bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 813: The association of androgen metabolizing enzymes and prostate cancer in a multiethnic study
Authors: Grant Delores J. , Howard Lauren , Wiggins Emily , De Hoedt Amanda , Vidal Adriana , Carney Skyla T. , Squires Jill , Magyar Clara E. , Huang Jiaoti , Freedland Stephen J. 
Published: July 2016

Abstract
Introduction: Uridine 5’-diphosphate-glucuronosyltransferase 2B (UGT2B) genes code for enzymes that catalyze the clearance of testosterone, dihydrotestosterone (DHT), and DHT metabolites in the prostate basal and luminal tissue. The expression of the UGT2B15, UGT2B17, and UGT2B28 enzymes has not been evaluated in prostate tissue samples from hormone therapy-naïve patients.
Methods: We determined the expression of the three enzymes in 190 prostate tissue samples from surgical specimens of a multiethnic cohort of patients undergoing radical prostatectomy at the Durham Veterans Affairs Medical Center. The association between each biomarker's percent positive and H-score and the risk of biochemical recurrence (BCR) was tested using separate Cox proportional hazards models. In an exploratory analysis, UGT2B17 total positive and H-score were split at the median and we tested the association between UGT2B17 group and risk of BCR.
Results: The median follow-up was 118 months (IQR: 85-144). We found no association between UGT2B15 or UGT2B28 and risk of BCR. However, there was a trend between UGT2B17 and BCR (HR = 1.01, 95% CI 1.00-1.02, p = 0.11), though not statistically significant. Upon further investigation, we found patients with UGT2B17 total positive above the median had a significant increased risk of BCR on univariable analysis (HR = 1.57, 95% CI 1.02-2.43, p = 0.041) but this association was attenuated in the adjusted model (HR = 1.50, 95% CI 0.94-2.40, p = 0.088).
Conclusions: Our findings suggest that UGT2B17 overexpression was associated with a significant increased risk of BCR. These results are consistent with previous reports that show UGT2B17 significantly expressed in prostate cancer metastases.
Citation Format: Delores J. Grant, Lauren Howard, Emily Wiggins, Amanda De Hoedt, Adriana Vidal, Skyla T. Carney, Jill Squires, Clara E. Magyar, Jiaoti Huang, Stephen J. Freedland. The association of androgen metabolizing enzymes and prostate cancer in a multiethnic study. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 813.
Abstract 821: Discovery of catechol moiety-containing natural compounds as direct ERK2 inhibitors by in vitro kinase assay and co-crystallography
Authors: Shin Seung Ho , Malakhova Margarita , Kurinov Igor , Lim Do Young , Bode Ann M. , Dong Zigang 
Published: July 2016

Abstract
Catechol (pyrocathechol, 1,2-dihydroxybenzene) is a chemical that is used by industry in the manufacture of certain products. Many natural compounds contain catechol as a functional group found in various fruits and vegetables such as apple, apricot, grape, bananas, soybean, peanut, pear, plum, mango, avocado, and mushroom. Extracellular signal-regulated kinase 2 (ERK2), a protein kinase that belongs to MAPK family, modulates many important functions such as cell growth, apoptosis and transcriptional regulation in cancer. The expression levels of ERK2 mRNA and protein are reportedly very high in many human cancers, including leukemia, colon, breast, lung and skin cancer. Previously, we reported that norathyriol and caffeic acid, which possess the catechol moiety, and catechol itself directly bind and inhibit ERK2 kinase activity. Those findings led us to test catechol moiety-containing natural compounds, luteolin, quercetin, fisetin, 7,3’,4’-trihydroxyisoflavone, and cyanidin, against ERK2 kinase activity. We found that all of these compounds directly bind to ERK2 and inhibit its activity. We further confirmed the results by resolving a co-crystal structure of ERK2 bound with luteolin in the ATP binding site. To apply this finding to cancer, the effect of the compounds was tested on the K562 human myelogenous leukemia cell line where ERK2 is highly expressed and knock-down of the protein reduced anchorage-independent growth. Five newly-found ERK2 inhibitors (luteolin, quercetin, fisetin, 7,3’,4’-trihydroxyisoflavone and cyanidin) and three known ERK2 inhibitors (norathyriol, caffeic acid and catechol) decreased cell viability of K562 at 40 ìM. When the eight compounds were used at the same dose in combination (5 ìM each and 40 ìM total), the mixture inhibited ERK2 and reduced cell viability of K562 cells. In summary, using in vitro kinase assays and co-crystallography, we identified new ERK2 inhibitors that contain the catechol functional group, and showed anti-cancer effects of the compounds by cell viability assay and soft agar assay. This work impacts the cancer prevention community by showing that many natural compounds can work together targeting ERK2, an important target in cancer.
Citation Format: Seung Ho Shin, Margarita Malakhova, Igor Kurinov, Do Young Lim, Ann M. Bode, Zigang Dong. Discovery of catechol moiety-containing natural compounds as direct ERK2 inhibitors by in vitro kinase assay and co-crystallography. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 821.
Abstract 826: Benzyl isothiocyanate inhibits breast cancer-induced osteoclastogenesis
Authors: Pore Subrata K. , Sehrawat Anuradha , Singh Shivendra V. 
Published: July 2016

Abstract
Breast cancer is a major public health issue for women worldwide and 70% of the disease preferentially metastasizes to bone resulting in its destruction. Advanced breast cancer releases osteoclastogenic factors to promote bone resorption. As bone metastasis with breast cancer is associated with high mortality, osteoclastogenesis is a potential therapeutic target. We have shown previously that benzyl isothiocyanate (BITC), which is present in edible cruciferous vegetables, inhibits breast cancer development in a transgenic mouse model. The present study was designed to determine effect of BITC on breast cancer-induced osteoclastogenesis. We employed well-established in vitro osteoclast co-culture system of Raw 264.7 murine macrophage cells with human breast cancer cells for this assessment. BITC treatment significantly inhibited the number as well as size of osteoclasts in a dose dependent manner in every co-culture experiment. In addition, BITC downregulated both mRNA and protein levels of macrophage colony stimulating factor (MCSF) and receptor activator of NF-êB ligand (RANKL) which are key factors for formation of osteoclasts. Moreover, receptor activator of NF-êB ligand (RANKL)-induced osteoclast differentiation as well as bone resorption was suppressed in the presence of BITC. On the other hand, BITC induced osteoprotegerin (OPG) acting as a decoy receptor of RANKL and negatively regulated osteoclast formation. Quantitative PCR analysis revealed that mRNA levels of osteoclastogenesis-related cytokines and proteins (IL-1â, IL-6, TNF-á, GM-CSF, OPG, RUNX2) were repressed in BITC-treated breast cancer cells. Taken together, BITC showed inhibitory activity on breast cancer-mediated osteoclastogenesis. This study was supported by the grant CA129347 awarded by the National Cancer Institute.
Citation Format: Subrata K. Pore, Anuradha Sehrawat, Shivendra V. Singh. Benzyl isothiocyanate inhibits breast cancer-induced osteoclastogenesis. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 826.
Abstract 851: Analysis of cancer-initiating mosaic mutation in germline samples of pediatric cancer patients by next generation sequencing
Authors: Ma Xiaotu , Yergeau Donald , Vadodaria Bhavin , Nakitandwe Joy , Easton John , Shurtleff Sheila , Zhang Jinghui 
Published: July 2016

Abstract
A cancer predisposition mutation can occur during post-zygotic stages resulting in a mosaic mutation pattern across tissues. Mosaic germline mutations such as those affecting RB1, TP53 and AKT1 are important for clinical testing. However, it is challenging to detect mosaic mutation by genome-wide sequencing approaches as a mutant allele present at a low fraction in a germline sample can be caused by either tumor-in-normal contamination or mosaicism. Here we propose a two-step analytical approach to distinguish between these two possibilities. The first involves assessing the level of tumor-in-normal contamination using all clonal somatic mutations identified through the analysis of tumor purity and chromosome ploidy. The second step determines the probability of mosaicism for a candidate variant by calculating the binomial probability of its mutant allele fraction (MAF) under the contamination hypothesis. We applied this process to 1,172 paired tumor-normal pediatric cancer samples analyzed by whole-genome or whole-exome sequencing. Six mosaic variants were identified, including three pathogenic TP53 mutations with a mutant allele fractions (MAF) ranging from 0.2 to 0.3, one RB1 mutation in a retinoblastoma case with a MAF of 0.08, one IDH1 p.R132H mutation in an acute myeloid leukemiaý case with a MAF of 0.21, and one mosaic RYR2 p.E1690D mutation in an osteosarcoma case with a MAF of 0.11. At the same time, we were able to reject three candidate TP53 variants caused by contamination with MAFs ranging from 0.06 to 0.33. All predicted mosaic mutations were verified by ultra deep sequencing at 10,000X coverage. This experience demonstrates the feasibility of detecting germline mosaicism from whole-genome or whole-exome sequencing of paired tumor-normal samples and would caution accurate analysis of tumor-in-normal contamination when evaluating candidate germline mosaicism.
Citation Format: Xiaotu Ma, Donald Yergeau, Bhavin Vadodaria, Joy Nakitandwe, John Easton, Sheila Shurtleff, Jinghui Zhang. Analysis of cancer-initiating mosaic mutation in germline samples of pediatric cancer patients by next generation sequencing. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 851.
Abstract 882: TMPRSS2-ERG drives global mistargeting of mammalian SWI/SNF (BAF) complexes in prostate cancer
Authors: Sandoval Gabriel J. , Pulice John L. , Takeda David Y. , Schenone Monica A. , Pop Marius , Boulay Gaylor , Rivera Miguel N. , Ronco Lucienne , Hahn William C. , Kadoch Cigall 
Published: July 2016

Abstract
Prostate cancer remains one of the leading causes of cancer-related death in men. Chromosomal rearrangements resulting in the fusion of the androgen regulated gene TMPRSS2 and the ETS-family transcription factor ERG occur in over 50% of all prostate cancer cases. Recent studies enabled by genome-wide methodologies have implicated altered epigenomic landscapes and changes in DNA accessibility as major contributors to ERG-driven oncogenesis, however the precise mechanism underlying the ERG transcriptional signature has to date remained unclear. Here we performed the first endogenous purification and SILAC-mass spectrometric analysis of ERG in TMPRSS2-ERG prostate cancer cells. Remarkably, we demonstrate that ERG directly interacts with the mammalian SWI/SNF (BAF) ATP-dependent chromatin remodeling complex, which was recently shown to be mutated in &gt;20% of human malignancies. ERG co-localizes with BAF complexes genome-wide, resulting in specific ERG-dependent BAF complex targeting to sites enriched in known ERG, FOXA1, and HOXB13 motifs; additionally, loss of ERG in TMPRSS2-ERG driven cell lines results in dramatic retargeting of BAF complexes away from ERG-dependent sites, to sites enriched in known AR and CTCF motifs. Importantly, ERG-driven BAF complex retargeting contributes to activation of TMPRSS2-ERG prostate cancer gene expression signatures. We map the ERG-BAF interaction to a specific region within the ERG amino acid sequence and find that this region is required to bind BAF complexes. These studies reveal a novel, unexpected mechanism of action of ERG-driven oncogenesis and offers new strategies for therapeutic intervention.
Citation Format: Gabriel J. Sandoval, John L. Pulice, David Y. Takeda, Monica A. Schenone, Marius Pop, Gaylor Boulay, Miguel N. Rivera, Lucienne Ronco, William C. Hahn, Cigall Kadoch. TMPRSS2-ERG drives global mistargeting of mammalian SWI/SNF (BAF) complexes in prostate cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 882.
Abstract 89: Whole-exome sequencing and immune profiling of early-stage lung adenocarcinoma
Authors: Kadara Humam , Choi Murim , Zhang Jiexin , Parra Cuentas Edwin , Rodriguez Canales Jaime , Gaffney Stephen , Zhao Zi-Ming , Behrens Carmen , Fujimoto Junya , Chow Chi-Wan , Kalhor Neda , Moran Cesar , Rimm David , Swisher Stephen G. , Gibbons Don L. , Heymach John V. , Kaftan Edward , Townsend Jeffrey , Lynch Thomas J. , Schlessinger Joseph , Lee J. Jack , Lifton Richard , Wistuba Ignacio I. , Herbst Roy S. 
Published: July 2016

Abstract
PURPOSE: Lung adenocarcinomas (LUADs) lead to the preponderance of deaths attributable to lung cancer. We performed whole-exome sequencing (WES), comprehensive immune profiling and clinicopathological analysis of LUADs to better understand the molecular pathogenesis of this disease and identify clinically relevant molecular markers.
METHODS: We performed WES of 108 paired surgically resected stage I-III LUADs and normal lung tissues using the Illumina HiSeq 2000 platform. Additionally, ten immune related markers (PD-L1, PD-1, CD3, CD4, CD8, CD45ro, CD57, CD68, FOXP3 and Granzyme B) were profiled by imaging-based immunohistochemistry in a subset of LUADs (n = 92). Associations among mutations, immune markers and clinicopathological variables were analyzed using ANOVA and Fishers Exact tests. Cox proportional hazards regression models were employed for multivariate analysis of clinical outcome.
RESULTS: LUADs in this cohort exhibited an average of 243 coding mutations per tumor. We identified 28 genes with significant enrichment for mutation. SETD2-mutant LUADS exhibited relatively poor recurrence-free survival (RFS) and mutations in STK11 and ATM were associated with poor RFS in KRAS-mutant tumors. EGFR, KEAP1 and PIK3CA mutations were predictive of poor response to adjuvant therapy. Immune marker analysis demonstrated that PD-L1 expression was increased in smoker compared to non-smoker LUADs and, along with other immune markers, was positively correlated with somatic mutation burden. Moreover, immune marker levels including PD-L1 were elevated in TP53-mutant LUADs. In contrast, STK11 and U2AF1 mutant tumors exhibited a suppressed immune response and LUADs with PIK3CA mutations exhibited markedly decreased tumoral PD-L1 expression.
CONCLUSION: Our study highlights mutations that may impact clinical outcome and personalized strategies for immune-based therapy of early-stage LUAD patients.
Citation Format: Humam Kadara, Murim Choi, Jiexin Zhang, Edwin Parra Cuentas, Jaime Rodriguez Canales, Stephen Gaffney, Zi-Ming Zhao, Carmen Behrens, Junya Fujimoto, Chi-Wan Chow, Neda Kalhor, Cesar Moran, David Rimm, Stephen G. Swisher, Don L. Gibbons, John V. Heymach, Edward Kaftan, Jeffrey Townsend, Thomas J. Lynch, Joseph Schlessinger, J. Jack Lee, Richard Lifton, Ignacio I. Wistuba, Roy S. Herbst. Whole-exome sequencing and immune profiling of early-stage lung adenocarcinoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 89.
Abstract 914: Sox10 regulates stem- and mesenchymal-like features in mammary cells
Authors: Dravis Christopher , Wahl Geoffrey M. 
Published: July 2016

Abstract
To discover mechanisms that mediate the initiation and progression of aggressive and stem-like breast cancers, we characterized signaling networks that are present in the mammary stem cells responsible for fetal and adult mammary development. These analyses identified a signaling axis between FGF signaling and the transcription factor, Sox10. Here we report that Sox10 is specifically expressed in mammary cells that exhibit the highest levels of stem/progenitor activity. This includes fetal and adult mammary cells in vivo and mammary organoids in vitro. Sox10 is functionally relevant, as its deletion reduces stem/progenitor competence, while its overexpression increases stem/progenitor activity. Intriguingly, we also discover that Sox10 overexpression elicits epithelial-to-mesenchymal transition (EMT) in mammary organoids in an FGF signaling-dependent manner. Further, modulation of Sox10 levels can induce sequential EMT, migratory, and clonogenic behaviors that strikingly resemble proposed mechanisms of metastasis. Consistent with these findings, we report that Sox10 is preferentially expressed in the most stem- and EMT-like triple negative breast cancer subtypes, which suggest that Sox10 may reprise these same functions during tumorigenesis. Indeed, we find that in an autochthonous mouse model of basal-like breast cancer, Sox10 is expressed at high levels and that these Sox10+ tumor cells exhibit characteristics that are similar to mammary cells in which Sox10 is ectopically expressed. Collectively, these results demonstrate a signaling mechanism through which stem and mesenchymal-like states are acquired in mammary cells, and indicate possible therapeutic targets to counter these functions in breast cancers for which targeted therapies are currently unavailable.
Citation Format: Christopher Dravis, Geoffrey M. Wahl. Sox10 regulates stem- and mesenchymal-like features in mammary cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 914.
Abstract 924: Upregulation of the MET transcript is consistently associated with invasion and tumor budding in colorectal cancer
Authors: Bradley Conor , Dunne Philip , McQuaid Stephen , Bingham Victoria , Lawler Mark , Salto-Tellez Manuel , Johnston Patrick , Van Schaeybroeck Sandra 
Published: July 2016

Abstract
Background:
The c-MET proto-oncogene is frequently overexpressed (50-60%), amplified (1-3%), and mutated (1-3%) in colorectal cancer (CRC). Hepatocyte growth factor (HGF)-dependent and independent activation of c-MET has been associated with increased survival and resistance to targeted therapies. This study aimed to investigate the role of the HGF/c-MET axis in regulating migration/invasion in CRC, using pre-clinical models and clinical samples.
Methods:
In order to model CRC tumour cell invasion, we have generated invasive CRC subpopulations using Boyden Invasion chambers. To model the CRC microenvironment, we have used a range of co-culture techniques with CRC cells and colon fibroblasts. Migration/invasion was determined using xCELLigence System (Roche). c-MET expression in parental and invasive cell lines was measured using Western blotting and qRT-PCR. c-MET expression in CRC FFPE tissues was measured using IHC and RNAScope®.
Results:
We identified marked upregulated expression of c-MET at both the protein and transcript levels in our invasive CRC cell line models. Importantly, both parental and invasive subpopulations were found to be inherently dependent on c-MET for migration, as RNAi against c-MET abrogated migration/invasion in both parental and invasive models. We also demonstrated that stimulation of CRC cells with rh-HGF resulted in increased CRC cell migration/invasion. In addition, co-culture of CRC cells with colonic myofibroblasts, resulted in marked increases in migratory and invasive capacity, and this was dependent on HGF/c-MET signaling. Interestingly, stimulation with myofibroblast conditioned medium or HGF promotes rapid degradation of c-MET at the protein level, followed by recycling, while MET transcript remains unaltered, illustrating a dynamic expression of c-MET protein in response to activation. We further showed that MET is transcriptionally upregulated in tumour budding foci at the invasive front of a cohort of stage III CRC tumors. Intriguingly, c-MET protein levels do not correlate with the transcript, most likely due to a similar protein degradation process observed in our aforementioned in vitro models.
Conclusions:
We show for the first time a key role for transcriptional upregulation of MET as a molecular driver of tumour invasion, both in vitro and in stage III CRC tumours.
Citation Format: Conor Bradley, Philip Dunne, Stephen McQuaid, Victoria Bingham, Mark Lawler, Manuel Salto-Tellez, Patrick Johnston, Sandra Van Schaeybroeck. Upregulation of the MET transcript is consistently associated with invasion and tumor budding in colorectal cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 924.
Abstract 932: AR signaling differentially regulates the growth of prostate epithelial cells
Authors: Yu Xiuping , Yang Shu 
Published: July 2016

Abstract
The prostate is an androgen-dependent organ. Androgen stimulates the growth of normal prostatic cells, as well as prostate cancer (PCa). However, AR signaling does not always promote cell proliferation, in some cases, it may even inhibit the growth of prostatic cells. In this study, we used NHPrE, a cell line derived from normal human prostate epithelia, to study how AR signaling modulates the growth of prostatic cells and to explore the mechanisms involved in AR's differential function in vitro and in vivo. Our results showed that inducing AR signaling in NHPrE cells suppressed their growth in vitro, concomitant with a reduction of Myc. In contrast, ectopic expression of AR in NHPrE cells induced the expression of Myc and pSTAT3 and drove the development of invasive PCa in vivo, suggesting a distinct in vivo function of AR signaling in prostatic cells. Furthermore, our data showed that the presence of prostate stromal cells over-rode androgen-mediated growth inhibition on NHPrE/AR cells in vitro; and IL-6/pSTAT3 was implicated in this stromal/epithelial communication. In conclusion, our study showed that AR signaling differentially regulated the growth of prostatic cells in vitro and in vivo through a mechanism that involved stromal/epithelial interactions.
Citation Format: Xiuping Yu, Shu Yang. AR signaling differentially regulates the growth of prostate epithelial cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 932.