bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract LB-143: ErbB2, EphrinB1, Src kinase and PTPN13 signaling complex regulates MAP kinase signaling in human cancers
Authors: Vermeer Paola D. , Bell Megan , Lee Kimberly , Vermeer Daniel W. , Wieking Bryant , Drapkin Ronny I. , Ganesan Shridar , Lee John 
Published: August 2012

Abstract
Tyrosine kinases, like the ErbB and Src families, can mediate potent oncogenic growth and are successful therapeutic targets of human cancers. However, many cancer cells overcome or successfully modulate these downstream signaling cascades in the absence of growth factor or kinase over-expression. We have previously identified a cellular phosphatase, PTPN13 that significantly modulates mitogenic signaling and can function as tumor suppressors. Decreased PTPN13 expression enhances ErbB2-mediated MAP Kinase activation, and is also associated with decreased survival in breast cancer. Here we show that PTPN13 regulates a signaling complex consisting of ErbB2, Src, and EphrinB1. To our knowledge, this signaling complex has not been previously described. Co-immunoprecipitation, proximity ligation assay and immunofluoroscence studies demonstrate that EphrinB1, a PTPN13 substrate, interacts with ErbB2. In addition, the oncogenic V660E ErbB2 mutation enhances this interaction, while Src kinase mediates EphrinB1 phosphorylation and subsequent MAP Kinase signaling. Decreased PTPN13 function further potentiates these changes. The association of oncogene kinases (ErbB2, Src), a signaling transmembrane ligand (EphrinB1) and a phosphatase tumor suppressor (PTPN13) suggest that EphrinB1 may be a relevant therapeutic target in cancers harboring ErbB2-activating mutations and decreased PTPN13 expression.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-143. doi:1538-7445.AM2012-LB-143
Abstract LB-151: Spred1 and neurofibromin interact to negatively regulate Ras/Raf/MEK/ERK signaling
Authors: Stowe Irma B. , Stowe Timothy , McCormick Frank , Mercado Ellen 
Published: August 2012

Abstract
The Ras/Mitogen Activated Protein Kinase (MAPK) plays a critical role in cell signaling downstream of receptor tyrosine kinases. The conserved Sprouty family proteins function as feedback regulators of Ras/MAPK signaling. Loss of function mutations in one family member, SPRED1, cause Legius syndrome, an autosomal dominant human disorder that resembles neurofibromatosis type 1 (NF1). Spred1 functions as a negative regulator of the Ras/MAPK pathway, however, the underlying molecular mechanism is poorly understood. We found Spred1 functioned by reducing Ras-GTP levels; SPRED1 loss-of function mutations identified in Legius syndrome patients were unable to regulate Ras activity levels. The N-terminal EVH1 domain of Spred1 was found to be crucial for its inhibitory function. Thus, we utilized tandem affinity purification of wild-type Spred1 and EVH1 domain mutants found in Legius syndrome to identify novel binding partners of the N-terminus. Analysis of protein complexes by mass spectrometry revealed neurofibromin, the NF1 gene product, as a novel Spred1 interacting protein. We show that neurofibromin is a Spred1 binding partner that is necessary for Spred1's inhibitory function. Spred1 requires neurofibromin to down-regulate Ras-GTP levels, and the interaction with Spred1 is required for neurofibromin localization to the plasma membrane. This novel mechanism leads to a better understanding of the regulation of the neurofibromin tumor suppressor protein.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-151. doi:1538-7445.AM2012-LB-151
Abstract LB-152: PIK3CA mutation spectrum in urothelial carcinoma reflects cell context-dependent signalling and phenotypic outputs
Authors: Ross Rebecca L. , Askham Jon M. , Knowles Margaret A. 
Published: August 2012

Abstract
Activating p110α mutations are frequently observed in urothelial carcinoma (UC). Their specific effects in urothelial cells and the reason for the large excess of helical domain mutations relative to kinase domain mutations have not been studied. Thus we investigated the phenotypic consequences of hotspot and UC-specific rare PIK3CA mutations in immortalized normal human urothelial cells (NHUC) and mouse fibroblasts (NIH3T3). Our results show that in NHUC, all PIK3CA mutants activate the AKT pathway. The potency of AKT downstream activation by helical and kinase domain mutants was related to the frequency of mutation occurrence in UC (E545K&gt;E542K&gt;H1047R). In NIH3T3, the H1047R kinase domain mutant induced significantly higher levels of AKT activation relative to helical domain mutant forms and this was reflected in their abilities to promote anchorage-independent growth. In NHUC, only E542K and E545K helical domain mutant forms conferred a significant proliferative advantage at confluence and in nutrient limiting conditions. Both types of mutant forms induced NHUC cell motility, though no significant differences were found between helical and kinase domain mutant forms. Our findings indicate that the cellular consequences of mutant PIK3CA are both cell type- and mutation-specific. This provides a rationale for the observed PIK3CA mutation spectrum in UC and suggests that helical domain mutations may confer a selective advantage in the urothelium in vivo by overcoming normal contact-mediated inhibitory signals and allowing nutrient-independent proliferation.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-152. doi:1538-7445.AM2012-LB-152
Abstract LB-205: Identification of tumorigenic cells in KrasG12D-induced lung adenocarcinoma
Authors: Yu John , Cho Huan-Chieh 
Published: August 2012

Abstract
We established an inducible KrasG12D-driven lung adenocarcinoma in CCSP-rtTA/TetO-Cre/LSL-KrasG12D mice that enable pursuits of the cellular and molecular processes involved in Kras-induced tumorigenesis. To investigate the cellular origin of this cancer, we first report a strategy using FACS fractionation that could highly enrich bronchiolar Clara and alveolar type II cells, respectively. The EpCAM+MHCII− cells (bronchiolar origin) were more enriched with tumorigenic cells in generating secondary tumors than EpCAM+MHCII+ cells (alveolar origin) in primary tumors that had been already initiated with oncogenic Kras activation. In addition, secondary tumors derived from EpCAM+MHCII− cells showed diversity of tumor locations compared to those derived from EpCAM+MHCII+ cells. In the alveolar region, secondary tumors from EpCAM+MHCII− cells expressed not only bronchiolar epithelial marker, panCK, but also differentiation marker, proSPC, consistent with the notion that cancer-initiating cells display not only the abilities for self-renewal but also the features of differentiation to generate heterogeneous tumors with phenotypic diversity. Furthermore, high level of ERK1/2 activation and colony-forming ability as well as lack of Sprouty-2 expression were also observed in EpCAM+MHCII− cells. Therefore, these results suggest that bronchiolar Clara cells are the origin of cells and tumorigenesis for KrasG12D-induced neoplasia in the lungs.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-205. doi:1538-7445.AM2012-LB-205
Abstract LB-206: A new platform for diagnosis and therapeutic targeting of cancer stem cells
Authors: Ertem Server A. , Moore Malcolm AS 
Published: August 2012

Abstract
The present failure of most current therapies to cure cancers is thought to be the relative resistance of cancer initiating cells (CIC), also known as cancer stem cells, to chemotherapy and radiation. Following repeated cancer treatments, tumors can remain with a high percentage of CIC and become more aggressive and resistant to further treatment. What has been missing up to now is a therapy directed at CIC also known as cancer stem cells. Without elimination of these cells, cancer recurrence is inevitable. We believe that the major objective of cancer therapy should be to target CIC specifically. However, there has not been a reliable method for detecting CIC within tumors that would allow prospective isolation of these cells in sufficient numbers for analysis, characterization and evaluation of novel therapeutics. This has proved to be a major barrier to development of effective CIC targeted cancer therapeutics. Advances in cancer therapy will depend on development of reliable early detection methods and targeting strategies specific for CIC. We have discovered a unique cell type with cancer initiating cell characteristics in metastatic cancers. These cells have a protective pericellular coat, divide rapidly and grow as chains of cells - thus the name catena = chain. In xenograft studies in mice, nearly every catena cell was shown to be a CIC. Catena are resistant to standard therapies (e.g. paclitaxel, cisplatin) and more than 1,000 pharmaceutical agents that are in development for cancer treatment. Catena lack all of the biomarkers currently used for cancer detection and are undetectable by current diagnostic tests that utilize monoclonal antibodies (e.g. to CA125, HE4, Mesothelin, WT1, CD44, EPCAM, CD133). We subsequently developed the CATENAE cell culture technology to propagate these cells in vitro while maintaining their cancer initiating properties. This technology provides for the first time adequate number of CIC for detailed analysis and could be the key to both better therapies and more efficient detection of cancer at an early stage when it is curable.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-206. doi:1538-7445.AM2012-LB-206
Abstract LB-208: Notch2 in vivo genetic labeling reveals novel epithelial subtypes within mammary luminal lineage
Authors: Sale Sanja , Lafkas Daniel , Artavanis-Tsakonas Spyros 
Published: August 2012

Abstract
Identification and characterization of normal epithelial subtypes in mammary gland is a fundamental step in understanding mammary development as well as carcinogenesis. In this study we utilized an inducible lineage tracing approach in combination with reconstitution assays and conditional in vivo cell ablation to systematically map the fate and define cellular hierarchy of normal mammary epithelial cells (MECs) in postnatal mammary gland. We used a set of novel genetically engineered mice designed to follow Notch receptor expressing cell lineages given that Notch activity has been associated with early precursor and stem cells in many tissues. We focused our attention on Notch2 expressing cells, which allowed us to define two novel epithelial subtypes within ductal and alveolar lineage displaying distinct morphological and functional characteristics. We operationally term them as LumS (Luminal Small) and LumL (Luminal Large) cells. LumS cells are positioned in regular intervals alongside ductal longitudinal axis and are grouped in a chain formation around a single large luminal cell forming a stereotypical “pit”. LumL cells are large, oval shaped and appear as either singlets or doublets. They are mostly, although not exclusively, positioned in close proximity to branching points. In lactating glands LumL cells also appear as singlets or doublets within each alveolus. Functional assays demonstrate that LumS and LumL cells are not multipotent stem cells but rather differentiated luminal subtypes that are involved in determining location of the future tertiary alveolar structures as well as branching morphogenesis. It remains to be determined whether LumS and LumL populations are the cells of origin for breast cancer subtypes. We note with interest however that a single nucleotide polymorphism (SNP) in Notch2 locus has recently been identified as a novel genetic risk factor for breast cancer and Notch2 mRNA was found to be enriched in ER+ luminal tumors suggesting the possibility of clonal expansion of one or more Notch2+ lineages.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-208. doi:1538-7445.AM2012-LB-208
Abstract LB-211: beta1 integrin targeting results in radiosensitization by controlling DNA repair mechanisms and chromatin organization
Authors: Dickreuter Ellen , Storch Katja , Eke Iris , Krause Mechthild , Baumann Michael , Cordes Nils 
Published: August 2012

Abstract
Integrin-mediated cell-extracellular matrix (ECM) interactions confer cancer cell resistance to therapy. Our own data and data of others generated in three-dimensional (3D) ECM-based cell cultures and in vivo provided evidence that particularly beta1 integrin targeting potently reduces this resistance involving downstream integrin signaling mediators like focal adhesion kinase, cortactin and JNK1. However, it remains unknown whether beta1 integrin inhibition affects the repair of radiation-induced DNA double strand breaks (DSB) and their distribution in eu- and heterochromatic DNA regions. Here, we show that 3D growth (cell culture, xenograft models) increased the amount of heterochromatin in human head and neck squamous cell (HNSCC) and lung carcinoma cell lines relative to 2D, induced higher radioresistance, reduced the number of chromosomal aberrations and gammaH2AX/53BP1-positive foci, which was accompanied by a shift of the euchromatin-to-heterochromatin DSB distribution from a 2:1 (2D) to a 1:1 (3D). Upon beta1 integrin inhibition using the inhibitory monoclonal antibody AIIB2 or siRNA, cells grown in 3D or as xenografts in nude mice were radiosensitized or showed a significant growth delay, respectively. The disruption of beta1 integrin-mediated cell-ECM interactions induced an increase in heterochromatin levels indicated by HP1alpha and H3K9me3 elevation. In line with these findings was a strong impairment of both ATM and DNA-PK and their associated downstream signaling pathways (e.g. Chk2, Mre11, Nbs1, Rad50) in beta1 integrin inhibited, irradiated cells relative to IgG isotype controls. In contrast to unchanged number of heterochromatic foci identified in stably transfected HP1alpha cells, kinetic DSB measurements revealed an increased number of euchromatic foci upon beta1 integrin blocking, which evidently showed strongly perturbed DSB repair. In conclusion, our data generated in 3D cell culture and tumor xenograft models suggest a regulatory function of beta1 integrin signaling in the repair of radiogenic DSBs and the organization of chromatin. In addition to our understanding of the initial steps deactivated upon beta1 integrin blocking, these findings bridge membrane bound integrin function to nuclear DNA repair processes, thus providing further insights into how integrins confer cancer cell radioresistance and why integrin targeting is potentially useful as adjuvant to conventional radio- and radiochemotherapy.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-211. doi:1538-7445.AM2012-LB-211
Abstract LB-247: mTORC1 enhances bortezomib-induced death in TSC-null cells by a c-MYC-dependent induction of the unfolded protein response
Authors: Babcock Justin T. , Nguen Hoa B. , He Yujun , Wek Ronald C. , Quilliam Lawrence A. 
Published: August 2012

Abstract
The ability of the proteasome inhibitor bortezomib to induce apoptosis of cancer cells is influenced by a variety of signaling pathways. We have found that control of c-MYC expression by the mammalian target of rapamycin complex-1 (mTORC1) plays a key role in determining drug sensitivity. Bortezomib treatment of Elt3 (rat TSC2-null leiomyoma) cells, that have high mTORC1 activity, activates the unfolded protein response (UPR) and apoptosis. Both effects were prevented by pretreatment of cells with the mTORC1 inhibitor, rapamycin, indicating mTORC1 dependence. Bortezomib also induced c-MYC expression in Elt3 cells in an mTORC1-dependent manner. c-MYC bound to the promoters of the UPR-induced transcription factors ATF4 and CHOP during bortezomib treatment. These data suggest direct involvement of an mTORC1/c-MYC-driven signaling pathway in the activation of the UPR. Consistent with this notion, overexpression of c-MYC in the presence of rapamycin was sufficient to rescue bortezomib induced CHOP and ATF4 expression, as well as apoptosis. These findings demonstrate that the induction ATF4/CHOP expression by mTORC1 via regulation of c-MYC is a major determinant in the ability of bortezomib to induce apoptosis of tumor cells. Since hypoxia and low nutrient levels in poorly vascularized tumors may contribute to down regulation of mTORC1, our data may help explain some of the difficulties in treating solid tumors with bortezomib and caution against the use of rapamycin in combination with proteasome inhibitors in cancer treatment.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-247. doi:1538-7445.AM2012-LB-247
Abstract LB-256: Targeting MLL1 methyltransferase activity for treatment of acute leukemia with MLL1 rearrangement
Authors: Townsend Elizabeth C. , Cao Fang , Karatas Hacer , Wang Shao-Meng , Dou Yali 
Published: August 2012

Abstract
Translocation of the MLL1 gene, which encodes for the histone methyltransferase, MLL1, is found in approximately 10% of all cases of acute leukemia and is generally associated with poor patient outcomes. Recent research has pointed to an essential function for the wild-type copy of MLL1 in these leukemias. In these cells, abnormal upregulation of MLL1-directed histone methylation and subsequent overexpression of MLL1 gene targets is an essential step in the development and progression of leukemia. Efficient MLL1-catalyzed histone methylation can only be achieved when MLL1 associates with the complex of WDR5, RbBP5 and Ash2L. MLL1 complex assembly is nucleated by a highly conserved interaction between the MLL1 SET domain and WDR5. We hypothesize that blocking histone methyltransferase activity of wild-type MLL1 through inhibition of the essential WDR5-MLL1 interaction will prevent abnormal gene upregulation and transformation in leukemias with MLL1 rearrangement. Using rational design, we have developed potent inhibitors for WDR5. We have demonstrated that the lead compound, MM-401, can disrupt the interaction of MLL1 with WDR5, and prevent assembly of the MLL1 complex. We have also shown that MM-401 specifically inhibits MLL1 complex activity, with an IC50=320nM. Using MLL1 fusion-transduced mouse bone marrow cells as a model, we have shown that treating leukemia cells with MM-401 inhibits expression of the MLL1 target oncogene, HoxA9, in a concentration-dependent fashion. Treatment of these cells with MM-401 also promotes differentiation of leukemia blasts in a dose dependent manner. Furthermore, MM-401 specifically impairs cell growth and viability of human leukemia cell lines with MLL1 rearrangement but does not alter growth of leukemia cell lines with mutations or translocations targeting other oncogenes. In conclusion, we have developed a potent inhibitor MM-401, which is the first in a novel class of inhibitors designed to target MLL1 methyltransferase activity, one of the most important chromatin modifying enzymes for transcription activation. We have further demonstrated that pharmacological inhibition of the MLL1 methyltransferase activity specifically targets leukemias with MLL1 rearrangement, and shifts leukemia cells away from the undifferentiated, rapidly proliferating state that is characteristic of aggressive AMLs. These results point to a promising new therapeutic target for leukemia treatment.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-256. doi:1538-7445.AM2012-LB-256
Abstract LB-26: The N-terminal projection domain of the microtubule associated protein Tau inhibits TNFα signaling
Authors: Debnath Shawon , Hannon Peter , Toropova Kristina , Nunez-Rodriguez Nelson , Alonso Alejandra , Fata Jimmie E. 
Published: August 2012

Abstract
Tumor Necrosis Factor-alpha (TNFα) is a multifunctional pro-inflammatory cytokine implicated in inducing both tumor promotion and tumor inhibition. This paradoxical effect can be partly explained by the fact that TNFα acts as a regulator of both proliferation and apoptosis; however the mechanisms and factors associated with how or whether a tumor cell responds to a microenvironment rich in TNFα have not been fully resolved. Here we provide evidence that the microtubule associate protein Tau inhibits TNFα signaling through its N-terminal domain and implicate it as a novel regulator of the cellular response to this key cytokine. Our findings indicate that over-expression of Tau in the human breast cancer cell lines MCF7, SkBr3 and in the pheochromocytoma cell line PC12 suppresses TNFα-induced apoptosis evident in the control cells. TNFα-induced cell apoptosis in control cells is triggered as early as 6 hrs post-treatment with hallmark features of cell shrinkage, membrane blebbing, disruption of tubulin architecture and caspase-3 activation. While over-expression of wild type full length Tau isoform in these cell lines, completely abrogates all TNFα-associated apoptotic phenotypes. Aside from inhibiting TNFα-induced apoptosis, Tau over-expression also interferes with TNFα-induced NFKB activation. This is evident by a significant decrease in NFKB nuclear translocation in Tau over-expressed cells compared to controls. Suppression of TNFα-signaling by Tau is not associated with its tubulin interaction since a truncated N-terminal projection domain lacking all microtubule binding domains still provides resistance to TNFα-induced apoptosis and NFKB activation. These findings lead us to conclude that the functional domain of Tau that regulates TNFα response lies within its N-terminal region and current studies investigating regions within this domain are ongoing. Our data provide direct evidence that the N-terminal domain of the microtubule associated protein Tau can inhibit TNFα signaling in tumor cells. These findings indicate a novel function for Tau and add to our knowledge of how a tumor cell responds to TNFα-signaling.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-26. doi:1538-7445.AM2012-LB-26