bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4167: KRas induces a Src/PEAK1/ErbB2 kinase amplification loop to drive pancreatic cancer growth, metastasis and therapy resistance
Authors: Kelber Jonathan A. , Reno Theresa , Kaushal Sharmeela , Metildi Cristina , Stoletov Konstantin , Weems Jessica , Park Fred D. , Wright Tracy , Mose Evangeline , Hoffman Robert M. , Lowy Andrew M. , Bouvet Michael M. , Klemke Richard L. 
Published: August 2012

Abstract
Early biomarkers and effective therapeutic strategies are desperately needed to treat pancreatic ductal adenocarcinoma (PDAC), which has a dismal 5-year patient survival rate. We recently identified PEAK1 (pseudopodium-enriched atypical kinase one, SGK269) as a catalytically active tyrosine kinase that associates with the cytoskeleton and regulates cell migration and proliferation. Tyrosine kinases are highly sought after candidates as biomarkers and therapeutic targets because they induce specific phoshorylation signatures and because their catalytic activity and downstream signals can be inhibited by small molecules. The goal of this current study was to assess the role of PEAK1 expression as a diagnostic/prognostic biomarker and potential therapeutic target in human malignancies. Here, we report that the novel tyrosine kinase PEAK1 is upregulated in human malignancies, including human PDAC and pancreatic intraepithelial neoplasia (PanIN). Oncogenic KRas induced a PEAK1-dependent kinase amplification loop between Src, PEAK1 and ErbB2 to drive PDAC tumor growth and metastasis in vivo. Suprisingly, blockade of ErbB2 increased Src-dependent PEAK1 expression, PEAK1-dependent Src activation and tumor growth in vivo, suggesting a mechanism for the resistance of PDAC to therapeutic intervention. Indeed, PEAK1 mediates multiple therapy resistance phenotypes that present major hurdles in the clinical treatment of this disease. Thus, PEAK1 is a novel biomarker, critical signaling hub, and new therapeutic target in PDAC.
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 4167. doi:1538-7445.AM2012-4167
Abstract 4170: Mutation and chemosensitivity profiling of 18 human melanoma cell lines
Authors: Kelter Gerhard , Krumbach Rebekka , Maier Armin , Giesemann Torsten , Vuaroqueaux Vincent , Foucault Frédéric , Metz Thomas , Fiebig Heinz-Herbert 
Published: August 2012

Abstract
Malignant melanomas account for a substantial proportion of cancers worldwide and are largely resistant to conventional therapy. The heterogeneity and the invasiveness of melanomas present notable challenges for anti-cancer treatment. Recently, several mutations in RAF, RAS, and PTEN were identified that allow for prognosis of cancer development and progression. Therefore, inhibitors of the RAF-MEK-ERK pathway form attractive candidates for molecular-based targeted treatment of melanoma cancer. Here, we present the molecular characterization and chemosensitivity profiling of 18 human melanoma cell lines. Eight of these were established by Oncotest from human tumor xenografts originally derived from primary patient material. The molecular profiling included mutational analysis for BRAF, PIK3CA, KRAS, NRAS, TP53, and PTEN by sequencing. The chemosensitivity profiles were determined in vitro using a fluorescence-based cytotoxicity assay and included commonly used chemotherapeutic agents for treatment of melanoma, targeted agents (sorafenib and bortezomib) and various BRAF (PLX-4032, PLX-4720, GDC-0879) and MEK (CI-1040, PD0325901) inhibitors. The clinically relevant BRAF V600E substitution was the most prevalent mutation and was found in more than 50% of the melanoma cell lines. The chemosensitivity profiling revealed diverse patterns of selectivity and potency with mean IC50 values between 0.4 nM (vinblastine) and 8.3 µM (carboplatin). Each of the BRAF inhibitors tested was clearly more active in melanoma cell lines carrying a BRAF mutation. On average, IC50 values of BRAF inhibitors were more than 20-fold lower for the BRAF V600E mutated cell lines compared to the wild type cell lines. However, the BRAF mutated cell line MEXF 462NL was resistant towards BRAF inhibitors and it is warranted to compare its gene expression profile and mutational status with BRAF mutated cell lines responding to BRAF inhibitors. By using an ex vivo clonogenic assay, similar activity patterns for BRAF inhibitors were found, with mutated BRAF tumor xenografts showing markedly higher sensitivity. Potential synergistic activity of BRAF inhibitors with other inhibitors of the RAF-MEK-ERK pathway or with standard chemotherapeutic agents will be presented. The mutational status of selected cancer related genes, as well as responsiveness towards many cytotoxic and targeted agents was analyzed for 18 melanoma cell lines. This extensive genotypic and phenotypic characterization makes this melanoma cell line panel a valuable tool for in vitro profiling of novel compounds, in particular inhibitors of the RAF-MEK-ERK pathway.
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 4170. doi:1538-7445.AM2012-4170
Abstract 4173: IKBKE/IKKα is a prognostic marker and is required for KRAS-driven tumorigenecity in non-small cell lung cancer
Authors: Kim Donghwa , Guo Jian-Ping , Gao Jingchun , Yu Catherine , Park John , Coppola Domenico , Haura Eric , Cheng Jin Q. 
Published: August 2012

Abstract
IKBKE (IKKα) is a serine/threonine protein kinase that belongs to the IKK kinase family. Here we demonstrated that IKKα is frequently overexpressed and activated in NSCLC. Elevated protein levels of IKKα were detected in 16/30 (52.6%) cell lines and 91/176 (51.7%) primary tumors. Alterations of IKBKE are associated with overall survival but not tumor stage and grade. Enforcing expression of IKBKE decreases whereas knockdown of IKBKE increases the apoptosis induced by chemotherapeutic agents. Notably, suppression of IKBKE selectively induced cell death and inhibited tumor growth in NSCLC cell lines that depend on oncogenic K-Ras expression. Mechanistically, knockdown of IKBKE largely abrogated activating mutation of K-Ras-induced NFκB activation. These data suggest that IKBKE could be a poor prognostic marker and mediates K-Ras oncogenic function and signaling to NFκB.
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 4173. doi:1538-7445.AM2012-4173
Abstract 4175: Reactive oxygen species-dependent ERK and JNK activation is important to docasahexaenoic acid-induced cell cytotoxicity in human ovarian cancer cells
Authors: Jeong Soyeon , Jing Kaipeng , Shin Soyeon , Kim Nayeong , Oh Hye-Rim , Cho Eun-Ah , Heo Jun-Young , Park Ji-Hoon , Seo Kang-Sik , Han Jeongsu , Park Jong-Il , Park Seung-kiel , Kweon Ki-Ryang , Yoon Wan-Hee , Hwang Byung-Doo , Lim Kyu 
Published: August 2012

Abstract
Although abundant experimental evidences show that the Omega-3 polyunsaturated fatty acids (≥3-PUFAs) prevent carcinogenesis, the exact molecular mechanisms of the anti-cancer actions of α3-PUFAs in ovarian cancer remain incompletely understood. In the present study, the effectiveness of docosahexaenoic acid (DHA), a α3-PUFA, against ovarian cancer cells was investigated. We found that DHA induced cell cytotoxicity in three ovarian cancer cells including PA-1, MDAH2774 and ID8. DHA treatment inhibited the cell proliferation of PA-1 cells in a dose- and time-dependent manner. Meanwhile, DHA-treated ovarian cancer cells showed increased levels of caspase-3 activity, Annexin-V staining positive cells, TUNEL-positive cells and the portion of sub-G1 cells, suggesting that DHA-induced cell death is mainly associated with apoptosis. Western blot and immunocytochemistry assays revealed that DHA also remarkably increased the levels of phospho-ERK and phospho-JNK in both cytosol and nucleus. Moreover, knockdown ERK and JNK by small interfering RNAs partially attenuated the apoptosis induced by DHA, indicating that ERK and JNK activation is responsible for the apoptosis in DHA-treated ovarian cancer cells. In addition, we determined that the activation of ERK and JNK was associated with the reactive oxygen species (ROS) production induced by DHA. ROS scavenger, N-acetyl-L-cysteine (NAC), almost completely blocked the ERK and JNK phosphorylation as well as the apoptosis triggered by DHA. Together, these results indicate that DHA induces ROS and the ROS-dependent ERK and JNK activation is important to DHA-induced cell cytotoxicity in human ovarian cancer cells. [This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (2011-0006232 and 2011-0003060)].
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 4175. doi:1538-7445.AM2012-4175
Abstract 4179: Loss of Hsulf-1 promotes chemoresistance and tumorigenecity in ovarian cancer
Authors: He Xiaoping , Khurana Ashwani , Kaufmann Scott , Shridhar Viji 
Published: August 2012

Abstract
Human Sulfatase1 enzyme (HSulf-1) is down-regulated in a majority of ovarian cancer cell lines and primary tumors, but the functional consequence of this downregulation remains unclear. Here, we show that down-regulation of HSulf-1 by RNA interference resulted in an elevated level of phosphorylated Erk and phosphorqylated Akt as well as decreased Bim level in OV202 ovarian cancer cells. Treatment with PD98059 (p-Erk inhibitor) but not LY90024 (PI3K inhibitor) resulted in increased Bim level in Hsulf-1 knockdown cells, suggesting that increased Erk pathway plays a more important role in modulating Bim level after loss of HSulf-1. Consistently, the results of real-time PCR confirmed that there was no significant change in the mRNA level of Bim after knockdown of HSulf-1 expression. When treated with CDDP, OV202 cells with knockdown of HSulf-1 displayed more resistance to drug-induced apoptosis, with IC50 value 3-fold higher than cells with non-targeting shRNA (NTC), while SKOV3 cells with overexpression of HSulf-1 were more sensitive to CDDP-induced apoptosis compared to the control cells. Moreover, HSulf-1 downregulated OV202 cells showed remarkable growth of colonies in soft agar compared to no colony growing with NTC cells. When injected subcutaneously, HSulf-1 ShRNA clones but not NTC cells formed xenogrfts in nude mice. Importantly, rescuing Bim expression in HSulf-1 shRNA cells not only endowed cells sensitivity to CDDP treatment, but also significantly decreased numbers of colony formation in soft agar and significantly retarded tumor growth in nude mice. Collectively, these results strongly suggest that down-regulation of HSulf-1 promotes chemoresistance and tumorigenicity in ovarian cancer cells through post-translational downregulation of Bim level.
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 4179. doi:1538-7445.AM2012-4179
Abstract 4180: The sterile 20-like kinase Tao-1 controls tissue growth by regulating the Hippo tumor suppressor pathway
Authors: Poon Carole LC , Lin Jane I. , Zhang Xiaomeng , Harvey Kieran F. 
Published: August 2012

Abstract
The Hippo tumour suppressor pathway is a complex signalling network that controls developmental tissue growth and is frequently deregulated in different human cancers. A key question in Hippo signalling is how the Hippo kinase (MST1/2 in mammals) is activated by upstream regulatory inputs to limit tissue growth. Using a genetic screen in Drosophila melanogaster, we identified the sterile 20-like kinase, Tao-1, as a novel Hippo pathway member that activates Hippo. Tao-1 controls various biological phenomena including microtubule dynamics, animal behaviour and brain development. Here, we describe a previously unappreciated role for Tao-1 as a regulator of epithelial tissue growth by modulating activity of the core Hippo pathway kinase cassette. Tao-1 functions together with Hippo to activate Warts-mediated repression of Yorkie. Tao-1's ability to control SWH pathway activity is evolutionarily conserved as human TAO1 can suppress activity of the Yorkie orthologue, YAP. Human TAO1 controls SWH pathway activity by phosphorylating, and activating, the Hippo orthologue, MST2. Importantly, given that Hippo pathway activity is subverted in many human cancers, our findings identify human TAO kinases (TAO1, TAO2 and TAO3) as candidate tumor suppressor genes.
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 4180. doi:1538-7445.AM2012-4180
Abstract 4181: Absence and/or functional loss of the tumor suppressor Tnk1 is associated with various human neoplasms
Authors: Hoare Kishalay , Flagg Tammy , Zamora Bernadetta M. , Reinhard Mary K. , Hoare Sarasija , May W.Stratford 
Published: August 2012

Abstract
The protein tyrosine kinase activity of Tnk1 (Thirty-eight negative kinase) is required for cell growth suppression due to the fact that the kinase-dead Tnk1 triggers aberrant cell growth, including anchorage independent growth with hyperactivation of Ras (Hoare et. al. 2003; Azoitie et.al. 2007). Mechanistically, the cell growth suppression is associated with the inhibition of Ras activity and the down-stream Raf1-MAPK growth pathway (Hoare et.al. 2003) resulting in G2-M phase cell cycle arrest. A tumor suppressor role of Tnk1 was subsequently confirmed by developing the Tnk1 knockout mouse model by homologous recombination. The TNK1 knockout mice develop many types of tumors upon aging, with B-cell lymphomas, hepatomas, hepatocellular carcinomas, lung adenomas and adenocarcinomas being the most frequent malignancies (Hoare et.al. 2008; May et. al. 2010). Significantly, 40% of Tnk1-/-mice and 26% of Tnk1+/− mice had more than one tumor type develop, likely reflecting Tnk1's broad tumor suppressor function. To confirm the tumor suppressor function of the 72 kDa Tnk1 in human tumors and cell lines, we screened for Tnk1's expression and analyzed its intrinsic/auto kinase activity and in vitro kinase activity. Results indicate that in tumors and cell lines, Tnk1 is either expressed or absent. In B-/T-lymphoma and lung adenocarcinoma cell lines, to name a few, such as Ramos, Jurkat, REH and A549, absence of Tnk1 is associated with aberrant Ras activity, suggesting that loss of Tnk1 expression may contribute to tumor development. In patient specimens and cell lines namely, K562, T47D, MCF7, NCI H82, NCI H387, HEPG2 and HUH, the expressed Tnk1 is found to lack auto-kinase activity and is therefore, inactive in vivo. This data indicates that tumor growth depends on the maintenance of Tnk1 in its inactive form through interaction(s) with scaffolding protein(s) and/or due to SNPs found in its kinase domain. Strikingly, the Hodgkin lymphoma cell line L540 is found to express a tyrosine phosphorylated 60 kDa truncated Tnk-(C17ORF61) fusion gene product (termed tTnk1) raising doubt that it is an activated form of Tnk1 (Gu et. al. 2010). Interestingly, we found that t-Tnk1 is kinase-dead, as it fails to Y-phosphorylate Grb2, a Tnk1 substrate. This supports the concept that t-Tnk1 and/or functionally inactive Tnk1 expressed in tumor cells may function in a dominant negative manner to maintain tumor growth. In conclusion, Tnk1, in human, also functions as a tumor suppressor.
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 4181. doi:1538-7445.AM2012-4181
Abstract 4187: A novel genome-wide assay identifies chromatin domains involved in stem cell behavior
Authors: Okino Steven T. , Kong Michelle , Wang Yan 
Published: August 2012

Abstract
The activity of DNA regulatory elements are often controlled by chromatin structure. Active regulatory elements are located within “open” or “accessible” chromatin. If a regulatory element is in a “closed” or “inaccessible” chromatin environment it is functionally silenced. We find that when permeabilized cells are treated with nuclease in situ, small DNA fragments, corresponding to accessible chromatin, can be readily isolated. These small DNA fragments, when analyzed by next-generation sequencing, provide a global map of active genomic regulatory domains. We used this technology to identify chromatin domains involved in stem cell behavior using NTera2 cells as a model system. By comparing differentiated and undifferentiated NTera2 cells we identified more than 500 genomic regions that are accessible only in undifferentiated cells. We then used these results, together with ENCODE data analyzing human embryonic stem cells and human cancer cells, to identify genomic regulatory regions that are active only in stem cells. Importantly, many of these regions are proximal to genes that are associated with cell “stemness” (NANOG and LIN28 are examples). In addition, several uncharacterized genes that have RNA expression characteristics similar to NANOG and LIN28 were identified. Interestingly, several stem-cell specific active regulatory domains were found adjacent to previously uncharacterized, stem-cell specific non-coding RNA transcript regions. These findings demonstrate that this approach can serve as a new discovery tool to identify chromatin regions that control stem cell behavior. In addition, chromatin regions associated with other biological or pathological states could also be identified using this approach.
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 4187. doi:1538-7445.AM2012-4187
Abstract 4203: Analysis of the association of Notch pathway genes with ID4 and Ikaros gene expression in leukemia
Authors: Dalay Nejat , Gurbuz Orkun 
Published: August 2012

Abstract
The Notch signal pathway plays an important role in several cellular processes in a variety of tissues. In the hematopoiesis Notch expression is involved in various aspects of cellular regulation and aberrant Notch signaling components have been associated with malignant transformation. Hes1 (hairy/enhancer of split 1) gene is a Notch target gene coding for a transcriptional repressor that is necessary to maintain progenitor cell populations. HES1 can bind promoter regions of the cyclin-dependent kinase inhibitors and repress their expression. Hes-1 expression can be stimulated by growth factors The Hey family of transcriptional repressors are canonical direct targets of Notch and function as downstream effectors of Notch signaling. Expression of HES1 and HEY proteins can vary in different cell types suggesting an additional mechanism of transcription regulation. Ikaros is a member of the Kruppel transcription factor family. Expression of Ikaros down-regulates expression of the Notch target genes. Deregulation of Ikaros and Notch signalling cooperate to promote leukemogenesis, providing evidence that they function in converging pathways. The ID4 (inhibitor of differentiation 4) gene is a member of the family of ID helix-loop-helix proteins that function as dominant negative regulators of basic transcription factors. In certain cancer types downregulation of the ID4 gene has been reported resulting in low or no expression of the ID4 protein. In the current study the expression of the Hes1, Hey1, Ikaros and ID4 genes was investigated in 110 patients with acute and chronic leukemias and 32 healthy controls by real time PCR using the ΔΔCt method. Both Hes1 and Hey1 expression levels were significantly increased in the patients in all disease groups. ID4 expression was significantly decreased in % 86.4 of the patients. Expression of these genes was strongly associated. Expression of the Ikaros gene decreased only in the subgroup of patients with CML while it increased in patients with acute leukemias and CLL. Our data suggest that the Notch pathway genes Hes1 and Hey1 are activated in leukemias and may contribute to the disease development while the ID4 gene is supressed, possibly by methylation.
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 4203. doi:1538-7445.AM2012-4203
Abstract 4204: Gene expression changes of DNA repair genes in lymphocytes of breast cancer patients
Authors: Perez-Mayoral Julyann , Matta Jaime L. , Dutil Julie 
Published: August 2012

Abstract
Breast cancer is the most commonly diagnosed cancer among women in Puerto Rico. Previous studies have shown that dysregulation of DNA repair genes expression is important for carcinogenesis. However, most of the studies have focused on measuring DNA repair gene expression levels in tumor samples. Our preliminary studies had shown that women with decreased DNA repair capacity (DRC) are at increased risk of breast cancer. We hypothesized that changes in DRC levels may be partly explained by changes in gene expression of DNA repair genes. Our objective was to assess the contribution of the expression levels of 43 DNA repair and damage response genes in lymphocytes of breast cancer cases and controls of Puerto Rican origin. We measured the gene expression profile of 43 DNA repair genes in lymphocytes of 6 breast cancer cases with low DRC and 10 controls with high DRC using a custom SuperArray (SABiosciences). Of the 43 genes analyzed through the SuperArray, XPC, CETN2 and CCNH showed the largest fold-changes. To validate the results, we used a TaqMan-based gene expression assay in lymphocytes of 30 breast cancer cases and 30 controls. Our results showed that breast cancer cases had a 3.4x less XPC expression (p=0.002) and 2.2x less CCNH expression (p=0.01) than controls. Validation of the CETN2 SuperArray results is underway. In conclusion, we found that the XPC gene and CCNH were expressed less in breast cancer cases than in controls. Understanding the gene expression changes that occur prior to tumor development is an important step towards enhancing cancer prevention and detection strategies.
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 4204. doi:1538-7445.AM2012-4204