin Yi, Zhipin Liang, Ruixia Ma, Yaguang Xi. Mir-182 is involved in sulindac anticancer activity in colon 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 1480. doi:10.1158/1538-7445.AM2017-1480