bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3107: The role of LIN28 in atypical teratoid rhabdoid tumor (ATRT) pathogenesis
Authors: Phi Ji Hoon , Choi Seung Ah , Kim Yong Hwy , Kim Young-Hoon , Park Chul-Kee , Wang Kyu-Chang , Kim Seung-Ki 
Published: May 2015

Abstract
Atypical teratoid rhabdoid tumor (ATRT) is a highly malignant brain tumor developing almost exclusively in children. It belongs to the embryonal brain tumor group which consists of primitive tumors recapitulating early embryogenesis of nervous system. It is known that loss of INI protein expression is the hallmark of ATRT pathogenesis. LIN28 is a key gene in embryonic development and maintenance of pluripotency in stem cells. Considering the primitive nature and young age onset of ATRT, LIN28 may be an important co-player in ATRT pathogenesis.
We explored the expression and functional role of LIN28 in ATRT. In tumor tissues, LIN28 is highly expressed in ATRT compared with medulloblastomas, another embroynal tumor, whereas primary let-7 microRNA is down-regulated in ATRT. ATRT also showed higher expression of CCND1 and MYC and lower expression of CDKN1C. Knockdown of LIN28 with siRNA in ATRT cell lines resulted decreased cell viability, proliferation, and migration capability. Suppression of CCND1 and MYC expression and enhanced expression of CDKN1C were also observed. Knockdown of LIN28 lead to decreased expression of other pulripotency genes (OCT4 and NANOG) and signature of mesenchymal-epithelial transition was observed after suppression of LIN28. We then introduced wild-type INI1 into ATRT cells by transfection. Restoration of INI in ATRT cell lines lead to decreased expression of LIN28 and CCND1.
These results showed that LIN28 is regulated by INI1 and that loss of INI1 protein in ATRT results in unopposed expression of LIN28 and related oncogenes such as CCND1, leading to tumorigenesis. Therefore, the strategic role of LIN28 in ATRT may be utilized as an important therapeutic target.
Citation Format: Ji Hoon Phi, Seung Ah Choi, Yong Hwy Kim, Young-Hoon Kim, Chul-Kee Park, Kyu-Chang Wang, Seung-Ki Kim. The role of LIN28 in atypical teratoid rhabdoid tumor (ATRT) pathogenesis. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3107. doi:10.1158/1538-7445.AM2014-3107
Abstract 3133: The anti-tumor effects of acetazolamide and sulforaphane on bronchial carcinoids: Preclinical modeling and mechanism
Authors: Mokhtari Reza Bayat , Islam Syed S. , Baluch Narges , Aitken Karen , Kumar Sushil , Cheng Hai-Ling Margaret , Yazdanpanah Mehrdad , Adeli Khosrow , Zhou Yuanxiang , Cutz Ernest , Yeger Herman 
Published: May 2015

Abstract
Background: The prognosis of patients with metastatic bronchial carcinoid remains poor despite current conventional and targeted therapies. Here we evaluated the therapeutic potential of acetazolamide (AZ; a pan carbonic anhydrase inhibitor affecting pH regulation and homeostasis) and sulforaphane (SFN; a natural isothiocyanate compound targeting multiple pathways in cancer cells), for their anti-cancer properties. Methods: In vitro and in vivo studies were conducted on H-727 (typical carcinoid) and H-720 (atypical carcinoid) bronchial carcinoid cell lines. We developed a lung orthotopic bronchial carcinoid tumor xenograft model in NOD/SCID mice. Results: AZ and/or SFN significantly inhibited cell viability and clonogenic capacity in a dose-dependent manner (0-80 μM, 48 hours and 7 days). AZ and/or SFN downregulated phosphoH3, Ki67, EPCAM, CA9, Akt1 and upregulated p21 and Nrf2 proteins compared to controls as confirmed by Western blot. Upregulation of Nrf2 gene expression was confirmed by qPCR. AZ and/or SFN significantly reduced xenograft growth and serotonin content after two weeks treatment. In the lung orthotopic model, MR imaging at 3 Tesla precisely identified growth of H-727 injected cells in the ipsilateral side, and revealed liver metastasis as confirmed by histology. A tumor initiating cell (TIC) fraction isolated under stem cell culture conditions showing significantly enhanced tumorigenicity was also studied. Conclusions: AZ and/or SFN inhibited tumor survival, proliferation, invasiveness, serotonin secretion and tumorigenic potential of bronchial carcinoid cell lines. Since the combination of AZ+SFN was more effective than either single agent, we postulate that AZ potentiates the effects of SFN by inhibiting PI3K/AKT, which could enhance the inhibitory effect of SFN on P21, Ki67 and phosphoH3. Interestingly, Nrf2 upregulation by both AZ and by SFN suggested a potent antioxidant response. The lung orthotopic tumor model of bronchial carcinoids permits study of carcinoid metastatic progression. As the doses used in this study are clinically bioavailable we suggest that AZ and SFN may have promising potential for carcinoid therapy and resolution of the carcinoid syndrome.
Citation Format: Reza Bayat Mokhtari, Syed S. Islam, Narges Baluch, Karen Aitken, Sushil Kumar, Hai-Ling Margaret Cheng, Mehrdad Yazdanpanah, Khosrow Adeli, Yuanxiang Zhou, Ernest Cutz, Herman Yeger. The anti-tumor effects of acetazolamide and sulforaphane on bronchial carcinoids: Preclinical modeling and mechanism. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3133. doi:10.1158/1538-7445.AM2014-3133
Abstract 3138: IL-6/Stat3 signaling is an indispensable modulator of oncogene-induced cellular senescence
Authors: Pencik Jan , Schlederer Michaela , Hassler Melanie , Gruber Wolfgang , Aberger Fritz , Kennedy Richard , Walker Stephen , Rose-John Stephan , Poli Valeria , Eferl Robert , Esterbauer Harald , Aksoy Osman , Herac Merima , Mazal Peter , Haitel Andrea , Susani Martin , Moriggl Richard , Culig Zoran , Kenner Lukas 
Published: May 2015

Abstract
IL-6/Stat3 signaling plays a role as a proto-oncogene in various tumors including prostate cancer, where IL-6 has been explored as therapeutic target. Deficiency of Pten, one of the most commonly mutated genes in cancer, directly triggers a senescence program critically depending on the p19Arf-p53 fail-safe pathway. We identified a novel and unexpected tumor suppressive role of IL-6/Stat3 signaling in a Pten-deficient murine prostate cancer model. Our data provide evidence that activation of IL-6/Stat3 signaling axis is implicated in oncogene-induced senescence (OIS). Strikingly, genetic ablation of IL-6 strongly promoted prostate cancer initiation, progression and metastasis in Pten-deficient mice. Mechanistically, IL6/Stat3 signaling regulates p19Arf-p53-induced senescence by modulating expression of the ubiquitin ligase MDM2 in pre-neoplastic cells. Critically, in prostate cancer patients low expression of Stat3 or p14Arf, the human homologue of p19Arf, correlates with poor survival. Therefore, the IL-6/Stat3 signaling axis may represent a novel molecular target for senescence-based cancer therapies.
Citation Format: Jan Pencik, Michaela Schlederer, Melanie Hassler, Wolfgang Gruber, Fritz Aberger, Richard Kennedy, Stephen Walker, Stephan Rose-John, Valeria Poli, Robert Eferl, Harald Esterbauer, Osman Aksoy, Merima Herac, Peter Mazal, Andrea Haitel, Martin Susani, Richard Moriggl, Zoran Culig, Lukas Kenner. IL-6/Stat3 signaling is an indispensable modulator of oncogene-induced cellular senescence. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3138. doi:10.1158/1538-7445.AM2014-3138
Abstract 3141: Epithelial-to-mesenchymal transition and therapy resistance in BRCA1-associated breast cancer
Authors: Miltenburg Martine Van , Jonkers Jos 
Published: May 2015

Abstract
Despite progress in the treatment of breast cancer, patients with triple-negative breast cancer (TNBC) have limited means for therapy. Since TNBCs do not express HER2, estrogen and progesterone receptors, TNBC patients cannot be treated with Herceptin or endocrine therapy. TNBCs frequently harbor defects in homologous recombination (HR) due to (epi)genetic inactivation of BRCA1, making them sensitive to the clinical PARP1 inhibitor olaparib. However, long-term treatment of BRCA1-deficient mouse mammary tumors with olaparib results in drug resistance. The growing awareness that epithelial-to-mesenchymal transition (EMT) may influence therapy response prompted us to investigate whether olaparib sensitivity of BRCA1-deficient TNBCs is affected by MET, a known EMT inducer that is over-expressed in TNBC and associated with poor survival. For this purpose we have developed a breast cancer GEMM-ESC pipeline, using female GEMM-ESCs derived from our well-validated K14cre;Brca1F/F;Trp53F/F (KB1P) mouse model, of which females spontaneously develop BRCA1-deficient TNBC due to cre-mediated deletion of Brca1 and Trp53 in epithelial tissues. The MET proto-oncogene, was introduced in the Col1a1 locus and resulting KB1P-MET ESCs were injected into blastocysts and good quality chimeras were monitored for mammary tumor formation. Our preliminary data show that BRCA1-deficient mouse mammary tumors with engineered overexpression of MET show accelerated growth, undergo EMT and show intrinsic resistance to olaparib. The underlying mechanisms are, however, unclear. Currently we are studying the impact of EMT-regulators on BRCA1-associated mammary tumorigenesis and assess the contribution of EMT-regulators to olaparib resistance in genetically engineered mouse models of BRCA1-associated breast cancer. Together, these studies will provide novel insights into the roles of EMT regulators in BRCA1-associated breast tumor development, metastasis and therapy resistance.
Citation Format: Martine Van Miltenburg, Jos Jonkers. Epithelial-to-mesenchymal transition and therapy resistance in BRCA1-associated breast cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3141. doi:10.1158/1538-7445.AM2014-3141
Abstract 316: Modifying autophagy through combination treatments as a potential therapeutic strategy in head and neck squamous cell carcinoma (HNSCC)
Authors: Ahmed Omar G. , Kuo Wen-Liang , Wei Tai-Fen , Messer Jeannette S. , Sharifi Marina , Nagilla Madhavi , Macleod Kay , Cohen Ezra E.W. 
Published: May 2015

Abstract
Introduction: Autophagy, a catabolic process, can play a crucial role in cancer cell survival. Modifying this process has shown to be an effective mechanism of inducing cell death. In order to explore this concept, we induced autophagy with one agent (Akt-inhibitor MK-2206), and decreased autophagosomal trafficking with other agents (Paclitaxel and Nocadazole) by disrupting the microtubule networks. We hypothesized that by modifying autophagy through this combination, it would lead to an accumulation of autophagosomes and eventual cell death in a synergistic manner.
Methods: SCC 61 and Cal 27 HNSCC cell lines were used to explore this hypothesis. SCC 61 cells were transduced with an m-Cherry GFP LC3B vector in order to detect autophagosomes under both fixed and live cell confocal microscopy. Cell viability and apoptosis assays were performed. A siRNA ATG 7 KO SCC 61 cell line was used to detect if in fact autophagy was important for this therapeutic approach.
Results: There was an accumulation of autophagosomes with the combination of an Akt inhibitor and microtubule disrupters. A decrease in fusion of autophagosome to lysosome was seen when cells were treated with an agent, which disrupted the microtubule networks (Paclitaxel) but even more dramatically when treated with the combination (MK-2206 and Paclitaxel). Moreover, accumulation of autophagosomes occurred prior to induction of apoptosis with combination treatment. These effects were decreased with siRNA ATG 7 KO in SCC 61 cells, which were more resistant to combination treatment compared to control.
Discussion: Manipulating autophagy with Akt inhibition (induction) and Paclitaxel (decreasing autophagic trafficking) leads to an accumulation of autophagosomes and eventual cell death in a synergistic manner. This therapeutic approach of altering the normal autophagic process warrants further investigation.
Citation Format: Omar G. Ahmed, Wen-Liang Kuo, Tai-Fen Wei, Jeannette S. Messer, Marina Sharifi, Madhavi Nagilla, Kay Macleod, Ezra E.W. Cohen. Modifying autophagy through combination treatments as a potential therapeutic strategy in head and neck squamous cell carcinoma (HNSCC). [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 316. doi:10.1158/1538-7445.AM2014-316
Abstract 3161: Non-cell autonomous regulation of collective invasion be an epigenetically distinct subpopulation of tumor cells
Authors: Prechtl Amanda , Westcott Jill , Dang Tuyen , Maine Erin , Pearson Gray 
Published: May 2015

Abstract
Diverse genetic and epigenetic traits can promote variant behaviors in subpopulations of cells within primary tumors. In some cases, these heterogeneous subpopulations may compete against each other for clonal dominance to improve tumor fitness. By comparison, the extent to which tumor cell subpopulations cooperate during malignant progression is not well understood. Here, we find that a commensal relationship can exist between epigentically distinct subpopulations of tumor cells during collective invasion.
Using quantitive phenotypic analysis and live-cell imaging, we discovered that a subpopulation of cells, termed trailblazer cells, has an enhanced ability to collectively invade. Trailblazer phenotype was heritable and trailblazer subpopulations were derived from 5 triple-negative breast cancer cell lines. The percentage of trailblazers cells within a population ranged from between 0.5% and 90% of the parental population. Gene expression profiling identified a 29-gene expression signature that distinguished trailblazer cells from non-trailblazer cells and identified patients with poor outcome, A cohort of genes trailblazer signature genes were necessary for the formation of actin-rich projections that facilitate path generation during collective invasion. In addition, the trailblazer gene DOCK10 was necessary for spontaneous metastasis to the lung. The path generating function of a small subpopulation of trailblazer cells was sufficient to induce the collective invasion of large population of naturally occurring non-trailblazer cells in organotypic culture. Trailblazer cells were also sufficient to induce the invasion of a mouse model of ductal carcinoma in situ. Taken together, our results suggest that a rare subpopulation of tumor cells with an enhanced ability to collectively invade can promote metastatic progression through cell autonomous and non-cell autonomous mechanisms. Thus, our results support a paradigm shift towards identifying both the cell autonomous and the non cell-autonomous regulatory mechanisms of cell biological processes within heterogeneous tumors to understand neoplastic progression and develop new intervention modalities.
Citation Format: Amanda Prechtl, Jill Westcott, Tuyen Dang, Erin Maine, Gray Pearson. Non-cell autonomous regulation of collective invasion be an epigenetically distinct subpopulation of tumor cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3161. doi:10.1158/1538-7445.AM2014-3161
Abstract 3168: Tumor cells express genome-derived DNA in the cytosol
Authors: Shen Yu J. , Bert Nina L. , Koo Christine X. , Samantha Ho S. , Ishii Ken J. , Raulet David H. , Gasser Stephan 
Published: May 2015

Abstract
Type I interferons (IFNs) are secreted by infected cells in response to the recognition of nucleic acids. DNA damage and the ensuing DNA damage response also induce the expression of IFNs by poorly understood mechanisms. Here we show the presence of extramitochondrial single-stranded (ss) and double-stranded (ds) DNA in the cytosol of mouse and human tumor cells. The DNA only partially co-localized with autophagosomes, stress granules or lysosomes, but a majority was associated with mitochondria. Genotoxic agents increased the amount of DNA in the cytosol of tumor cells with low levels of constitutive cytosolic DNA. Cloning of ssDNA and dsDNA present in the cytosol of mouse tumor cells showed that at least some of the cytosolic DNA is derived from unique genomic loci. Cloned cytosolic DNA sequences often contained genomic retroelements. In silico analysis of the cloned DNA indicated that cytosolic DNA is predicted to form putative triplex DNA structures. Overexpression of Rnaseh1, which degrades intermolecular triplex structures called R-loops, reduced the levels of cytosolic ssDNA and dsDNA, while overexpression of Trex1, the major 3’-5’ DNA exonuclease, decreased the amount of cytosolic ssDNA but not dsDNA. Upregulation of IFNs in response to genotoxic agents was impaired in cells expressing Rnaseh1 or Trex1. In summary, we provide evidence that DNA damage in tumor cells induces the accumulation of genomic DNA in the cytosol and the production of type I IFNs in many tumor cells, which may contribute to immunosurveillance of cancers.
Citation Format: Yu J. Shen, Nina Le Bert, Christine XE Koo, Ho SW Samantha, Ken J. Ishii, David H. Raulet, Stephan Gasser. Tumor cells express genome-derived DNA in the cytosol. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3168. doi:10.1158/1538-7445.AM2014-3168
Abstract 3169: APOBEC-mediated cytosine deamination is a prominent mutagenic mechanism in human papillomavirus-driven cancer
Authors: Henderson Stephen , Chakravarthy Ankur , Su Xiaoping , Boshoff Chris , Fenton Tim R. 
Published: May 2015

Abstract
APOBEC3B cytosine deaminase activity has recently emerged as a significant mutagenic factor in human cancer. APOBEC activity is induced in virally infected cells and APOBEC signature mutations occur at high frequency in cervical cancers, over 99% of which are caused by high risk variants of Human Papillomavirus (HPV). We tested the hypothesis that APOBEC-mediated mutagenesis plays a particularly important role in HPV-associated cancer by analysing head and neck squamous cell carcinoma (HNSCC), a tumor type for which exome sequence data from The Cancer Genome Atlas project are available from both HPV+ and HPV- variants. We show that HPV+ tumors express more APOBEC3B and harbor a higher proportion of APOBEC signature mutations than HPV- tumors. The APOBEC mutational signature is absent from hepatitis virus-associated hepatocellular carcinoma, indicating it is not simply a consequence of the immune response to persistent viral infection. We also uncover a strong linear relationship between APOBEC signature mutations and APOBEC-independent mutations in both HNSCC and in breast cancer, such that in high APOBEC subsets (HPV+ HNSCC and HER2-amplified breast cancer), the proportion of mutations due to APOBEC activity is consistently increased, regardless of the overall mutational burden in the tumor. Finally, HPV+ HNSCC and cervical cancer show particularly strong enrichment for APOBEC signature mutations in known cancer genes, implicating APOBEC activity as a key driver of HPV-induced transformation.
Citation Format: Stephen Henderson, Ankur Chakravarthy, Xiaoping Su, Chris Boshoff, Tim R. Fenton. APOBEC-mediated cytosine deamination is a prominent mutagenic mechanism in human papillomavirus-driven cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3169. doi:10.1158/1538-7445.AM2014-3169
Abstract 3192: The environmental estrogen bisphenol A (BPA) regulates mammary gland stem cells
Authors: Nichols Cydney , Ding Xiangming , Miranda-Carboni Gustavo , Krum Susan Amy 
Published: May 2015

Abstract
A study by the Centers for Disease Control revealed detectable levels of the environmental toxin Bisphenol A (BPA) in urine samples from over 92% of people in the NHANES (National Health and Nutrition Examination Survey) study. BPA is a small molecule used in the polymerization of polycarbonate plastics. These plastics are widely used in food containers, water bottles, dental fillings and toys, among many other products. BPA is similar to the synthetic estrogen diethylstilbesterol (DES) and can bind to estrogen receptor alpha (ERα) or estrogen receptor beta (ERβ). Because BPA is lipophilic and has been detected in mammary gland fat in humans, we hypothesize that BPA is an estrogen mimic in the stromal adipocytes in the breast and can induce stem cell proliferation and survival, leading to breast tumor formation. Indeed, BPA increases the size and number of mammospheres from normal mouse mammary gland and from human MCF7 breast cancer cells. Adipocytes co-cultured with mammospheres increased the size of the spheres, and BPA further increased the size of adipocyte co-cultured mammospheres. BPA upregulates the stem cell markers Nanog, OCT4 and SOX2 in mammospheres. ERα and pCREB were shown to bind to an enhancer downstream of the SOX2 gene after BPA treatment. Finally, BPA increased the size of tumor xenografts in NUDE mice. Together these experiments demonstrate that BPA may induce breast cancer via ERα and pCREB regulation of breast cancer stem cells.
Citation Format: Cydney Nichols, Xiangming Ding, Gustavo Miranda-Carboni, Susan Amy Krum. The environmental estrogen bisphenol A (BPA) regulates mammary gland stem cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3192. doi:10.1158/1538-7445.AM2014-3192