bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3085: ERα phosphorylation on Ser167 in the development of endometrial cancer
Authors: Gonzalez Sandra Herrero , Cristofano Antonio Di 
Published: August 2012

Abstract
Endometrial carcinoma (EC) is the most common malignancy of the female genital tract. Type I (endometrioid) EC is associated with elevated estrogen signaling. One of the earliest genetic events in human type I EC is loss of the tumor suppressor gene PTEN. Loss of PTEN allows unrestrained activation of the AKT kinase, which, in turn, regulates such key processes as proliferation, survival, cell size, and mRNA translation. We have previously shown, using a Pten+/− mouse model, that the neoplastic lesions develop even in the absence of estrogen, suggesting that there might exist a functional and physiological link between loss of Pten and hormone-independent increased estrogen receptor activity. Previous studies have suggested that AKT can phosphorylate and activate estrogen receptor alpha (ERα) at Ser167, promoting the activation of this nuclear receptor both in vivo and in vitro, even in the absence of ligand. In order to define in vivo the role of ERα phosphorylation on Ser167 in normal endometrial physiology and during neoplastic transformation, we have designed a knock-in approach to introduce the S167A mutation in the mouse germline (ERαA/A). These mice are viable and fertile. We bred ERαA/A mice to Pten+/− mice to test whether ERα phosphorylation on Ser167 is required for the development of endometrial hyperplasia and carcinoma. We found that, at the age of 6 months, the uterus weight of ERαA/A/Pten+/− mice was significantly reduced compared to that of Pten+/− mice. To elucidate whether inhibition of ERα phosphorylation on Ser167 affects cell cycle progression, we analyzed BrdU incorporation in primary cultures of control and ERαA/A endometrial epithelial cells, and found that impairment of ERα phosphorylation on Ser167 leads to a significant reduction of the number of actively proliferating cells. In order to understand the molecular mechanisms responsible for this cell cycle impairment, we analyzed by real-time PCR the expression levels of cell cycle-related genes in the uterus of control and ERαA/A mice. Surprisingly, our results indicate that many genes related with the G2/M phase of the cell cycle, like Ccna2 or Ccnb1, and spindle formation, like Plk1 or Tpx2, are deregulated in ERαA/A uteri, compared to wild-type controls. In conclusion, our results indicate that ERα phosphorylation on Ser167 is an obligatory pathway for the development of endometrial lesions consequent to loss of Pten in endometrial cancer, at least in part by affecting the expression of cell cycle 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 3085. doi:1538-7445.AM2012-3085
Abstract 3087: CD24 regulates tumor cell behaviour in a c-Src dependent fashion
Authors: Bretz Niko P. , Schlange Thomas , Salnikov Alexei V. , Noske Aurelia , Perne Claudia , Moldenhauer Gerhard , Kristiansen Glen , Altevogt Peter 
Published: August 2012

Abstract
CD24 is a glycosyl phosphatidylinositol (GPI)-anchored membrane protein that is frequently over-expressed in a variety of human carcinomas and is correlated with poor prognosis. In cancer cell lines, changes of CD24 expression can alter several cellular properties like invasion, proliferation and adhesion in vitro and tumor growth in vivo. However, little is known about the mechanisms by which CD24 mediates these effects. Here we have analyzed functional consequences of CD24 knock-down or over-expression in human cancer cell lines of different tumor entities (ovarian, lung, glioma). We show that presence or absence of CD24 was crucial to regulate the amount and activity of c-Src in lipid rafts. CD24-mediated effects on tyrosine-phosphorylated c-Src had impact on regulation of target genes affecting tumor cell invasion, proliferation and apoptosis. Invasive potential of tumor cells was controlled by the expression of the tissue factor pathway inhibitor-2 (TFPI-2), a potent inhibitor of extracellular matrix degradation that can block tumor cell invasion and metastasis. Silencing of CD24 or c-Src enhanced TFPI-2 expression and diminished invasion of SKOV3ip and A549 cells into matrigelTM. Conversely, over-expression of CD24 reduced TFPI-2 expression and enhanced invasion. Furthermore, an inverse correlation between expression of CD24 and TFPI-2 was observed by immunohistochemical analysis of primary breast cancers (N = 1174). TFPI-2 expression was highest in CD24 negative samples and lowered with increasing CD24 expression. Patients with a CD24 low/TFPI-2 high phenotype showed significantly better survival compared to CD24 high/TFPI-2 low patients (p=0.001). Additionally, STAT3 expression and phosphorylation were reduced by CD24 silencing. Diminished STAT3 activity was confirmed by specific reporter assays. Src depletion abrogated levels of p-STAT3 (Y705). In line with that, expression of classical STAT3 target genes like MCL-1, Cyclin D1 and Survivin was reduced after CD24 knock-down. Suppressed cell proliferation and enhanced apoptosis were observed in CD24 knock-down cells, suggesting a pivotal role of regulated target genes. An antibody to CD24 was effective in reducing tumor growth of lung- and pancreatic cancer xenografts in mice. Antibody treatment affected the level of Src-activity in the tumor and altered expression of STAT3 target genes. Our results provide evidence that CD24 regulates TFPI-2 and STAT3 activity via the c-Src non receptor tyrosin kinase. Targeting of CD24 by antibodies could represent a novel strategy for anti tumor therapy.
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 3087. doi:1538-7445.AM2012-3087
Abstract 3091: A sumoylation-dependent transcriptional subprogram is required for Myc-driven tumorigenesis
Authors: Kessler Jessica D. , Kahle Kristopher T. , Sun Tingting , Meerbrey Kristen L. , Schlabach Michael R. , Schmitt Earlene M. , Skinner Samuel O. , Xu Qikai , Li Mamie Z. , Hartman Zachary C. , Rao Mitchell , Yu Peng , Dominguez-Vidana Rocio , Liang Anthony C. , Solimini Nicole L. , Bernardi Ronald J. , Yu Bing , Hsu Tiffany , Golding Ido , Luo Ji , Osborne C. Kent , Creighton Chad , Hilsenbeck Susan G. , Schiff Rachel , Shaw Chad A. , Elledge Stephen J. , Westbrook Thomas F. 
Published: August 2012

Abstract
Myc is an oncogenic transcription factor frequently dysregulated in human malignancies. While the transcriptional programs and other functions of Myc have been intensively studied, there remains no effective strategy for inhibiting Myc in patients. To search for pathways that support the Myc oncogenic program, we employed a next-generation RNAi screen for Myc-synthetic lethal (MySL) genes. Using this strategy, we have identified several cellular processes required to tolerate oncogenic Myc. Key among these is the core sumoylation machinery, and we define the Sumo-activating enzyme (SAE) as a central component in this MySL network. Loss of SAE drives synthetic lethality with Myc, and the enzymatic activity of SAE is required to support the Myc oncogenic state. Inactivation of SAE leads to mitotic catastrophe and cell death selectively upon Myc hyper-activation. Mechanistically, depletion of SAE switches a subprogram of Myc transcriptional targets governing mitotic spindle function from activated to repressed, a subprogram we term Sumoylation-dependent Myc Switchers, or SMS genes. Notably, SMS genes are required to tolerate Myc hyper-activation, and SAE and the SMS program are required for Myc-dependent breast cancer cell survival in vitro and tumor growth and progression in vivo. Importantly, patient survival significantly correlates with levels of SAE and SMS gene expression in Myc-high tumors. Collectively, these studies reveal a mitotic vulnerability of Myc-driven cancers and demonstrate that inhibiting sumoylation can selectively impair mitosis and survival in an oncogenic Myc-dependent manner. We propose that drugs targeting SAE and its downstream SMS targets may have therapeutic benefits for patients with Myc-driven cancer.
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 3091. doi:1538-7445.AM2012-3091
Abstract 3093: Elucidation of c-KIT- dependent signaling to MITF
Authors: Phung Bengt , Sun Jianmin , Schepsky Alexander , Steingrimsson Eirikur , Rönnstrand Lars 
Published: August 2012

Abstract
MITF, the master regulator of melanocytes, is a basic basic- helix- loop-helix- leucine zipper transcription factor that is essential for the development of melanocytes. MITF is also a lineage- survival oncogene in melanoma and recently, it has been shown that germline mutations in MITF predispose to this malignant disease. In melanoma, MITF has been proposed to act as a rheostat where high levels of MITF contribute to a proliferative phenotype whereas low levels result in a more invasive phenotype. The biological output generated by high or low levels of MITF is well characterized. However, how the activity of MITF is regulated to mediate these effects is less well known. It has been proposed that MITF is phosphorylated upon ligand induced activation of the receptor tyrosine kinase c- KIT. C-KIT engages the MAP kinase signaling cascade where ERK2 directly phosphorylates Ser73 of MITF and P90RSK phosphorylates the Ser409 residue of MITF. As a consequence, MITF activity increases and the protein is subjected to ubiquitin dependent degradation.Here, we show for the first time that c-KIT induces phosphorylation of MITF through the survival PI3 kinase- AKT pathway, the P38 stress pathway as well as the well-known MAP kinase-ERK signaling pathway. In addition, we show that the SRC kinase upstream of ERK is essential for c-KIT induced MITF activation. Moreover, we used several c-KIT phosphorylation site mutants to map the specific sites that are involved in the mediating transcription activation potential of MITF. These mutants also show less effects on MITF-mediated proliferation.We have generated phosphorylation specific antibodies against Ser73 and Ser409 of MITF and characterized the phosphorylation pattern of MITF using these reagents. Our results suggest that there is a particular relationship between Ser73 and Ser409 with subsequent effects on function. Based on our findings, we propose that phosphorylation of MITF might act as negative feedback mechanism that keeps MITF activity in check. Our model challenges the current knowledge of MITF modulation and provides insights that may have a profound impact on our understanding of the role of MITF in melanocyte and melanoma biology.
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 3093. doi:1538-7445.AM2012-3093
Abstract 3098: ERCC1 gene copy number variations in resected non-small cell lung cancer
Authors: Friboulet Luc , Olaussen Ken A. , Valent Alexander , Tang Ximing , Tang Tao , Li Yuanyuan , Behrens Carmen , Vielh Philippe , Robin Angélique , Goubar Aïcha , Validire Pierre , Wistuba Ignacio , Soria Jean-Charles 
Published: August 2012

Abstract
Introduction: ERCC1 allows removal of branched DNA structures at essential steps in DNA repair pathways such as Nucleotide Excision Repair (NER), Fanconia-dependent Interstrand Cross-Link Repair (ICL-R), long-patch base excision repair (BER), and Single Strand Annealing (SSA). ERCC1 expression is a prognostic and predictive biomarker of chemotherapy effect in NSCLC. The most frequent method to determine ERCC1 status is the evaluation of gene expression (IHC or RT-PCR). Here, we studied the prevalence of ERCC1 copy number variation (CNV) using FISH. Methods: FISH was performed with Poseidon™ dual color probe set, ERCC1 (19q13) and ZNF443 (19p13) on a panel of 17 NSCLC cell lines and 324 FFPE tumor samples from resected NSCLC patients (103 from IGR, Villejuif, France, 221 from MDACC, Houston, USA). Gene amplification (GA) and high polysomy (HP) were defined following actual consensus rules for EGFR assessment. Results: ERCC1 copy number was increased (&gt;2) in a large majority of cell lines (13/17) of which three displayed gene amplification (GA) (H2342, CN=5; H1299, CN&gt;12; HOP62, CN&gt;15). In human samples, overall ERCC1 gene abnormalities were detected in 65 cases (20.1%) including 31 GA (6.9%, the majority with clusters) and 34 HP (13.7%, more frequent in squamous cell carcinomas). In patients with ERCC1 expression status available (immunohistochemistry) we found a non-significant trend for higher ERCC1 expression in HP patients compared to GA and low CNV patients (P=0.06). Despite a 3-fold increase in IC50 of cisplatin in cell lines with ERCC1 gene amplification compared to normal cells (with no CNV) the ERCC1 FISH status seemed unable to predict chemosensitivity in resected NSCLC patients. In patients not treated with chemotherapy, DFS was significantly longer in patients with normal ERCC1 FISH status of the tumor compared to patients with ERCC1 gene amplification (P=0.02). Conclusion: ERCC1 copy number variation is a frequent event in NSCLC and could reflect genomic instability, but the clinical relevance of this observation needs further investigation.
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 3098. doi:1538-7445.AM2012-3098
Abstract 31: Activated phosphatidylinositol-3 kinase: An oncogene that increases gap junctional, intercellular communication
Authors: Geletu Mulu , Greer Samantha , Raptis Leda 
Published: August 2012

Abstract
Gap junctions are channels that connect the cytoplasm of adjacent cells. Gap junctional, intercellular communication (GJIC) is blocked in cells transformed by oncogenes such as the middle Tumor antigen of polyoma virus (mT), an oncoprotein which associates with and is tyrosine-phosphorylated by cSrc family members. Specific phosphotyrosines provide docking sites for the phosphotyrosine binding domain of Shc (mT-tyr250) and the SH2 domain of the phosphatidylinositol 3-kinase (mT-tyr315), resulting in the activation of their downstream signaling cascades, Ras/Raf/Erk and PI-3 kinase/Akt, respectively. To examine the effect of these mT-initiated pathways upon gap junctional communication and neoplasia, GJIC was assessed in mT-mutant-expressing, rat liver epithelial T51B cells which normally have extensive GJIC, using a novel technique of in situ electroporation we developed. The results show that although low levels of wt-mT are sufficient to interrupt gap junctional communication, GJIC suppression still requires an intact tyr250 site, that is activation of the Ras pathway. In sharp contrast, activation of the PI-3 kinase pathway is not required for GJIC suppression. It is remarkable that T51B cells expressing a mutant deficient in binding of Shc, hence activation of the Ras pathway, are still morphologically transformed and do grow into tumors in syngeneic rats, albeit with an altered morphology. These results indicate that GJIC suppression requires Ras but not PI-3 kinase/Akt signalling, and is independent of full neoplastic conversion in rat liver epithelial cells. Since PI3k activation by mT increases GJIC, we examined whether PI3k might have a positive role upon GJIC. The results showed that PI3k pharmacological inhibition eliminates GJIC, concomitant with apoptosis induction. We next expressed a form of PI3k rendered constitutively active through the addition of a myristylation signal (myr-PI3k). The results demonstrated that myr-PI3k causes an increase in GJIC. Therefore PI3k, although in an activated form it can act as an oncogene, it plays a positive role upon gap junctional, intercellular communication.
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 31. doi:1538-7445.AM2012-31
Abstract 310: Oncogene-specific regulation of immune responses during tumorigenesis
Authors: Juric Vladislava , Wang Chunmei , Chen Xin , Bishop J. Michael 
Published: August 2012

Abstract
Oncogenes can induce inflammatory signaling, leading to the recruitment of immune cells to tumor site. Immune cells can further influence tumor development by either restraining or facilitating tumorigenesis. Here, we investigated how distinct oncogenes shape the immune responses during tumorigenesis in vivo. We utilized several established mouse models of liver cancer in which tumorigenesis is driven by the overexpression of MYC, MET, or AKT+RAS oncogenes. We evaluated the immune cells at early vs. late stages of tumor development by immunohistochemical staining of liver tissues using lineage-specific immune cell markers. In addition, we assessed activation of the pro-inflammatory NFκB pathway by immunoblot detection of IkBα and phospho-Ser(536)-NFκB levels in liver lysates, as well as by immunohistochemical analysis of NFκB (p65) nuclear localization. Histological analysis revealed leukocytic clustering around hepatocytes in pre-neoplastic livers in MYC and AKT+RAS, but not in the MET liver tumor model. Moreover, the leukocyte profiles identified in pre-neoplastic livers and liver tumors were different in MYC vs. AKT+RAS model. Finally, we found that the NFκB pathway was inactive in MYC and AKT+RAS tumors, but hyperactivated in MET tumors. In summary, our results suggest that the type of tumor-initiating oncogenic lesion profoundly influences the identity of recruited immune cells and activation of NFκB pathway in the course of tumorigenesis. We are currently in the process of elucidating the mechanisms behind oncogene-mediated regulation of immune responses, which may reveal novel targets for anti-cancer therapy.
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 310. doi:1538-7445.AM2012-310
Abstract 3100: Identifying novel chromosomal fusions out of RNAseq data from oropharyngeal cancers
Authors: Wang Vivian W. , Laborde Rebecca R. , Asmann Yan W. , Li Yang , Ma Jian , Eckloff Bruce W. , Tombers Nicole M. , Olsen Steven M. , Moore Eric J. , Olsen Kerry D. , Smith David I. 
Published: August 2012

Abstract
Chromosome rearrangements that result in gene fusions have important roles in the initial steps of tumorigenesis especially in leukemias and lymphomas, but the biological and clinical impact of gene fusions in the common solid tumor has been less appreciated. We previously generated RNAseq data from 12 oropharyngeal tumors along with matched normal tissue from the same patients. We utilized and compared two bioinformatic pipelines, SnowShoes-FTD and FusionHunter to identify two novel fusion events involving of MGST3-ZMAT5 and MS4A7-DKFZp586P0123. These fusions were validated utilizing. Reverse transcriptase polymerase chain reaction (RT-PCR) and Sanger sequencing validated. In the first translocation the 5′ UTR of MGST3 was fused with exon 1 of ZMAT5, and in the second translocation the exon 2 of MS4A7 was fused with 3′ UTR of DKFZp586P0123. These precise fusions were not present in the matched normal tissue, however, they were only found in the single tumor in which they were identified. Given a growing and powerful set of high-throughput massively parallel sequencing technologies, the future for genome-wide analysis of chromosome rearrangement appears open in many directions. Ultimately, we hope that this integrative methodology will elucidate key aspects of tumor biology as well as generate novel targets for cancer diagnostics and therapy.
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 3100. doi:1538-7445.AM2012-3100
Abstract 3103: Differences in the DDR enzymes activation kinetics between normal and cancer cells could be utilized to achieve targeted cellular sensitivity towards genotoxic agents
Authors: Khalil Hilal S. , Tummala Hemanth , Hupp Tedd , Zhelev Nikolai 
Published: August 2012

Abstract
The DNA damage response (DDR) pathway is a complex signalling network that is activated when eukaryotic cells undergo DNA damage caused by exposure to genotoxic agents. Depending upon the type and scale of DNA damage, the DDR can either cause cell cycle arrest if the DNA lesions are repairable, or trigger apoptosis if the DNA lesions are beyond the repair capacity of the cell. A variety of enzymes take part in this complex signalling network that decides cellular fate after DNA damage, and is comprised of kinases, phosphatases and glycosylases. Here we explored the kinetics of activation of these key enzymes, the rates of their product formation and the interplay between them that impact the decision making process of the cell. We exposed normal (MCF10A, HaCat) and breast cancer cell lines (MCF7, MDA MB231, MDA MB468) to different combinations of radiomimetic drugs, UV radiation and enzyme inhibitors in a time and dose dependent manner and looked at the resulting enzyme activation rates of DDR kinases such as ATM, ATR, Chk1, Chk2, and DDR phosphatases PP2A and WIP1. We studied the effects of such enzymatic activation on their substrates P53, E2F1, BRCA1 and γ-H2AX and examined its outcome on cell survival. Firstly, we have identified key differences in enzyme activation kinetics that impacted the cell fate decision between normal and cancer cell lines. In addition we established treatment regimes based on those differences that bias the cell fate decision towards apoptosis in cancer cells and cell cycle arrest and repair of DNA in their normal counterparts. Thus, we have demonstrated a link between the rate of induction of different enzyme activities in the DDR pathway, the resulting product formation and cellular sensitivity to genotoxic agents. We have successfully used such information to devise a combinatorial drug treatment regime that is selective for cancer cells. Elucidation of the enzyme activation kinetics in a time and dose dependent manner of the proteins governing cell fate decision can be used to achieve targeted cellular selectivity and sensitivity with lesser side effects on normal cells.
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 3103. doi:1538-7445.AM2012-3103