bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2938: Polo-like kinase 1: a potential therapeutic target for the management of patients with triple negative breast cancer
Authors: Maire Virginie , Némati Fariba , Marty-Prouvost Bérengère , Dumont Aurélie , Richardson Marion , Vincent-Salomon Anne , Lang Guillaume , Tesson Bruno , Rigaill Guillem , Barillot Emmanuel , Marangoni Elisabetta , Decaudin Didier , Roman-Roman Sergio , Pierré Alain , Cruzalegui Francisco , Depil Stéphane , Tucker Gordon C. , Dubois Thierry 
Published: August 2012

Abstract
Breast cancers are composed of molecularly distinct subtypes with different clinical outcomes and responses to therapy. Our aim is to discover potential therapeutic targets for triple negative breast cancer (TNBC), a poor prognosis subgroup with no targeted therapy available yet. Gene expression profiling on a cohort of 160 breast cancers including 40 TNBC revealed that the polo-like kinase 1 (PLK1), a protein kinase, is specifically over-expressed in TNBC compared to the other breast cancer subtypes. High PLK1 expression was confirmed at a proteomic level by reverse phase protein array and tissue microarray. In TNBC cell lines grown as monolayers, RNAi-mediated PLK1 depletion or small compound (BI-2536)-mediated PLK1 inhibition induced an increase in phosphorylated H2AX, G2/M arrest and apoptosis, resulting in a decrease in cell viability. In addition, a soft-agar colony assay showed that PLK1 silencing impaired tumorigenicity of TNBC cell lines. With cells grown in extracellular matrix gels (Matrigel), BI-2536 induced apoptosis specifically in TNBC cancerous versus “normal” cell lines. The in vivo anti-tumor effect of BI-2536 was investigated in two TNBC xenografts derived from patient's biopsies. When administrated as a single agent, the PLK1 inhibitor significantly impaired the tumor growth. Most importantly, administration of BI-2536 in combination with adriamycin + cyclophosphamide chemotherapy led to 100% complete response (9/9 mice). Altogether, our observations point out that PLK1 may represent an attractive therapeutic target, in association with conventional chemotherapy, for the management of patients with TNBC.
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 2938. doi:1538-7445.AM2012-2938
Abstract 2953: Anticipating new biochemical mechanisms of resistance to Raf inhibition in Melanoma
Authors: Antony Rajee , Emery Caroline , Garraway Levi A. 
Published: August 2012

Abstract
More than 50% of melanoma's harbor the V600E activating mutation in BRAF, which constitutively activates the Mek/Erk signaling cascade leading to tumor cell proliferation. The BRAF(V600E) mutation predicts responsiveness to RAF inhibitors, which led to FDA approval of the RAF inhibitor vemurafenib (PLX4032) in 2011. Although several mechanisms of resistance to RAF inhibition have been described, no resistance-associated point mutations involving the RAF genes themselves have been detected in the clinical setting thus far. This is in contrast to well described resistance mechanisms to receptor tyrosine kinase inhibitors, which frequently involve secondary mutations within the target kinase. To gain additional insights in this regard, we created randomly mutagenized cDNA library of BRAF (V600E) and it's homolog C-RAF and expressed individually in A375(V600E B-RAF) cells in the presence of PLX4720, an analogue of PLX4032. The resistance clones emerged from the screen were characterized by massive parallel sequencing and the mutant alleles were further recreated via site directed mutageneis in the respective cDNA's. However, no candidate mutations occuring in BRAF (V600E) could be validated as bona fide resistance alleles. In contrast, we identified 11 alleles that engendered sustained Mek phosphorylation in the setting of PLX4720 exposure. Upon ectopic expression, three of these alleles conferred profound pharmacologic resistance to PLX4720. Two of these resistance alleles clustered within the 14-3-3 consensus binding site of C-RAF, and the third occurred in the kinase domain (ATP binding domain, activation segment). 14-3-3 proteins are known to stabilize and activate C-RAF through phosphorylation of key serine and tyrosine residues. Toward this end, some C-RAF resistance alleles promoted increased BRAF heterodimerization and increased kinase activity. Each of these alleles remained sensitive to the Mek inhibitor AZD6244. On the basis of these findings, we speculate that mutations in C-RAF that alter 14-3-3 binding, promoted dimerization, and/or enhance intrinsic kinase activity may conceivably mediate resistance to RAF inhibition - particularly as more potent inhibitors become utilized. Ongoing work involves investigating the clinical relevance of this phenomenon.
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 2953. doi:1538-7445.AM2012-2953
Abstract 2955: c-Myc suppresses DNA double-strand break repair
Authors: Li Zhaozhong , Owonikoko Taofeek K. , Sun Shi-Yong , Xiao Zhi-Qiang , Doetsch Paul W. , Khuri Fadlo R. , Curran Walter J. , Deng Xingming 
Published: August 2012

Abstract
c-Myc is a potent oncogenic molecule that promotes tumorigenesis through the induction of genomic instability. The exact mechanism(s) involved remains to be elucidated. Here we discovered that α-ray ionizing radiation (IR)-induced double-strand DNA breaks (DSBs) promote c-Myc to form foci and to co-localize with γ-H2AX. Conditional expression of c-Myc in HO15.19 c-Myc-null cells using the Tet-Off/Tet-On inducible expression system results in downregulation of Ku DNA binding and suppressed activities of DNA-PKcs and DNA end-joining, leading to inhibition of DSB repair and enhanced chromosomal and chromatid breaks. Expression of c-Myc reduces both signal and coding joins with decreased fidelity during V(D)J recombination. Mechanistically, c-Myc directly interacts with Ku 70 protein at the N-terminus via its MBII domain. Removal of the MBII domain from c-Myc abrogates its inhibitory effects on Ku DNA binding, DNA-PKcs and DNA end-joining activities, which results in loss of c-Myc's ability to block DSB repair and V(D)J recombination. Interestingly, c-Myc directly disrupts the Ku/DNA-PKcs complex in vitro and in vivo. Thus, c-Myc suppression of DSB repair and V(D)J recombination may occur through inhibition of the non-homologous end-joining pathway, which leads to increased DNA damage, genetic instability and carcinogenesis.
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 2955. doi:1538-7445.AM2012-2955
Abstract 2958: The novel protein kinase STK17A is a direct p53 target gene that mediates response to genotoxic and nutritional stress in a cancer cell context-dependent manner
Authors: Mao Pingping , Jardine Mary , Niemaszyk Lynn , Haghkerdar Jessica , Yang Eric , yanco Esty G. , Desai Damayanti , Beyrouthy Maroun , Kerley-Hamilton Joanna S. , Freemantle Sarah J. , Spinella Michael J. 
Published: August 2012

Abstract
STK17A (DRAK1) is a largely uncharacterized serine/threonine kinase that belongs to the death-associated protein kinase family. Prior microarray studies demonstrated that STK17A is induced with cisplatin in testicular cancer-derived human embryonal carcinoma (EC) cells. We now demonstrate the STK17A in a novel p53 target gene that is induced by a variety of DNA damaging agents in a p53-dependent manner in a number of different cell contexts. A consensus and functional p53 response element was found upstream of the STK17A promoter and endogenous p53 was shown to bind to this site in a cisplatin-dependent manner. Knockdown of STK17A conferred resistance to cisplatin-induced growth suppression and apoptotic cell death in EC cells. This was associated with up-regulation of detoxifying and antioxidant genes and reduction in reactive oxygen species (ROS), whereas overexpression of STK17A increased ROS levels in EC cells. Interestingly, we found that STK17A is highly overexpressed in clinical glioblastoma (GBM) and cell lines compared to its expression in normal brain tissue and other cancers. High STK17A expression in GBM patients correlated with poor clinical outcome and decreased survival. STK17A knockdown in GBM cells decreased clonagenic cell growth, soft agar tumorigenicity, and survival in response to genotoxic and nutritional stress. Preliminary data will be presented implicating STK17A in the regulation of autophagy and the proximal autophagy component, ULK1. These findings indicate that STK17A may be added to a growing list of direct p53 target genes involved in autophagy that includes TIGAR, Sestrins, DAPK1 and DRAM and that by impacting autophagy STK17A may modulate response to genotoxic and nutritional stress in a cell context-depend manner. This study also suggests that STK17A is a potential novel prognostic maker and therapeutic target for GBM.
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 2958. doi:1538-7445.AM2012-2958
Abstract 2967: CCL3 autocrine signaling regulate retention of metastasis associated macrophages and promote breast cancer metastasis
Authors: Qian Bin-Zhi , Kitamura Takanori , Pollard Jeffrey W. 
Published: August 2012

Abstract
Macrophages abundantly found in the tumor microenvironment enhance malignancy. At metastatic sites a distinct population of metastasis associated macrophages (MAMs) promotes tumor cell extravasation, seeding and persistent growth. These macrophages are derived from circulating inflammatory monocytes recruited by CCL2/CCR2 chemokine signaling. Our current study identified a distinct gene expression signature of the MAMs in comparison with resident macrophages in lung and spleen. Majority of these genes encodes cell surface proteins and secreted factors which mediate MAM's interaction with the metastatic microenvironment. Interestingly, we identified another chemokine, CCL3, is highly expressed by MAMs in a CCL2/CCR2 dependent manner. This indicates that CCL2 not only regulate MAM recruitment but also its function. RNA interference mediated CCL3 knockdown significantly reduced their potential in promoting tumor cell extravasation in vitro. Anti-CCL3 antibody and genetic ablation of CCL3 significantly reduced tumor cell metastatic potential in vivo. Importantly, MAM also express high level of CCR1 and CCR5, receptors for CCL3, upon differentiation. Anti-CCL3 inhibitory antibody significantly reduced MAM retention in pulmonary metastasis. Together, our data indicates an autocrine signaling via CCL3 regulated by CCL2/CCR2 controls MAM retention and promote breast tumor lung metastasis which identified a novel therapeutic target for treating metastatic breast disease.
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 2967. doi:1538-7445.AM2012-2967
Abstract 2985: Predicting the impact of mutations in cancer using an integrated pathway approach
Authors: Ng Sam , Thusberg Janita , Benz Stephen , Vaske Charles , Ellrott Kyle , Zhu Jing , Yau Christina , Collisson Eric , Mooney Sean , Benz Christopher , Haussler David , Stuart Joshua 
Published: August 2012

Abstract
The major mechanism by which cancer arises is through somatic mutations. These mutations can lead to alterations in gene regulation as well as changes in protein structure and function. Individual tumors can contain hundreds to thousands of mutations. It is critical to distinguish mutations that have an important role defining the cancer - driver mutations - from mutations that are unimportant to the tumor - passenger mutations. Differentiating driver and passenger events is essential for understanding cancer disease mechanisms, which can help guide treatment decisions as well as identify novel targets for treatment. Genomic probing with technologies such as expression arrays and high-throughput RNA sequencing provide insight into changes in gene regulation in cancer, but determining the tumorigenic role of a coding mutation is less clear. Genomic data coupled with pathway information may provide insight into the functional impact of a mutation to particular genes. We are developing a mutation prediction method based on integrated pathway analysis to discriminate loss-of-function, neutral, and gain-of-function mutations. Utilizing the set of regulatory interactions annotated for a given gene, we can detect a discrepancy in the downstream effects of an altered gene compared to what is expected from its upstream influences. We show that a score based on this discrepancy is highly predictive of the presence of a mutation and that the directionality of this discrepancy also reflects the gain- or loss-of-function in a gene. Application of our method to a set of known driver mutations reveals that there is a significantly strong signal for loss- and gain- of functional mutations in the surrounding network, demonstrating the sensitivity of this approach. In addition, when applied to the negative control of passenger mutations, the method predicts little pathway impact, indicating this approach also has high specificity. Application of this approach to all recurrent mutations in ovarian and glioblastoma multiforme cancers from the TCGA project identifies several important driver mutations across these cohorts. We also highlight the novel utility of this specific approach by comparison to earlier published approaches including MutSig, CHASM, and MutPred.
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 2985. doi:1538-7445.AM2012-2985
Abstract 2999: Gene expression signature of differential response to chemotherapy in sporadic pediatric osteosarcoma
Authors: Martin Jeff W. , Koti Madhuri , Chilton-MacNeill Susan , van Wijnen Andre J. , Squire Jeremy A. , Zielenska Maria 
Published: August 2012

Abstract
Osteosarcoma is the most common pediatric bone malignancy. Genomic instability, karyotypic heterogeneity and dysregulated gene expression are typical of osteosarcoma tumors, for which treatment is often multimodal and aggressive. Tumor necrosis in response to neoadjuvant chemotherapy is used to estimate outcome and survival, because reliable clinical diagnostic and prognostic biomarkers have not yet been described for this tumor. Our objective in the current study was to identify new molecular biomarkers for osteosarcoma based on differential mRNA expression levels of genes found to be consistently involved in the pathogenesis of osteosarcoma. The NanoString nCounter System utilizes color-coded probe pairs, which allow multiplexed expression analysis of specific genes in solution-phase hybridization with digital output. Advantages of the system are a higher sensitivity than microarrays and the utilization of small amounts of total RNA without requiring cDNA synthesis. We first determined the efficacy and consistency of the system using total RNA extracted from snap-frozen and formalin-fixed, paraffin-embedded osteosarcoma tissue specimens. We then verified that the NanoString assay was consistent with RT-PCR analysis of our samples, after which we subjected a cohort of osteosarcoma tumors to the expression assay. Seventeen genes, including many with well-described functions in osteosarcoma, were analyzed for expression in a cohort of tumors as well as normal human osteoblasts. Expression values of normal human osteoblasts were compared with those of tumors with more than 90% necrosis post-chemotherapy (an indicator of good prognosis) and of tumors with less than 90% necrosis post-chemotherapy (an indicator of poor prognosis). Of note, we found that tumors with poor response to chemotherapy had statistically significant up-regulation of CDKN1C, FOS, and RUNX2. The RUNX2 gene is located at chromosome 6p21.1, which frequently undergoes genetic amplification in osteosarcoma. Amplification-related overexpression of RUNX2 has been previously reported (Martin et al 2010, Sadikovic et al 2010) as a poor prognosticator for chemotherapy response, and the involvement of bone morphogenetic pathways downstream of RUNX2 are being addressed by multiplex analyses of differential gene 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 2999. doi:1538-7445.AM2012-2999
Abstract 3009: Alternative pre-mRNA splicing in digestive tract malignancy
Authors: Miura Koh , Ohnuma Shinobu , Fujibuchi Wataru , Ishida Kazuyuki , Sasaki Iwao 
Published: August 2012

Abstract
Alternative pre-mRNA splicing plays an important role in the generation of functional diversity of genome. The process of pre-mRNA splicing is regulated by cis- and trans-elements, and their deregulations result in aberrantly-spliced individual variants and aberrant expression profiles. Accumulating evidence has revealed that aberrant splicing contributes to a number of diseases including human neoplasms. Germ line mutations in cis-element of tumor suppressor genes such as MMR genes, APC gene, and CDH1 gene are involved in Lynch syndrome, familial adenomatous polyposis, and hereditary diffuse gastric cancer, respectively. In addition, somatic mutations in cis-elements also play a role in tumorigenesis. These genetic alterations including nonsense, missense, or silent mutations in cis-elements, led to aberrant transcripts by exon skipping, retention of the intron, or introduction of new splice site (Miura et al., Cancer Science 2011 Feb;102(2):309-16). We present our results and current knowledge of the regulatory mechanism underlying alternative pre-mRNA splicing and aberrant splicing, particularly focusing on digestive tract malignancies.
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 3009. doi:1538-7445.AM2012-3009
Abstract 301: Ccl17 and Ccr4 co-localize in mouse lung adenomas in vivo and are associated with epithelial cell migration in vitro
Authors: Stein Lauren , Tichelaar Jay W. 
Published: August 2012

Abstract
Lung cancer is the leading cause of cancer deaths among men and women in the United States and improved treatments are urgently needed. Like many cancers, long-term inflammation is now recognized to be a contributing factor in the progression of lung cancer from a benign to a malignant state. Exactly how inflammation contributes to lung cancer is incompletely understood. Chemokines are a group of proteins that function by attracting immune cells to areas of higher chemokine concentrations. Specific chemokine-chemokine receptor pairs control the migratory response of many inflammatory cell types. It is known that chemokines and chemokine receptors can also have direct effects on cancer cells. Using in situ hybridization, we determined that the chemokine Ccl17 and its receptor Ccr4 are coordinately induced in tumor cells in transgenic and benzo(a)pyrene-induced mouse models of lung cancer. In addition, multiple subsets of T lymphocytes within mouse lung tissue express Ccr4. Immunohistochemistry localized CCR4 to cancer cells in 11 of 32 (34%) human non-small cell lung cancer biopsies while staining was not detected in 12 non-neoplastic lung biopsies. We identified human lung cancer cell lines expressing CCR4 using flow cytometry and immunofluorescence. Treatment of human NCI-H292 lung cancer cells with CCL17 peptide induced migration in a collagen-dependent manner in a transwell migration assay. The presence of Ccr4 on both lung cancer cells and lymphocytes suggests that this receptor has multiple roles in regulating lung tumor promotion and progression. Characterization of these roles may provide novel targets to inhibit lung tumor progression. Future studies will directly address the function of Ccr4 during lung tumorigenesis in vivo.
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 301. doi:1538-7445.AM2012-301
Abstract 3067: Regulation of PAX2 expression/activity by hypoxia and EGF in breast cancer cells
Authors: Lacombe Catherine , Beauchemin David , Annabi Borhane , Themsche Céline Van 
Published: August 2012

Abstract
Breast cancer is the most common cancer in women and is associated with the highest mortality rate after lung cancer. The leading cause of deaths associated with this cancer is metastasis, but cellular and molecular mechanisms controlling the metastatic ability of breast cancer cells are only partially elucidated. There is direct and indirect evidence suggesting that PAX2, a transcription factor preferentially activated in breast cancer cells of the luminal subtype, could reduce the invasive and metastatic ability of these cells, by downregulating the expression of ERBB2. It is thus primordial to understand the mechanisms regulating the expression and activity of PAX2 in breast cancer cells. Specifically, because hypoxic conditions prevailing in the center of solid primary tumours are known to regulate the expression of many genes controlling invasion and metastasis, we are investigating the impact of hypoxia-mimicking agent cobalt chloride (CoCl2) on PAX2 expression in breast cancer cells. Similarly, because EGF growth factor regulates the expression and/or activity of many genes controlling invasion and metastasis, we are determining the impact of EGF exposure on PAX2 activation and/or gene expression in ER+ MCF-7 cell line. The identification of factors and mechanisms regulating the expression and activity of PAX2 in breast cancer cells will help understand the biology of this emerging factor in breast cancer cells and may provide multiple strategies to control invasion and metastasis of these 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 3067. doi:1538-7445.AM2012-3067