bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1906: CXCR4 is a novel target of cancer chemopreventative isothiocyanates in prostate cancer cells
Authors: Amjad Ali I. , Sakao Kozue , Vyas Avani R. , Chinni Sreenivasa R. , Parikh Rahul , Singh Shivendra V. 
Published: August 2015

Abstract
Isothiocyanates (ITCs) derived from cruciferous vegetables, including phenethyl isothiocyanate (PEITC) and sulforaphane (SFN), exhibit in vivo activity against prostate cancer in xenograft and transgenic mouse models, and thus are appealing for chemoprevention of this disease. Watercress constituent PEITC and SFN-rich broccoli sprout extract are under clinical investigation but the molecular mechanisms underlying their cancer chemopreventive effects are not fully understood. The present study demonstrates that chemokine receptor CXCR4 is a novel target of ITCs in prostate cancer cells. Exposure of prostate cancer cells (LNCaP, 22Rv1, C4-2, and PC-3) to pharmacologically applicable concentrations of PEITC, benzyl isothiocyanate (BITC), and SFN (2.5 and 5 μmol/L) resulted in downregulation of CXCR4 expression. None of the isothiocyanates affected secretion of CXCR4 ligand (stromal-derived factor-1). In vivo inhibition of PC-3 xenograft growth upon PEITC treatment was associated with a significant decrease in CXCR4 protein level. A similar trend was discernible in the tumors from SFN-treated TRAMP mice compared with those of control mice, but the difference was not significant. Stable overexpression of CXCR4 in PC-3 cells conferred significant protection against wound healing, cell migration, and cell viability inhibition by ITCs. Inhibition of cell migration resulting from PEITC and BITC exposure was significantly augmented by RNA interference of CXCR4. This study demonstrates, for the first time, that cancer chemopreventive ITCs suppress CXCR4 expression in prostate cancer cells in vitro as well as in vivo. These results suggest that CXCR4 downregulation may be an important pharmacodynamic biomarker of cancer chemopreventative ITCs in prostate adenocarcinoma.
Citation Format: Ali I. Amjad, Kozue Sakao, Avani R. Vyas, Sreenivasa R. Chinni, Rahul Parikh, Shivendra V. Singh. CXCR4 is a novel target of cancer chemopreventative isothiocyanates in prostate cancer cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1906. doi:10.1158/1538-7445.AM2015-1906
Abstract 1908: Evaulate biomarkers in NSCLC tumors receiving neoadjuvant chemotherapy
Authors: Pataer Apar , Shao Ruping , Correa Arlene M. , Behrens Carmen , Roth Jack A. , Wistuba Ignacio I. , Swisher Stephen G. 
Published: August 2015

Abstract
In previous study, we have evaluated the ability of histopathologic response criteria to predict overall survival (OS) and disease free survival (DFS) and observed that the percentage of residual viable tumor cells were associated with OS and DFS in 192 NSCLC patients receiving neoadjuvant chemotherapy. In current study, we examined the selected protein biomarkers by IHC in surgical specimens of 98 NSCLC patients receiving neoadjuvant chemotherapy. All NSCLC patients treated with neoadjuvant chemotherapy received a platinum and taxane-based. For IHC analysis of protein markers, we selected candidate biomarkers (VEGFR2, EZH2, ERCC1 and Rad51) on the basis of the literature. Next, the results of VEGFR2, EZH2, ERCC1 and Rad51 expression were analyzed with regard to pathologic response and overall survival time of the patients. The surgical pathologic stage, percentage of viable tumor cells and Rad51 were associated with OS in 98 NSCLC patients receiving neoadjuvant chemotherapy in univariate and multivariate analysis. We found that patients with high-level expression of Rad51 had a poorer prognosis than did those with low-level expression. We observed that Rad51 expression was associated with pathologic response (viable tumor cells). However, there is no association between VEGFR2, EZH2, or ERCC1 expression and pathologic response (viable tumor cells). We further examined K-Ras and EGFR Mutation in these NSCLC tumors receiving neoadjuvant chemotherapy. We analyzed the hotsport mutations in K-Ras gene (Codon 12 and 13) and EGFR gene (Exon 19 and 21) by pyrosequencing and confirmed by direct sequencing method in 98 NSCLC tumors receiving neoadjuvant chemotherapy. We observed both methods had similar results on these patients’ samples. The L858R mutation results in an amino acid substitution at position 858 in EGFR, from a leucine (L) to an arginine (R). This mutation occurs within exon 21, which encodes part of the kinase domain,We found K-Ras mutation tended to be associated with OS, but not EGFR mutation. There is no association between percentage of viable tumor cells, VEGFR2, EZH2, ERCC1, Rad51 expression and K-Ras or EGFR mutation.
Citation Format: Apar Pataer, Ruping Shao, Arlene M. Correa, Carmen Behrens, Jack A. Roth, Ignacio I. Wistuba, Stephen G. Swisher. Evaulate biomarkers in NSCLC tumors receiving neoadjuvant chemotherapy. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1908. doi:10.1158/1538-7445.AM2015-1908
Abstract 1938: Comprehesive RNA-sequencing pipeline of cancer xenograft models
Authors: Hwang Jinha , Kim Jong-Il , Choi Jee-Soo , Kim Min Jung , Lee Charles 
Published: August 2015

Abstract
Since a solid pipeline for massively parallel sequencing in cancer xenograft model has not been built yet, it is necessary to establish a precise analysis pipeline. Massively parallel sequencing on xenograft samples result in mixed sequencing reads from the engrafted human tumor cells and murine tissue. It is necessary to accurately distinguish between these reads for subsequent data analysis. In the present study, we constructed an integrated RNA-Seq pipeline including genomic variation, expression profiling, and fusion gene analysis. To distinguish these reads into individual species, we used the merged reference that incorporates the two genome reference from human (hg19) and mouse (mm10). We tested our pipeline using 6 Primary and 4 metastatic gastric tumor of 6 patients and their derivative xenografts sequencing data. There were almost same amount of ambiguous reads when we aligned sequencing reads to merged reference or separate reference genome. Using merged reference, we efficiently distinguished compound sequencing reads between human and mouse without repetitive alignment processes. The proportion of sequencing reads from mouse in xenograft samples widely ranged from 2.64% to 49.25% per each sample. For expression profiling, we used HTSeq-count for measuring expression level of each sample. As expected, human-specific reads of ECM-receptor and focal adhesion related genes were specifically down-regulated in the xenograft tumors compared to primary tumor and normal tissues suggesting the depletion of human cells from the microenvironment of engrafted tumor tissues. Mouse-specific reads of those genes were highly expressed in the engrafted tissue. Differentially expressed genes between engraft tumor and paired normal tissue were shown to be enriched in the cell cycle and p53 signaling pathway and these showed that engrafted tumor tissues well represent characteristics of cancer cells.
Note: This abstract was not presented at the meeting.
Citation Format: Jinha Hwang, Jong-Il Kim, Jee-Soo Choi, Min Jung Kim, Charles Lee. Comprehesive RNA-sequencing pipeline of cancer xenograft models. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1938. doi:10.1158/1538-7445.AM2015-1938
Abstract 1952: Adverse effects of erythropoietin stimulates tumor growth via EphB4
Authors: Pradeep Sunila , Huang Jie , Mora Edna , Nick Alpa , Cho Minsoon , Wu Sherry , Rupaimoole Rajesha , Xiong Chiyi , Li Chun , Lopez-Berestein Gabriel , Jackson David , Sood Anil 
Published: August 2015

Abstract
Abstract: While recombinant human erythropoietin (rhEpo) has been widely used to treat anemia in cancer patients, concerns about its adverse effects on patient survival have emerged. However the lack of correlation between expression of the canonical EpoR and rhEpo's effects on cancer cells prompted us to consider the existence of an alternative Epo receptor. Methods: We analyzed the membrane-bound portion of the proteome for candidate receptors possessing structural, regulatory, and functional features consistent with Epo binding and tumorigenic signaling. To examine the potential for EphB4 binding to Epo, we generated EpoR−/- MEFs from EpoR−/- mice. We injected A2780-shControl and-shEpoR cells, shEphB4 or -shEpoR/shEphB4 cells in nude mice to study rhEpo induced tumor progression. We also assessed potential effects of tumoral EpoR or EphB4 expression on the effects of ESA treatment in patients with ovarian (N = 175) or breast (N = 88) cancer. Results: Through systems-based approaches we identified EphB4 as an alternate Epo receptor. MST experiments with fluorophore labeled rhEpo demonstrated binding to EpoR with an apparent dissociation constant (KD,app) of 28.0 ± 14.0 nM and EphB4 with a KD,app value of 880.6 ± 128.6 nM. EphB4 and EphrinB2 bound with a KD,app value of 140.5 ± 28.3 nM. We showed that [I125]rhEpo can bind to these cells EpoR−/- MEFs cells.
EphB4 triggered the downstream signaling via STAT3 and promoted rhEpo-induced tumor growth and progression. rhEpo stimulated in vivo growth of A2780-shControl (p&lt;0.01) and-shEpoR cells (p&lt;0.01), but not -shEphB4 or -shEpoR/shEphB4 cells. In human ovarian and breast cancer samples, expression of EphB4 rather than the canonical EpoR correlated with decreased disease-specific survival in rhEpo-treated patients. Conclusion: These results identify EphB4 as a critical mediator of erythropoietin-induced tumor progression in cancer patients and further provide a novel and clinically significant dimension to the biology of erythropoietin.
Citation Format: Sunila Pradeep, Jie Huang, Edna Mora, Alpa Nick, Minsoon Cho, Sherry Wu, Rajesha Rupaimoole, Chiyi Xiong, Chun Li, Gabriel Lopez-Berestein, David Jackson, Anil Sood. Adverse effects of erythropoietin stimulates tumor growth via EphB4. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1952. doi:10.1158/1538-7445.AM2015-1952
Abstract 1961: Anti-endocrine therapy in breast cancerresistance can be circumvented by targeting ribonucleotide reductase M2 usingthe pharmaceutical agent Didox
Authors: Shah Khyati N. , Elford Howard L. , Faridi Jesika S. 
Published: August 2015

Abstract
Breast Cancers (BC) that are sensitive to anti-endocrine therapies such as tamoxifen develop resistance despite their initial favorable response. To gain mechanistic insight on endocrine resistance, gene expression profiling was performed to determine the transcripts that are differentially expressed post-tamoxifen therapy under conditions of prolonged drug treatment and development of resistance. This resistance outcome is the result of the cancer cells invoking survival functions that are up-regulated leading to enhanced cell proliferation and cell motility networks. These networks were validated in a larger panel of breast cancer cells. Here, we report the activation of Growth factor signaling and IKK-βsignaling, NFκB signaling, in BC cells upon acquired resistance to ER blockade by anti-endocrine therapy. Moreover, ribonucleotide reductase (RRM2) was revealed as a key contributor to acquired tamoxifen resistance. An RNA interference screen demonstrated that suppression of RRM2 by the RR inhibitor Didox results in down-regulation of Her2 and EGFR, modulates ER-α signaling, alters NFκB activity and expression, and decreases anti-apoptotic pathways. Indeed, concomitant treatment of tamoxifen and Didox causes blockade of ER and RRM2 induced prolonged ER inhibition and severely impairs the growth of resistant tumor cells. Collectively, these results identify distinct mechanisms that mediate secondary resistance to anti-endocrine therapies, all of which reactivate RR signaling. These observations provide a rational strategy to overcome the multifaceted clonal heterogeneity that emerges when tumors are treated with targeted agents. We propose that Didox and an anti-hormonal therapy should be tested in BC patients who become refractory to anti-endocrine therapies.
Citation Format: Khyati N. Shah, Howard L. Elford, Jesika S. Faridi. Anti-endocrine therapy in breast cancerresistance can be circumvented by targeting ribonucleotide reductase M2 usingthe pharmaceutical agent Didox. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1961. doi:10.1158/1538-7445.AM2015-1961
Abstract 1963: Analysis of aryl substitution and intramolecular ligand H-bonding in selective inhibitors of the MEK5/ERK5 cascade
Authors: Flaherty Patrick T. , Cavanaugh Jane C. , Gupta Mohit , Vechery Colin , Chakrabarty Suravi , Monlish Darlene , Wright Thomas 
Published: August 2015

Abstract
Mitogen Activated Protein Kinase (MAPK) pathways initiate with external signaling, proceed through a sequence of protein kinases, and alter cell proliferation, growth, and survival. MAPK pathways proceed through a well-ordered sequence but are interconnected and modified by the cell's internal needs. The MEK-catalyzed phosphorylation of its target ERK represents the most selective interaction of MAPK signaling cascades. The type III MEK1/2 inhibitor, Mekinist, was recently approved by the FDA for the treatment of unresectable or metastatic melanoma with BRAF V600E or V600K mutations. This success suggests inhibitors of other MEK/ERK cascades may be reasonable strategies for anti-cancer therapeutic strategies. Despite the likely involvement of MEK5 phosphorylation of ERK5 in early and triple negative breast cancers, prostate cancer, and renal cancer, little work has been focused on developing selective MEK5 inhibitors. We have previously described an initial series of anthranilic acid derivatives structurally derived from the known non-selective MEK inhibitor PD0325901. To explore structural requirements for selective inhibition of MEK5 versus MEK1/2, aryl substitution and the role of proposed internal hydrogen bonding of the ligand were examined with novel compounds. These were tested at 10 μM in MDB-MB-213 cells subsequently treated with EGF to induce MEK1/2 and MEK5 phosphorylation. Western blot analysis following electrophoresis using IR-tagged antibodies raised against pERK1/2, pERK5, ERK1/2, or ERK5 permitted determination of total and relative inhibition of MEK-mediated generation of pERK. Incubation with PD0325901 resulted in full suppression of both pERK1/2 and pERK5. For the aryl substitutions examined, omission of the halogens on the pendant phenyl group (SC-1-181) abolished MEK1/2 inhibition(0% decrease in pERK1/2) yet retained good MEK5 inhibition (82% decrease in pERK5). Disruption of an internal nitrogen-acyl hydrogen bond preferentially decreased MEK5 inhibition (SC-2-32: 40% and 16% decrease in pERK5 and pERK1/2 respectively). This establishes early evidence of significant variation in specificity of MEK type III binding sites that may be exploited as pharmacological tools and possibly as therapeutic agents for cancers overexpressing MEK5.
Citation Format: Patrick T. Flaherty, Jane C. Cavanaugh, Mohit Gupta, Colin Vechery, Suravi Chakrabarty, Darlene Monlish, Thomas Wright. Analysis of aryl substitution and intramolecular ligand H-bonding in selective inhibitors of the MEK5/ERK5 cascade. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1963. doi:10.1158/1538-7445.AM2015-1963
Abstract 1967: Elucidation of signaling pathways that mediate gastrin-induced JNK activation and pGSK3β/Snail induction in gastric cancer cells
Authors: Basu Aninda , Sondarva Goutam , Santha Sreevidya , Rana Ajay , Rana Basabi 
Published: August 2015

Abstract
The gastrointestinal peptide hormone gastrin is known to regulate various cellular processes including proliferation, migration and metastasis in gastrointestinal cells. Our previous studies indicated that amidated gastrin (G-17) induced gastric cancer cell migration through two separate signaling axes. These revealed that inhibition of Glycogen Synthase Kinase-3β (GSK3β) was necessary to activate G17-induced migratory pathways in gastric cancer cells. Incubation of AGSE gastric cancer cells overexpressing CCK2 receptor (CCK2R) with G17 resulted in a dose and time dependent increase of GSK3βSer9 phosphorylation, indicative of an inhibition of the kinase. Treatment with G-17 was also associated with increased Snail expression, a downstream target of GSK3β and p21-activated protein kinases (PAKs). In a second pathway, G-17 also induced JNK phosphorylation through activation of Mixed Lineage Kinase 3 (MLK3). This axis also promotes gastric cancer cell migration via CCK2R. In the present study our goal was to determine whether PAKs, which are effectors for the Rho GTPases Cdc42 and Rac and are central players in cell proliferation, survival and motility, are involved in the G-17 effects on gastric cancer cells. Our studies showed that in AGSE cells when pretreated with a commercially available PAK4 inhibitor PF 3758309, G-17 was unable to phosphorylate GSK3β and G-17-induced Snail expression was markedly inhibited. G17-induced p-JNK expression was also significantly attenuated with PAK4 inhibitor pretreatment. The inhibitory effect was stronger when PAK4 inhibitor was used in combination with a pan-MLK inhibitor CEP11004. The involvement of PAK4 in G17-induced events were also confirmed by using the PAK4 siRNA. Knockdown of PAK4 inhibited G17-induced p-JNK expression which was more pronounced when both PAK4 and MLK3 were knocked down in AGSE gastric cancer cells. However, knocking down PAK4 alone does-not seem to inhibit G-17-induced p-GSK3β expression completely, which suggest the potential involvement of other PAK family members. Studies are currently underway to determine which PAK(s) is involved in mediating G17-pGSK3β-Snail axis and also to elucidate any crosstalk of PAK4 and MLK3 in this pathway. Elucidation of the signaling pathways that mediate G17-induced cellular events will be very important in designing therapeutic approaches in the future to restrict gastric cancer cell migration and metastasis.
Citation Format: Aninda Basu, Goutam Sondarva, Sreevidya Santha, Ajay Rana, Basabi Rana. Elucidation of signaling pathways that mediate gastrin-induced JNK activation and pGSK3β/Snail induction in gastric cancer cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1967. doi:10.1158/1538-7445.AM2015-1967
Abstract 1972: LIN28 gene targets are key mediators of breast cancer disease processes
Authors: Kinyamu Harriet K. , Yang Jun , Bennett Brian , Grimm Sara , Bushel Pierre , Archer Trevor 
Published: August 2015

Abstract
LIN28 is an evolutionally conserved RNA-binding protein with critical functions in developmental timing, pluripotency and reprogramming. At the molecular level, most studies indicate that LIN28 modulates gene networks and biological processes by negatively regulating miRNA biogenesis and post-transcriptionally regulating mRNA translation. In addition, increasing evidence suggests that LIN28 is an oncogene, promoting cell growth in various cancers, including breast cancer; however the molecular mechanisms underlying these effects are not known. To provide mechanistic insights into how LIN28 modulates the gene networks that control breast cancer disease processes, we integrate next generation technologies, biochemical approaches and computational analysis to identify LIN28 mRNA targets.
Our results demonstrated that endogenous LIN28 binds 843 mRNAs, ∼3.5% of the total human reference genome in breast cancer cells. Gene ontology analyses reveal that the genes targeted by LIN28 are enriched in those that control cell metabolism. Furthermore, using proteomics analysis, we identify heteronuclear ribonucleoprotein A1 (hnRNP A1), a protein with multiple roles in mRNA metabolism, as a LIN28 interacting partner. Importantly, hnRNP A1 is overexpressed and linked to increased cell proliferation and transformation in a wide variety of cancers, including breast cancer. Moreover, and consistent with the observation that majority of mRNAs bound by LIN28 are involved in metabolism, hnRNP A1 is known to regulate the expression of key enzymes that control metabolism in cancer cells. In-depth analysis of the transcriptomes of LIN28 and hNRNPA1 siRNA-treated cells reveal that these two proteins cooperate to regulate alternative splicing and the steady state mRNA expression of genes implicated in various aspects of breast cancer biology. Most notably, depleting LIN28 results in differential isoform expression of the ENAH gene, which is linked to breast cancer metastasis. In summary, by integrating genomic, biochemical and computational approaches, we identify a broad network of LIN28 targets that modulate cancer cell metabolism, cancer cell invasiveness and the immune response, processes that are hallmarks of breast cancer.
Citation Format: Harriet K. Kinyamu, Jun Yang, Brian Bennett, Sara Grimm, Pierre Bushel, Trevor Archer. LIN28 gene targets are key mediators of breast cancer disease processes. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1972. doi:10.1158/1538-7445.AM2015-1972