bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 917: mTOR kinase inhibition relieves feedback inhibition of RTK and PI3K signaling in breast cancer cells
Authors: Rodrik-Outmezguine Vanessa S. , Chandarlapaty Sarat , Cao Nen , Smith Paul , Guichard Sylvie , Rosen Neal 
Published: June 2012

Abstract
Activation of mitogenic signaling by receptor tyrosine kinases is regulated by negative feedback. Feedback is in part mediated by mTORC1/S6K dependent downregulation of IRS proteins which downregulate IGF/insulin receptor signaling. Rapamycin, an mTORC1 inhibitor, relieves this feedback and causes induction of phosphorylation of AKT at Serine 473 via IGF activation of mTORC2 leading to the activation of AKT kinase and signaling. This relief of feedback inhibition of mTORC2/AKT signaling may attenuate or abolish the antitumor activity of rapamycin. mTOR kinase inhibitors that inhibit both mTORC1 and mTORC2 complexes have now been developed to circumvent these problems. We now find that AZD8055 is a potent and selective inhibitor of both mTORC1 and mTORC2 and thus abolishes AKT phosphorylation at Ser473 as well as 4EBP1 and S6K phosphorylation, in contrast to rapamycin which effectively inhibits only the last and which activates the first. This drug potently inhibited the proliferation of tumor cells, especially those in which PI3K/AKT signaling is dysregulated and sometimes induced their death. However, AZD8055 does potently reactivate receptor tyrosine kinase signaling. It enhanced receptor tyrosine kinase phosphorylation and expression and caused a profound, HER-kinase dependent activation of ERK and PI3K signaling. It reactivated phosphorylation of AKT Thr308 and AKT substrates, but not that of Ser473 AKT. These data suggest that inhibition of the phosphorylation of AKT at Serine 473 is not sufficient to inhibit AKT signaling. Furthermore, relief of feedback inhibition of RTK function by mTOR kinase inhibitors leads to reactivation of both ERK and AKT signaling.
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 917. doi:10.1158/1538-7445.AM2011-917
Abstract 920: Mislocalization of the polarity protein Scribble promotes tumorigenesis in the mouse mammary gland
Authors: Feigin Michael E. , Rosenberg Avi Z. , Cardiff Robert D. , Muthuswamy Senthil K. 
Published: June 2012

Abstract
Recent evidence from our lab has demonstrated that the basolateral polarity protein Scribble is frequently mislocalized in human tumors and can cooperate with ErbB2 and Myc to induce mammary tumors. However, we do not know if mislocalization of Scribble can initiate cell transformation and tumorigenesis. To test the hypothesis that Scr mislocalization can induce tumorigenesis, we generated transgenic mice expressing a Scr point mutant that has been shown to mislocalize to the cytosol, under the control of the MMTV promoter (ScrP305L). ScrP305L mice develop mammary tumors with long latency, suggesting that secondary genetic events are required for tumor initiation. The tumors are histologically diverse, and immunohistochemical and gene expression analysis indicate that they express high levels of basal markers, including cytokeratins 5, 6 and 14, and low levels of the luminal marker E-cadherin. Inspection of the developing virgin mammary gland reveals that Scr mislocalization impairs tertiary branching and ductal density. While primary and secondary ducts appear normal, tertiary branches fail to form, suggesting a defect in luminal differentiation. These changes can be observed as early as eight weeks after birth; however, by one year of age, multifocal hyperplasias are apparent in most mice. We conclude that mislocalization of Scribble in the mouse mammary gland impairs luminal differentiation, resulting in branching defects and, through acquisition of secondary genetic events, tumors of varying histotype.
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 920. doi:10.1158/1538-7445.AM2011-920
Abstract 923: Separating the wheat from the chaff: A first look at the Cancer Cell Lines Encyclopedia sequencing data
Authors: Kryukov Gregory V. , Berger Michael F. , Stransky Nicolas , Barretina Jordi , Onofrio Robert , Caponigro Giordano , Sougnez Carrie , Monahan John , Shefler Erica , Venkhatesan Kavitha , Cibulskis Kristian , Morais Paula , Sivachenko Andrey , Meltzer Jodi , Lawrence Michael , Ramos Alex , Getz Gad , Platform Broad's Genome Sequencing , Thibault Joseph , Mahan Scott , Jones Michael , Morrissey Michael , Sonkin Dmitry , Ardlie Kristin G. , Golub Todd , Weber Barbara , Warmuth Markus , Sellers William , Harris Jennifer , Schlegel Robert , Garraway Levi A. 
Published: June 2012

Abstract
Comprehensive characterization of cancer genomic alterations and understanding their functional roles are important steps in the development of personalized cancer treatments. The Cancer Cell Lines Encyclopedia project aims to relate genomic alterations to drug sensitivity of cancer cells. Cancer cell lines are indispensable resource for researchers because of their convenience for high-throughput profiling and availability for follow-up experiments.
We sequenced the coding regions of 1645 genes in over 800 cancer cell lines representing 32 different tumor types. Genes were selected on their likelihood to be cancer-related and sequenced using next-generation Illumina technology after hybrid selection of exonic regions. Although, the absence of matched normal cell lines precludes direct distinction of somatic from germline mutations, we were able to select a subset of mutations highly enriched in somatic events combining the following three approaches: subtraction of known polymorphisms, prediction of strongly detrimental mutations (including computational predictions of amino acid substitutions’ effects on protein function) and detection of abnormal linkage disequilibrium patterns for recurring mutations.
We then searched for the three independent indicators of the potential involvement of mutated genes in cancer: the presence of an unusually high fraction of strongly damaging mutations within a gene, statistically significant deviation of distribution of mutations between cancer types from random expectation and clustering of mutations within a gene. Combined analysis of these lines of evidence revealed both known and novel potential tumor suppressors and oncogenes.
These data should become an import resource for cancer researchers in their search for personalized cancer therapies.
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 923. doi:10.1158/1538-7445.AM2011-923
Abstract 93: Usefulness of DNA methylation analysis using gastric washes as a treatment marker for early gastric cancer
Authors: Watanabe Yoshiyuki , Ohishi Yoshichika , Hiraishi Tetsuya , Oikawa Ritsuko , Maehata Tadateru , Suzuki Hiromu , Toyota Minoru , Itoh Fumio 
Published: June 2012

Abstract
Aim: Although minimal invasive treatment is widely accepted for early stage of gastric cancer, we still do not have any appropriate risk markers to detect residual neoplasia and some potential of recurrence. We previously reported that aberrant DNA methylation is an early and frequent process in gastric carcinogenesis and could be useful for detection of gastric neoplasia, and that methylation analysis of DNA recovered from gastric washes was used to detect gastric neoplasia (Gastroenterology 2009). Here, we hypothesized gastric washes also can determine whether gastric cancer (GCa) was removed curatively by endoscopic treatment or not. Our goal is to find and identify some candidate genes as a treatment marker using genome wide DNA methylation analysis and for early gastric cancer.
Method: We studied MCAM (Methylated CpG Island Amplification Microarray) analysis using 12 gastric washes (each 6 before and after endoscopic treatment in same patients) and identified candidate genes for further studies. Two of them are MINT25 and Sox17 (SRY (sex determining region Y)-box 17). We examined the DNA methylation status of these two genes in a validation set consisting of 128 washes samples (Pre, 64: Post, 64) at early gastric cancers by quantitative bisulfite-pyrosequencing analysis.
Results: These two genes showed significantly differential methylation between before and after treatment in GCa patient (MINT25, p&lt;0.0001: Sox17, p&lt;0.0001). Moreover, we could successfully identified the incomplete endoscopic mucosal resection case by Sox17 methylation status, and additional resection resulted in the proof of residual cancer and decrease of Sox17 methylation level in gastric wash.
Conclusion: We have developed a new methodology for gastric cancer detection by DNA methylation in gastric washes. It is easy and useful for early detection of recurrence after endoscopic treatment in GCa 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 93. doi:10.1158/1538-7445.AM2011-93
Abstract 936: Ubiquitin-mediated interaction of p210 Bcr-Abl with β-catenin supports disease progression in a murine model for chronic myelogenous leukemia
Authors: Chen Ru , Mahon Gwen , Tala Ilona , Whitehead Ian 
Published: June 2012

Abstract
Chronic myelogenous leukemia (CML) is a malignant hematopoietic stem cell disorder that is invariably associated with the expression of the p210 Bcr-Abl fusion protein. Although the deregulated, Abl-encoded tyrosine kinase activity is essential for disease progression, several studies have shown that Bcr encoded sequences are also necessary for p210 Bcr-Abl-mediated leukemogenesis. We have identified a non-classical ubiquitin binding domain (UBD) within the NH2-terminal Bcr sequences of p210 Bcr-Abl. Deletion of the UBD (p210 Bcr-Abl(ΔUBD)) does not impair the auto-or trans-kinase activity of p210 Bcr-Abl, nor does it impair the ability of p210 Bcr-Abl to interact with Grb2 and activate Erk1/2 signaling. Although β-catenin has been previously identified as a binding partner for Bcr and Bcr-Abl, p210 Bcr-Abl(ΔUBD) does not interact with β-catenin. Treatment with an E1 inhibitor impairs the interaction between β-catenin and p210 Bcr-Abl, suggesting that the interaction is ubiquitin-dependent. Over-expression of p210 Bcr-Abl, but not p210 Bcr-Abl(ΔUBD), leads to an accumulation of phosphorylated β-catenin, and at least two of its known transcriptional targets, cyclin D1 and c-Myc. Hyper-phosphorylation of β-catenin cannot be attributed to increased activity of GSK-3β or Pin-1. In a murine bone marrow transplantation model for CML, mice transplanted with hematopoietic cells that express p210 Bcr-Abl(ΔUBD) have significantly increased life spans compared to mice transplanted with p210 Bcr-Abl expressing cells. Delayed disease progression is associated with decreased levels of β-catenin, and reduced numbers of granulocyte macrophage progenitors (GMPs), in the bone marrow. Based on these observations we propose a model in which p210 Bcr-Abl may influence the Wnt signaling pathway, and leukemic expansion, by binding ubiquitinated β-catenin, and stabilizing it against degradation. Importantly, this activity is contained within Bcr sequences, and is independent of tyrosine kinase 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 936. doi:10.1158/1538-7445.AM2011-936
Abstract 938: Discovery of Dendrogenin A as the first endogenous alkylaminooxysterol present in mammals with potent cell differentiation and anticancer activity
Authors: Poirot Marc , de Medina Philippe , Paillasse Michael R. , Segala Grégory , Saati Tallal Al , Silvente-Poirot Sandrine 
Published: June 2012

Abstract
We recently reported that anti-tumor and chemopreventive drugs such as tamoxifen, raloxifene and docasahexaenoic acid are inhibitors at therapeutic doses of cholesterol epoxide hydrolase (ChEH), the enzyme that transforms cholesterol-5,6-epoxides (CE) into cholestane-3β,5α,6β-triol (CT) (de Medina et al, PNAS, 2010). Several lines of evidence point to the existence of an active metabolism centered on CE. We recently reported that the aminolysis of α-CE by biogenic amines under catalytic conditions generated powerful cell differentiating alkylaminooxysterols (de Medina et al, J Med Chem, 2009). Among these active molecules, Dendrogenin A (DDA) was synthesized, based on the hypothesis that it could be an endogenous metabolite formed by the reaction of α-CE with histamine at the level of the ChEH. In the present study, we report the existence of DDA in mammals at concentrations ranging from 70 to 500 pmol/g in tissues and at concentrations 70 to 500 times less in the circulation, while only trace levels of AF17, the regio-isomer of DDA, were detected. DDA was not found in a panel of cancer cells, suggesting a possible deregulation of its synthesis during oncogenesis. In addition, we showed that DDA is the most potent natural inhibitor of ChEH with an IC50 around 100 nM and it exhibits tumor differentiation and anti-tumor activity in cell and animal models. In vivo, these effects were associated with a T cell-mediated anti-tumor response. AF17 was found to be inactive in these different tests, showing a regio-selectivity of action of these compounds. In conclusion, our results shed light on a new metabolic pathway that generates the first endogenous steroidal alkaloid ever described in mammals that may have important functions in maintaining cell integrity and differentiation as well as immune system alert. The discovery of DDA reveals an unexpected cross-talk between cholesterol and histamine metabolism.
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 938. doi:10.1158/1538-7445.AM2011-938
Abstract 941: Targeting androgen receptor in estrogen receptor-negative breast cancer
Authors: Ni Min , Chen Yiwen , Bailey Shannon T. , Imai Yuuki , Liu X. Shirley , Brown Myles 
Published: June 2012

Abstract
Estrogen receptor (ER)-negative breast cancers account for 25-30% of all breast cancer cases and generally have a poor prognosis and little benefit from current endocrine therapy. Androgen receptor (AR) is expressed in 60-70% of human breast tumors independent of the ER status. Interestingly, while androgens inhibit the growth of ER+/AR+ breast cancer cells, they stimulate the growth of those that are ER-/AR+. However, the mechanism by which androgens and AR function to regulate breast cancer growth remains largely unknown. Analysis of gene expression microarray datasets from human breast tumors reveals enriched expression of AR in the ER- breast tumors that over-express HER2. Genome-wide analysis of the AR binding sites and androgen-regulated gene expression profiles in ER-/HER2+ breast cancer cells identified that AR mediates activation of oncogenic Wnt and HER2 signaling pathways through direct transcriptional up-regulation of WNT7B and HER3 in an androgen-dependent manner. Importantly, we demonstrate that FOXA1 and beta-catenin act as AR coactivators in inducing HER3, leading to the enforced HER2/HER3 signaling. Pharmacological inhibition of AR, Wnt or HER2 pathways impairs HER3 activation and androgen-stimulated tumor cell growth. While HER3 is receiving increased attention as a therapeutic target in HER2+ breast cancer, our study suggests that AR regulation may be yet another way to target HER3 in ER-/HER2+ tumors. Collectively, these findings not only highlight a previously unappreciated role of AR in breast cancer, but also reveals the mechanistic basis for targeting AR as a novel therapeutic opportunity for patients with invasive ER-/HER2+ breast tumors.
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 941. doi:10.1158/1538-7445.AM2011-941
Abstract 945: Metabolic syndrome increases the risk of primary liver cancer in the United States
Authors: Welzel Tania M. , Graubard Barry I. , Davila Jessica A. , El-Serag Hashem B. , McGlynn Katherine A. 
Published: June 2012

Abstract
Background: Hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC) are the two most common histologic types of primary liver cancer. Incidence rates of both HCC and ICC are increasing in the United States. Metabolic syndrome, characterized by increased fasting glucose level, central adiposity, dyslipoproteinemia and hypertension, has been linked with HCC and may also modify the risk of ICC. The magnitude of the association, however, has not been investigated at the population level in the US. We therefore examined the association between metabolic syndrome and the development of both primary liver cancers in the general U.S. population.
Methods: All persons aged 65 years and older diagnosed with histologically confirmed HCC and ICC between 1993 and 2005 were identified in the SEER-Medicare linked database. The cases were compared to a 5% sample of individuals residing in the same geographic regions of the SEER registries as the cases. The prevalences of metabolic syndrome and other risk factors for HCC (HBV, HCV, unspecified viral hepatitis, alcoholic liver disease, unspecified cirrhosis, biliary cirrhosis, hemochromatosis, Wilson's disease, smoking) and ICC (biliary cirrhosis, cholangitis, cholelithiasis, choledochal cysts, HBV, HCV, unspecified viral hepatitis, alcoholic liver disease, non-specified cirrhosis, inflammatory bowel disease, Crohn's disease, ulcerative colitis, smoking) were compared among the persons who developed cancer and the persons who did not. Adjusted odds ratios and 95% confidence intervals were calculated using logistic regression.
Results: A total of 3,649 HCC cases, 743 ICC cases and 195,953 persons without cancer met the study inclusion criteria. Metabolic syndrome was significantly more common among persons who developed HCC (37.1%) and ICC (29.7%) than among persons who did not (17.1%, p&lt;0.0001). In multiple logistic regression analyses that adjusted for demographics features and the other risk factors, metabolic syndrome remained significantly associated with an increased risk for HCC (OR=2.13; 95%CI=1.96-2.31, p&lt;0.0001) and ICC (OR=1.56; 95% CI = 1.32-1.83, p&lt;0.0001).
Conclusions: Metabolic syndrome is a risk factor for development of both HCC and ICC in the general U.S. population. Given that approximately one-third of U.S. adults have metabolic syndrome, these findings have implications for the future incidence of both HCC and ICC.
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 945. doi:10.1158/1538-7445.AM2011-945
Abstract 959: Targeting renal cell carcinoma with englerin A
Authors: Sourbier Carole , Ratnayake Ranjala , Scroggins Brad , Lee Min-Jung , Lee Sunmin , Trepel Jane , Beutler John , Neckers Len , Linehan W. Marston 
Published: June 2012

Abstract
Background: Englerin A (EA) is a natural product which has shown selective toxicity toward kidney tumor cells in the NCI60 panel. However, EA's targets and mechanism of action remain unknown.
Methods: Cytotoxicity of EA toward a panel of kidney cancer cell lines was assessed in vitro by MTT and cell counting, and in vivo using a human clear cell kidney cancer xenograft mouse model. The protein kinase C family was predicted as a likely molecular target of EA using QSAR methodology. This was confirmed by PKC kinase activity assays. EA's mechanism of action was investigated using western-blot analysis, meso-scale discovery technology, and immunohistochemistry.
Results: EA was cytotoxic in vitro and in vivo via induction of apoptosis. Comparison of EA's structure with other well-known compounds predicted the PKC family to be a potential drug target. Direct treatment of cell lysates with EA increased pan-PKC kinase activity, suggesting that EA directly activated at least one of the PKC isoforms. Further investigation showed that EA-dependant PKC activation inhibited the insulin pathway through inhibitory phosphorylation of Insulin Receptor Soluble 1 (IRS1) protein, and decreased phosphorylation status of Akt and GSK3beta. These data were reproduced in vivo, as phosphorylation of GSK3beta was reduced in RCC tumor treated with EA compared to tumor treated with vehicle.
Conclusion: The insulin/PI3K/Akt pathway has been previously shown by us and others to be critical for the survival of renal cell carcinoma. By activating PKCs, EA indirectly induces an “insulin resistant” phenotype which appears to be selectively lethal for RCC tumor cells. Thus, EA represents a novel potential therapeutic lead for renal 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 959. doi:10.1158/1538-7445.AM2011-959
Abstract 966: Snail mediated transcriptional repression and EMT requires zinc-finger and SNAG domain directed phosphorylation: Identification of the kinases and evaluation as therapeutic targets
Authors: Rauscher Frank J. , Hou Zhaoyuan , Peng Hongzhuang , White David E. , Wood Colleen 
Published: June 2012

Abstract
The Snail zinc-finger transcription factor is a master regulator of the Epithelial-Mesenchymal Transition (EMT) which occurs during the early steps in tumor metastasis. Snail is strongly up-regulated and causally involved in EMT: it binds directly to the promoters of genes which mediate EMT and functions largely as a repressor thereby regulating a comprehensive transcriptome which establishes and maintains the invasive mesenchymal phenotype. Snail is a marker for the malignant phenotype, prognosis and strongly predicts treatment failure, relapse and overall survival. Inhibiting the Snail pathway is a novel approach to metastasis prevention and therapeutics. We have: 1) identified the LIM protein AJUBA as a novel co-repressor for Snail-mediated EMT; 2) shown that the arginine methyltransferase 5 (PRMT5) complex is recruited to SNAIL through AJUBA and; 3) discovered that Snail/AJUBA/PRMT5 complex assembly in chromatin requires that the zinc-finger region of Snail be phosphorylated at serine/threonine residues in the DNA binding and repression domains and that these modifications are directly recognized by 14-3-3 proteins. The quaternary pSnail/AJUBA/PRMT5/14-3-3 complex is enriched at endogenous Snail target genes via ChIP. Mutation of the target amino acids Serine11 and Threonine177 to alanine concommitantly abolished: 14-3-3 binding, chromatin association of the complex, and transcriptional repression. Moreover, Snail induction of EMT and metastasis was inhibited. These studies suggest that targeting the Snail directed kinases for inhibition is a viable strategy for controlling tumor progression and metastasis. The Identification of these kinases and their regulation during tumor progression will be presented.
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 966. doi:10.1158/1538-7445.AM2011-966