bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2723: Host response to HMTV
Authors: Melana Stella M. , Fernandez-Cobo Mariana , Marin Tania , Nartey Teiko , Lee Ana , Moran Herberth , Holland James F. , Pogo Beatriz GT 
Published: June 2012

Abstract
Work from our laboratory demonstrated the presence of retroviral sequences homologous to the mouse mammary tumor virus (MMTV) in a large proportion of human breast cancers. These observations have been confirmed by others. A 660 bp sequence of the MMTV env gene, with no significant homology to any viral or human sequence reported in the GenBank, has been found in 40% of the U.S. human breast cancers studied. This sequence is expressed in most of the env positive tumors, and is not detected in the normal breast tissue of patients with env positive carcinomas, indicating its exogenous origin. A complete provirus structure with 95% homology to MMTV has been described and designated as human mammary tumor virus (HMTV). Betaretroviral particles from primary cultures of breast cancer cells (MSSM) have been isolated and characterized. Virion RNA is more than 90% homologous to MMTV RNA and to the HMTV proviral DNA previously identified.
To find out if these particles were infectious, co-culture experiments between MSSM cells and normal human epithelial breast cells, B and T human lymphocytes and human dendritic cells were performed. The results demonstrated that the recipient human cells became infected with HMTV. However, protein expression was only observed in 10-15% of the infected cells by FACS analysis suggesting the presence of an innate resistance to HMTV in human cells. We have then investigated whether human APOBEC and TRIM proteins are implicated in resistance to HMTV expression. The results indicated that APOBEC G and F, TRIM 5, 21 and 25 are all highly expressed in HMTV cells as measured by quantitative RT-PCR. Additional molecular changes seen in infected cells are disruption of the cytoskeleton and evidence for epithelial-mesenchymal transition (EMT).
Since expression of an endogenous retrovirus (HERV-K) env gene has been reported to be upregulated in human breast cancers we have also investigated its expression in HMTV-infected cells, primary MSSM cells and breast tumors by quantitative RT PCR. The results indicated that in all instances where HMTV was present, expression of HERV-K (HML-2) was less than the control counterpart.
In conclusion, HMTV is able to infect a variety of cells bringing about striking molecular changes. Whether these changes play a role in tumorigenesis remains to be shown.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2723. doi:10.1158/1538-7445.AM2011-2723
Abstract 2729: Proteomic analysis reveals a network of inflammatory genes in epidermis associated with skin tumor promotion susceptibility in DBA/2 and C57BL/6 mice
Authors: Shen Jianjun , Abel Erika L. , Riggs Penny K. , Angel Joe M. , Repass John , Hensley Sean C. , Schroeder Lisa , Traner Angelina , Chau Alexander , Ward Michael , Semmes O. John , Person Maria D. , DiGiovanni John 
Published: June 2012

Abstract
Genetic susceptibility to two-stage skin carcinogenesis is known to vary significantly among different stocks and strains of mice. In an effort to identify specific protein changes or altered signaling pathways associated with tumor promotion susceptibility by the phorbol ester, 12-O-tetradecanoylphorbol-13-acetate (TPA), a proteomic approach of two-dimensional (2-D) gel electrophoresis and mass spectrometry was used. In these experiments, we examined epidermal protein lysates and identified proteins that were differentially expressed in epidermis between promotion-sensitive DBA/2 and promotion-resistant C57BL/6 mice following TPA treatment. Among 19 differentially expressed proteins identified using this methodology were two calcium-binding proteins, S100A8 and S100A9. Their differential expression was further examined and validated by one or more of the following methods: i) one-dimensional (1-D) Western blot analysis; ii) 2-D Western blot analysis; iii) immunohistochemical analysis; and iv) quantitative real-time PCR. Further analyses revealed that S100A8 and S100A9 protein levels were also similarly differentially up-regulated in epidermis of DBA/2 vs C57BL/6 mice following topical treatment with two other tumor promoters, okadaic acid and chrysarobin. Pathway analysis of all 19 identified proteins from the present study suggested that S100A8/A9 could be linked to several inflammatory networks. Further analyses revealed significantly increased expression of several inflammation-related genes including TNF-α, NFκB and IL-22 in epidermis of TPA-treated DBA/2 mice. Follow-up studies confirmed that these three inflammation related genes were upregulated in epidermis of TPA-treated DBA/2 mice compared to similarly treated C57BL/6 mice. These data suggest that differential expression of inflammation related genes in epidermis contributes to TPA-induced inflammation and skin tumor promotion susceptibility in DBA/2 mice. Taken together, our present data provide further insight into potential molecular mechanisms for the differential susceptibility of DBA/2 and C57BL/6 mice in terms of both inflammation and skin tumor promotion.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2729. doi:10.1158/1538-7445.AM2011-2729
Abstract 2735: Osteopontin mediates tumorigenic transformation of a murine promotable cell line through promoting cell survival by an RGD-dependent suppression of caspase 8 activity
Authors: Hsieh Yu-Hua , Chang Pi-Ling 
Published: June 2012

Abstract
Osteopontin (OPN) is a cell adhesive, matricellular protein shown to be an important rate-limiting factor in tumorigenesis in vivo. Further, we have previously shown that addition of exogenous OPN promoted colony formation in an anchorage-independent growth assay of JB6 Cl41.5a cells, a preneoplastic mouse promotable cell line. In addition, down-regulation of the TPA (12-0-tetradecanoylphorbol-13-acetate)-induced OPN expression markedly suppressed TPA-induced colony formation of these cells. Collectively, these findings support the role of osteopontin in mediating neoplastic transformation of JB6 cells in vitro. In the present study, we hypothesize that induced-OPN stimulates the proliferation and/or prevents anoikis of JB6 cells grown in soft-agar and consequently, facilitates colony formation. To determine whether OPN promotes cell proliferation, cell cycle analyses by flow cytometry and direct cell counting of JB6 cells treated with soluble OPN were performed. Data from both of these analyses indicated that OPN-treated cells did not promote cell proliferation compared to non-treated controls. To determine whether OPN prevents anoikis of JB6 cells, annexin V and caspases activities were assesses on cells incubated with or without OPN and suspended on agar. Annexin V analyses showed that OPN significantly decreased anoikis of JB6 cells at 24 h by 41%. In the absence of OPN, suspended JB6 cells underwent anoikis through a sequential activation of caspases 8, 9 and 3 by 1, 3 and 18 h, respectively. Also, the addition of soluble OPN to suspended JB6 cells significantly suppressed caspase 8 activation when compared to non-treated cells. We next determined whether OPN's ability to suppress caspase 8 activity was mediated through its RGD- and/or DRVLFRI-binding motifs as they are known to transduce signals through integrin and CD44 receptors, respectively. Incubation of soluble RGD peptides with suspended JB6 cells suppressed caspase 8 activity. Similar results were obtained when suspended JB6 cells were incubated with OPN only or with RGD peptides and OPN. In contrast, RGE (non-specific peptides) and DRVLFRI peptides alone did not suppress caspase 8 activity of suspended JB6 cells unless OPN was added to these peptides. These findings suggest that OPN suppression of caspase 8 activity of suspended JB6 cells is mediated through its RGD cell-binding motif interacting with integrin receptors. In conclusion, osteopontin promotes tumorigenic transformation of JB6 cells by enhancing the survival of these cells through its RGD-dependent suppression of caspase 8 activity.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2735. doi:10.1158/1538-7445.AM2011-2735
Abstract 2737: The MUC1 membrane-bound mucin is an actor in renal tumor progression
Authors: Bouillez Audrey , Gnemmi Viviane , Butruille Caroline , Ringot Bélinda , Hémon Brigitte , van Seuningen Isabelle , Zini Laurent , Leroy Xavier , Aubert Sébastien , Perrais Michael 
Published: June 2012

Abstract
MUC1, an O-glycoprotein membrane-bound mucin, is overexpressed in clear-cell carcinomas (cRCC) with correlation to two prognostic factors, tumor-node metastasis stage and nuclear Fürhman grade. Previously (Aubert et al, Cancer Res 2009), we have shown that MUC1 was significantly overexpressed in metastatic cRCC vs non-metastatic cRCC and MUC1 is a target gene of HIF-1 transcription factor which is a part of the hypoxia pathway, the main renal carcinogenetic pathway. To better understand the roles of MUC1 in cRCC, we used two renal cell lines expressing MUC1 (Caki-2) or not (ACHN cells). Caki-2 cells were stably transfected with shRNA targeting MUC1 and ACHN cells with an expressing vector containing MUC1 cDNA. Flow cytometry assay and confocal microscopy showed a homogenous membrane expression of MUC1 but also in the nucleus. In vitro studies underlined MUC1 role in the invasion, migration and anchorage-independent growth. In contrast, MUC1 had no role in proliferation and clonogenicity. Cellular agreggation test showed that MUC1 expression is associated with a decrease of cell-cell interactions. Phospho-JNK and phospho-p38 levels were higher in MUC1 expressing cells. Transcriptomic analysis results performed on 44K Agilent Microarrays suggest that MUC1 is a candidate in chemoresistance. Subcutaneous xenograft will be also performed. Our results show that MUC1 plays a role in biological properties of renal cancer cells suggesting the important function for this mucin in tumor progression and confirms its potential as a therapeutic target in this type of cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2737. doi:10.1158/1538-7445.AM2011-2737
Abstract 2744: SNP-SNP interaction between a microRNA and its target gene increases risk of non-melanoma skin cancer
Authors: Nelson Heather H. , Marsit Carmen J. , Kuriger Jacquelyn K. , Karagas Margaret R. 
Published: June 2012

Abstract
Functional genetic variation in microRNA's has the potential to broadly impact disease processes given the large number of gene targets per microRNA. To date, there are only a few examples of functionally verified mirSNPs; among them is rs2910164 contained in the pre-mir-146a. mir-146a is an important modulator of immune responses, and therefore is of interest for non-melanoma skin cancer (NMSC), a highly antigenic cancer. Using a large population-based case control study of basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) in New Hampshire, we investigated the impact of this mirSNP on cancer risk, and potential interaction with one of its gene targets (RNASEL, rs486907). While there was no observed risk associated with the C allele of the mir-146a SNP (ORBCC = 0.91, 95% CI 0.74 – 1.10), ORSCC=1.06, 95% CI 0.86 – 1.30), there was a significant interaction between sunburn history and the mirSNP for BCC (pinteraction=0.002). In addition, there was strong interaction between the mir-146a SNP and genetic variation in its target gene RNASEL (BCC, pinteraction=0.01, SCC pinteraction=0.003). Importantly, our study is among the first to demonstrate snp-snp interaction in a microRNA and its target gene. Further, these data imply that RNASEL, an enzyme involved in cellular and viral RNA turnover, is controlled by this miRNA and that this process is important in skin cancer etiology.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2744. doi:10.1158/1538-7445.AM2011-2744
Abstract 2770: UGT2B17 copy number variation and the association with serum glucuonides and prostate cancer risk
Authors: Grant Delores J. , Hoyo Cathrine , Oliver Shannon , Gerber Leah , Taylor Loretta , Newman Kathryn , Shuler Katie , Calloway Elizabeth , Livingston Jonathan N. , Richardson Ricardo M. , Schildkraut Joellen , Freedland Stephen J. 
Published: June 2012

Abstract
Prostate cancer development and treatment has been associated with steroid hormones and/or steroid metabolites. While consensus seems to be building that serum testosterone levels are not related to disease risk, the role of genes involved in steroid metabolism have not been extensively studied. The UDP-glucuronosyltransferase (UGT) enzymes are part of a superfamily of genes involved in phase II detoxification of a wide variety of endogeneous and exogenous substances including bile, odorants, steroids, and drugs. The UGT2B17 gene is expressed in the prostate where it catalyzes the conjugation of a glucuronic acid moiety to steroids such as androstane-3α, 17βdiol. Several studies have examined whether a copy number variant (CNV) of UGT2B17 is associated with prostate cancer risk in case control studies, however, results have been inconclusive, and only one of the studies included African Americans. We examined the relationship of UGT2B17 CNV with prostate cancer risk aggressiveness in a hospital-based, case-control study conducted at the Durham Veterans Administration Hospital, and the relationship between serum levels of the glucuronide of androstane-3α, 17βdiol, AAG, in healthy Caucasians and African Americans. Levels of AAG were measured using ELISA. UGT2B17 genotype was determined by gene-specific copy number assays using Taqman Realtime PCR which showed 0, 1, or 2 alleles of the gene. Whereas CNV was not related to race (p=0.85), a higher CNV was significantly associated with higher androstane-3α, 17βdiol levels in healthy white men (p=0.018) but not non-white men (p=0.94). We found no association between CNV and cancer risk among all men (p=0.59) nor when stratified by white (p=0.70) vs. non-white (p=0.72). Among men with cancer, CNV was not related to Gleason score (p=0.32). These findings suggest that CNV may be associated with serum hormones levels, and these associations may differ between white and non-white men. Serum levels may be altered by other genetic or epigenetic factors in non-white populations. The role of CNV as a risk factor for prostate cancer requires further study in larger samples and with genetic and epigenetic variants. Funded by Department of Defense, NIH NCMHD P20 MD000175, S06-GM008049-33
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2770. doi:10.1158/1538-7445.AM2011-2770
Abstract 2773: Junction plakoglobin gene polymorphisms in prostate cancer and benign prostatic hyperplasia
Authors: Liu Jan , Chang Inik , Singh Kamaldeep , Dahiya Angela V. , Majid Shahana , Saini Sharanjot , Zaman Mohd S. , Chen Yi , Shahryari Varahram , Sandhu Herman , Yamamura Soichiro , Suh Seong O. , Deng Guoren , Tanaka Yuichiro 
Published: June 2012

Abstract
Junction plakoglobin (JUP) is a member of the catenin family that forms complexes with cadherins and these molecules play a role in cell adhesion and motility. Prior studies have demonstrated genetic alterations of the JUP gene to be a risk for diseases. In prostate, expression of JUP has been shown to be down-regulated in the carcinogenesis process and mutations of this gene may play a role in this process. In this study, we hypothesize that polymorphic variants of the JUP gene can be a risk factor for prostate cancer. To test this hypothesis, the genetic distributions of five JUP polymorphisms were analyzed in 131 normal healthy subjects, 132 benign prostatic hyperplasia (BPH), and 177 sporadic prostate cancer samples by sequence-specific PCR and sequencing. The polymorphic sites evaluated were codon 697 (Met to Leu, rs1126821) along with four locations in the promoter region at the following base pairs prior to the ATG start site: -3633 (C to G, rs12450138), -5971 (A to C, 11650969), -9598 (T to C, rs4479305), and -14959 (G to A, rs12937988). Results of these experiments demonstrate that the variants at the -5971 (P&lt;0.02) and -9598 (P&lt;0.07) sites are associated with prostate cancer when compared to normal controls. Odds ratio and 95% confidence interval for cancer were 2.55 and 1.37-4.75, respectively, for -5971 C/C genotype compared to wildtype; and 2.11 and 1.14-3.91, respectively, for -9598 C/C compared to wildtype. Likewise, the variant allele was significantly associated with prostate cancer for both polymorphic sites (P&lt;0.02). Linkage between the -5971, and -9598 sites were observed (D’ = 1). Haplotype analyses show the bases A and T, representing wildtype at the -5971 and -9598 sites, respectively, to be significantly reduced in prostate cancer (P&lt;0.01). However, no differences were observed for the Met697Leu, -3633, and -14959 polymorphic sites for prostate cancer. Also, BPH did not associate with any of the polymorphic sites as compared to healthy controls. This is the first report that evaluates JUP polymorphism in prostate cancer and these results are important in understanding their role in this disease.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2773. doi:10.1158/1538-7445.AM2011-2773
Abstract 2789: Discovery of a novel specific MEK and Raf inhibitor, CH5126766 (RO5126766), hit to lead study of a unique scaffold for kinase inhibitor to a clinical compound
Authors: Iikura Hitoshi , Aoki Toshihiro , Hyoudoh Ikumi , Furuichi Noriyuki , Watanabe Fumio , Ozawa Sawako , Sakaidani Masahiro , Matsushita Masayuki , Shimma Nobuo , Harada Naoki , Tomii Yasushi , Aoki Yuko , Takanashi Kenji 
Published: June 2012

Abstract
Background: Among tumor signaling pathways, the most frequently dysregulated in human cancer is Ras-Raf-MEK axis, and therefore allosteric MEK inhibitors and ATP competitive Raf inhibitors are being tested in clinical trials. However, these inhibitors result in marked activation of upstream signal of MEK in tumor cells, especially with mutant K-ras. This feedback activation or activation of Raf would attenuate the anticancer effects of these inhibitors. One of the strategies to prevent this attenuation will be blocking upstream signal concurrent with MEK inhibition. To validate the hypothesis, we executed a hit to lead study of our HTS hit showing MEK/Raf dual inhibition.
Methods and Results: To increase direct MEK inhibitory activity (by binding to MEK) of the HTS hit coumarin compound and indirect Raf inhibitory activity (by enhancement of the binding between B-Raf /C-Raf and MEK1), introduction of a sulfamide group afforded the best result, compared with similar functional groups such as urea, amide and sulfonamide. Fluorine-scan (C-H/C-F substitutions) and nitrogen-scan (CH/N substitutions) worked efficient to increase both MEK and Raf inhibitory activities and optimize physicochemical properties (water solubility, hERG inhibition, CYP inhibitions etc). These three key transformations afforded CH5126766, which has MEK1 (IC50 = 160 nM) and B-Raf (IC50 = 19 nM) inhibitions and excellent PK profiles (mouse BA 93%, CL 1.1 mL/min/kg, rat BA 66%, CL 0.7 mL/min/kg, monkey BA 82%, CL 0.1 mL/min/kg). The compound showed potent antitumor activity in human cancer xenograft model (HCT116) by once daily oral administration (128% of tumor growth inhibition at a 1 mg/kg dose).
Conclusion: SAR study of our novel type molecule (MEK and Raf dual inhibitor) affords identification of CH5126766. It showed strong antitumor efficacy in vivo, good PK in three animal species and good safety profiles. Thus, CH5126766 is now under clinical investigation with solid tumor patients.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2789. doi:10.1158/1538-7445.AM2011-2789
Abstract 2790: Discovery of novel Pim-1 inhibitors
Authors: Xiang Yibin , Hirth Bradforth H. , Liu Jinyu , Metz Markus , Asmussen Gary , Bieman Hans-Peter N. , Fitzgerald Maria , Fremgen Trish , Jancsics Katherine C. , Kothe Michael , Papoulis Andrew T. , Stepp David J. , Wei Ronnie , Skerlj Renato 
Published: June 2012

Abstract
Pim-1 is a proto-oncogene which encodes for the serine/threonine kinase of the same name. Recently, Pim-1 has been implicated in multiple human cancers, including prostate cancer, acute myeloid leukemia and other hematopoietic malignancies. Primarily expressed in spleen, thymus, bone marrow, prostate, oral epithelial, hippocampus and fetal liver cells, Pim-1 has also been found to be highly expressed in cell cultures isolated from human tumors.
As part of our continuing efforts to identify potential protein targets and inhibitors in the area of cancer treatment, we selected Pim-1 target and used fragment drug discovery platform to undertake the efforts in identification of novel inhibitors. Over 1800 fragments have been screened using SPR binding assay, followed by PIM1 kinase inhibition assay. Among many active fragments, we identified an interesting small fragment, 5-bromobenzofuran-2-carboxylic acid (1), which has IC50 of 8.1 uM in the Pim-1 kinase inhibition assay. The X-ray structure of 1 binding to Pim-1 revealed that the oxygen of the benzofuran is positioned towards the hinge site while the carboxylic acid interacts directly with the Lys-67. Guided by the X-ray structures, we generated many more potent inhibitors, among which, compound 2 with an aminicyclohexayl moiety at the 7-position is one of the most potent inhibitor with IC50 of 0.001uM in Pim-1 kinase inhibition assay. X-ray structure of 2 binding to Pim-1 indicated that compound 2 gained additional interactions by directly interacting of its nitrogen atom of the aminocycloheaxyl group with Asp127 as well as interacting through water bridges with Glu170 and Asn 171. Compound 2 has also potent activity in inhibiting Pim-2 with IC50 of 0.004 uM while is highly selective against most kinases in the Ambit kinase panel.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2790. doi:10.1158/1538-7445.AM2011-2790