bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1975: Role and activation mechanisms of myeloid zinc finger-1 (MZF1) in ErbB2-induced breast cancer invasion
Authors: Kallunki Tuula , Brix Ditte M. , Clemmensen Knut Kristoffer B. , Tvingsholm Siri A. , Rafn Bo , Moreira José , Gromova Irina , Jäättelä Marja 
Published: August 2015

Abstract
ErbB2 overexpression gives rise to a highly invasive, aggressive phenotype associated with an increased activity of lysosomal cysteine cathepsins B and L and with a pericellular accumulation of lysosomes at the close vicinity of the cell membrane, enabling lysosomal exocytosis and secretion of lysosomal contents to the extracellular space. We recently showed that ErbB2 expression level correlates positively with cysteine cathepsin B and L levels in primary breast cancer and that ErbB2 regulates the expression of cathepsins B and L leading to their increased activity in several ErbB2-positive breast cancer cell lines. We found that the increased cysteine cathepsin activity is essential for the invasion of ErbB2 overexpressing breast cancer cells in 3-dimensional (3D) Matrigel cultures and that it is mediated by a novel signaling network that involves TGFβR, ERK2-MAPK, PAK4, PKCα and CDC42bpβ kinases and two transcription factors, Myeloid Zinc Finger 1 (MZF1) and ETS1, which regulate the ErbB2-induced expression of cathepsins B and L.
We currently work on understanding the mechanisms that increase the transcriptional activity of MZF1 in breast cancer. Thus far we have identified two basic mechanisms that can increase MZF1 target gene expression: cancer-induced, increased levels of MZF1 and ErbB2 signaling-induced, increased transcriptional activity of MZF1. Our results thus far show that the level of MZF1 can be directly downregulated by specific, non-coding RNAs. The cancer-induced increase in the MZF1 level is most likely due to changes in the expression of these non-coding RNAs. Preliminary data employing two-dimensional SDS-PAGE as well as the factual involvement of several kinases downstream of ErbB2 for its transcriptional activity, suggests that MZF1, a prominent phosphoprotein, is activated by phosphorylation in response to ErbB2 signaling. Towards this end we have set up various experiments to verify the phosphorylation of MZF1 in response to ErbB2 signaling. We now aim at the identification of the ErbB2-regulated phosphorylation sites. With this work we expect to collect more information about the molecular mechanisms underlying ErbB2-induced invasion. Increased knowledge of the mechanisms is expected to enable the development of novel therapies and biomarkers for aggressive, ErbB2-positive breast cancer.
Citation Format: Tuula Kallunki, Ditte M. Brix, Knut Kristoffer B. Clemmensen, Siri A. Tvingsholm, Bo Rafn, José Moreira, Irina Gromova, Marja Jäättelä. Role and activation mechanisms of myeloid zinc finger-1 (MZF1) in ErbB2-induced breast cancer invasion. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1975. doi:10.1158/1538-7445.AM2015-1975
Abstract 1984: SOCS3 regulates IDO proteasomal degradation and inflammatory signaling in triple negative breast cancer
Authors: Ouzounova Maria , Lee EunMi , Novakovic Ena , Noonepalle Satish Kumar , Piranlioglu Raziye , Shi Huidong , Wicha Max , Korkaya Hasan 
Published: August 2015

Abstract
An intrinsic claudin-low subtype within the TNBC was recently identified based on low/absent expression of luminal differentiation markers, enrichment of epithelial-to-mesenchymal transition (EMT) and stem cell markers. Interleukin-6 (IL6), a potent pleiotropic cytokine, is induced in response to acute and chronic inflammation. IL6 is a key regulator of inflammatory responses and orchestrates these physiological functions by controlling the Suppressor of cytokine signaling 3 (SOCS3) mediated Stat3/NF-κB pathway. SOCS3 is a critical negative regulator of IL6-mediated pathways. We have showed that constitutive activation of inflammatory loop in transformed cells but not in their untransformed counterparts depends on proteolytic degradation of SOCS3. Several studies indicate that activation of the tryptophan-degrading enzyme indoleamine-2,3-dioxygenase (IDO) represents a key pathway suppressing anti-tumor immunity. Moreover a recent study in dendritic cells found that SOCS3 binds IDO via phosphotyrosine-containing peptides and target the IDO/SOCS3 complex for ubiquitination and subsequent proteasomal degradation. IDO is shown to be constitutively expressed by many tumors. We analyzed a panel of breast cancer cell lines and found an inverse correlation between SOCS3 and IDO1 protein levels. Interestingly IDO protein and transcript levels were significantly increased in TNBC compared to luminal cell lines, thus confirming that IL6-JAK-STAT inflammatory loop is responsible for IDO regulation. Enforced expression of stable form of SOCS3, lacking the PEST and SOCS box domain in TNBC cell lines resulted in decreased expression of IDO. Therapeutic targeting of the IDO-IL6-SOCS3 inflammatory loop would revert the immune suppression mediated by IDO in this breast cancer subtype. These studies would provide a strong rationale for development of inflammatory pathway targeted agents for the treatment of TNBC, an aggressive disease that currently lacks molecularly targeted therapeutics.
Citation Format: Maria Ouzounova, EunMi Lee, Ena Novakovic, Satish Kumar Noonepalle, Raziye Piranlioglu, Huidong Shi, Max Wicha, Hasan Korkaya. SOCS3 regulates IDO proteasomal degradation and inflammatory signaling in triple negative breast cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1984. doi:10.1158/1538-7445.AM2015-1984
Abstract 1988: Role of N- ZEB1 in epithelial-mesenchymal transition (EMT)
Authors: Llorens M Candelaria , Cabanillas Ana M. 
Published: August 2015

Abstract
Background: ZEB1 (Zn Finger E-box Binding Homeobox) transcription factor is important in both development and disease, including the TGFβ-induced epithelial-mesenchymal transition (EMT) by which many tumors undergo metastasis. ZEB1 contains 2 Zn finger domains (ZD1-ZD2) which bind DNA independently. ZEB1 expresses as two phosphorylated forms important for its biological role. We had characterized the role of phosphorylated C-term ZEB1. Aim: Our goal is to uncover the role of signaling pathway/s in the phosphorylation on N-term ZD1 (N-ZEB1) and characterize the functional role of N-ZEB1 in the process of EMT in mammary epithelial cells NMuMG. Results: A 728 aa fragment of N-ZEB1 was overexpressed in HEK293T cells and Immunoprecipitation with N-ZEB1 antibodies followed by western blot analysis with anti phospho kinases (AKT, MEK/ERK, PKC or PKA) substrate Antibodies. The results revealed that N-ZEB1 is solely phosphorylated by PI3K (AKT), MAPK and PKC pathways. IGF1-mediated phosphorylation can regulate nuclear localization of C-term ZEB1. Two N-ZEB1-GFP clones harboring first 490aa (eGFPZ1) and a 2nd clone of 130 aa, eGFPZ2 (included in the former) were transfected to CHO-K1 cells and treated with inhibitors and activators of kinase pathways for 15-60 minutes in serum free medium. Fluorescence microscopy techniques showed that IGF-1 induced relocation of a nuclear eGFPZ1 into the cytosol of CHO-K1 cells; on the contrary, eGFPZ2 was unresponsive to IGF-1. PMA/IONO (activator of PKC) treatment relocated both clones in the cytosol. Later on, NMuMG cells were used to investigate the role of N-ZEB1 in EMT. These epithelial cells, that can turn into mesenchymal type under TGFβ treatment, were stably transfected with eGFPZ2 or empty vector (control). The epithelial markers E-cadherin and actin assessed by Western blot and confocal microscopy were diminished or absent in eGFPZ2 cells. The activity of Matrix Metallo Proteases 2 was also increased in NMuMG-GFPZ2 cells. Also, proliferation, migration and invasion were significantly increased (P&lt;0.001, P&lt;0.001 and P&lt;0.05, respectively) in NMuMG-GFPZ2 cells vs. controls. Taking together, these results show that the cells were induced to EMT by N-ZEB1.
Conclusions: We have identified a small fragment in N-ZEB1 that is able to elicit the EMT program in a TGFβ independent manner. In addition, changes in ZEB1 cellular localization induced by either PKC or IGF-1 could regulate this transcription factor biological activity.
Citation Format: M Candelaria Llorens, Ana M. Cabanillas. Role of N- ZEB1 in epithelial-mesenchymal transition (EMT). [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1988. doi:10.1158/1538-7445.AM2015-1988
Abstract 199: Functional mechanism of hypoxia-inducible factor 1 alpha-mediated Dicer down-regulation
Authors: Lai Hui-Huang , Lyu Yu-Jhen , Li Jie-Ning , Su Jen-Liang , Chen Pai-Sheng 
Published: August 2015

Abstract
MicroRNAs (miRNAs) are generated by a multiple steps process that post-transcriptionally regulate the expression of target genes. Dysregulation of miRNAs is linked to human diseases including the development of human cancer. Abrogation of cellular global miRNAs maturation has been proposed to promote tumorigenesis and cancer metastasis. Hypoxia stress is the major cause of dysregulation of miRNAs and promotes tumor angiogenesis, metastasis and tumorigenesis which is a pivotal factor to switch on the cellular oncogenic features during tumor progression. Although hypoxia stress regulates expression of a subset of miRNAs, the upstream regulators controlling miRNAs regulation under hypoxia remain unclear. This study demonstrates the molecular mechanism of post-translational regulation of Dicer under hypoxia. Our results show that knockdown of hypoxia inducible factor 1 alpha (HIF-1α) up-regulates Dicer expression in colorectal cancer (CRC) cells. Overexpression of HIF-1α enhances ubiquitination of Dicer and subsequently promotes it recognition by autophagic receptor for autophagy-lysosomal degradation. We also find that HIF-1α enhances cancer cell migration by regulating Dicer-regulated miRNAs. In conclusion, we demonstrated that HIF-1α down-regulated Dicer and abolishes miRNA biogenesis to enhance cancer cell migration. This study may provide a potential therapeutic direction that targets the dysregulated miRNAs in tumor hypoxia for patients with poor prognosis and metastatic CRC.
Citation Format: Hui-Huang Lai, Yu-Jhen Lyu, Jie-Ning Li, Jen-Liang Su, Pai-Sheng Chen. Functional mechanism of hypoxia-inducible factor 1 alpha-mediated Dicer down-regulation. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 199. doi:10.1158/1538-7445.AM2015-199
Abstract 1990: The key role of MECOM complex locus and its products in high-grade ovarian carcinoma pathogenesis and clinical outcomes
Authors: Batagov Arsen O. , Yenamandra Surya Pavan , Jenjaroenpun Piroon , Ivshina Anna V. , Kuznetsov Vladimir A. 
Published: August 2015

Abstract
The ecotropic virus integration site 1(Evi1) transcription factor, encoded in the MECOM complex locus, is implicated in several cancers, including ovarian cancer(OC). High-grade serous OC(HG-SOC) represents its most common and aggressive form. The pathobiological and clinical roles of MECOM and its products in HG-SOC are poorly understood.
Here, across all HG-SOC stages and grades, our meta-analysis demonstrated MECOM amplification in about 80% and EVI1 overexpression in 100% HG-SOC samples, relative to normal controls. We observed that Evi1 directly promotes double-strand DNA breaks repair via binding to DNA recombination/repair protein complexes, including a novel Rad50 isoform.
To elucidate the molecular basis and clinical significance of these findings, we studied genome-wide genome-wide Evi1-DNA binding, DNA copy number alterations, gene expression and proteome-scale Evi1 interactions, combining cell line and clinical meta-data and network/pathway analyses. Our experiments revealed major, previously unknown Evi1-binding DNA motifs specifying expression of 309 target genes, whose protein products were classified into eight functional and prognosis-significant modules implicated in embryogenesis, EMT, RNA metabolism, cancer cell survival, retinoic acid, anti-viral and therapeutic responses. The Evi1 pathway modules can collectively stratify the HG-SOC patients into four high-confidence post-surgery survival subgroups(P&lt;1.0×10-50), over-performing previously reported HG-SOC predictors and clinical markers. This tumor stratification correlates with chemotherapy sensitivity and treatment outcomes.
Starting from early stages of HG-SOC, MECOM/Evi1 amplifies genomic instability and activates the Evi1 pathway that promotes most cancer hallmarks. Thus, MECOM/Evi1 and the Evi1 pathway provide mechanistic means for HG-SOC re-classification, introduces high-confidence early diagnostic and prognostic biomarkers and perspective therapeutic targets.
Citation Format: Arsen O. Batagov, Surya Pavan Yenamandra, Piroon Jenjaroenpun, Anna V. Ivshina, Vladimir A. Kuznetsov. The key role of MECOM complex locus and its products in high-grade ovarian carcinoma pathogenesis and clinical outcomes. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1990. doi:10.1158/1538-7445.AM2015-1990
Abstract 1995: Developing integrated single-cell metabolic/proteomic assays
Authors: Xue Min , Wei Wei , Su Yapeng , Shin Young Shik , Kim Jungwoo , Heath James R. 
Published: August 2015

Abstract
The technology boom of single-cell metabolomics and proteomics has led to exciting biological discoveries in the past decade. It has become widely acknowledged that resolving the intratumoral heterogeneity at single cell resolution can aid the understanding of cancer therapeutic response and progression, as well as facilitate the development of therapeutic interventions. Here we present an integrated assay that simultaneously quantifies the intracellular metabolites, glucose uptake, metabolic proteins and functional signaling proteins at the single-cell level. The measurement of metabolites is achieved through a series of competitive binding assays and is incorporated into the microfluidic-based single cell barcode chip platform. We demonstrate that this assay is capable of obtaining information from both protein and metabolic signaling pathways associated with tumor survival and progression, providing new insights into cancer heterogeneity and drug responsiveness.
Citation Format: Min Xue, Wei Wei, Yapeng Su, Young Shik Shin, Jungwoo Kim, James R. Heath. Developing integrated single-cell metabolic/proteomic assays. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1995. doi:10.1158/1538-7445.AM2015-1995
Abstract 200: Effects of H. pylori infection in regulation of miRNAs-associated with DNA mismatch repair
Authors: Santos Juliana C. , Brianti Mitsue , de Almeida Victor , Matheu Ander , Ribeiro Marcelo L. 
Published: August 2015

Abstract
It is well known that genetic and epigenetic inactivation of DNA mismatch repair (MMR) genes might leads to mutations in cancer-related genes and to cancer development. In gastric carcinogenesis, it has been shown that the infection by H. pylori, the major causative agent of gastric cancer, induces DNA damage and mutation and/or inhibits MMR DNA repair. Recently, it has been reported that miRNAs (miRs) have an important role in regulating genomic stability and MMR DNA repair. Thus, the aim of this work was to identify miRs regulating MMR pathway in H. pylori-associated gastric carcinogenesis
To evaluate the effects of H. pylori on miRs releated with MMR, AGS gastric carcinoma cell line and the H. pylori strains 26695, and P12 were used in co-culture experiments for 4, 8 and 12 h. As an initial screening, the AGS cells were co-cultured with H. pylori strain 26695 and subjected to Cancer PathwayFinder miRNA PCR Array (Qiagen) to determine the expression profile of 84 miRs. The expression levels of EXO1, MLH1, MSH2, MSH3, MSH6, POLD3, PMS1, and PMS2 were assessed by real-time PCR. Computational prediction of putative interaction of selected miRs to 3′UTR of MMR mRNAs were obtained from TargetScan, mirDB and MetaCore. The target validation was evaluated using mimics/inhibitors and luciferase gene reporter assays.
The results from the Cancer PathwayFinder PCR miRNA Array showded that H. pylori infection (strain 26695) modulates the expression of 23% (19/84) of the miRs after 4 and 12 h of infection, of which 89% were up-regulated and 11% down-regulated. Our data show that H. pylori infection significantly down-regulates the expression of all selected genes. The data generated from computational miR target prediction enriched with the gene expression fold induction indicated that 4 miRs (miR-150-5p, miR-155-5p, miR-3163, and miR-4775) modulated by H. pylori has at least one MMR target gene. Regarding the target validation, our results indicated that MLH1 and MSH2, are regulated by miR-150-5p. The miR-155-5p is involved in down-regulation of MLH1, MSH2, MSH3 and POLD3 expression. MSH3 is regulated by both miR-3163 and miR-4775. Briefly, this study shows that H. pylori impairs MMR DNA repair pathway thought a modulation of miR expression.
Citation Format: Juliana C. Santos, Mitsue Brianti, Victor de Almeida, Ander Matheu, Marcelo L. Ribeiro. Effects of H. pylori infection in regulation of miRNAs-associated with DNA mismatch repair. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 200. doi:10.1158/1538-7445.AM2015-200
Abstract 2005: Quantitative screening of serum protein biomarkers by reversed phase protein serum arrays
Authors: Kuang Zhizhou , Huang Ruochun , Luo Shuhong , Chen Yun-Ru , Lv Zhiqiang , Zhang Zhuo , Huang Ruo-Pan 
Published: August 2015

Abstract
Protein biomarkers can be key indicators for cancer diagnosis, prediction, and selection of successful cancer treatments. Protein biomarkers can be identified by 2 methods: antibody arrays which profile protein expression levels from a patient's serum, or reversed phase protein arrays to measure single or limited sets of proteins from many patients’ sera. The reversed phase protein arrays have been widely used for detection of signaling molecules in cell lysates, however, this approach has been difficult to adapt to serum samples. Several years ago, we developed a sensitive method called the enhanced protein array to quantitatively measure serum protein levels from large numbers of patient samples. Here, we further refine the technology on several fronts: 1. simplifying the experimental procedure; 2. optimizing multiple parameters to make the assay more robust; 3. establishing a method for more accurate quantification. Using this technology, we quantitatively measured the protein expression levels of Nidogen-1 and CEACAM-1 from 164 serum samples from hepatocellular carcinoma (HCC) and equal number of control and found that both Nidogen-1 and CEACAM-1 expression levels are significantly increased in HCC patients. Our work reveals promise for using reversed phase protein serum arrays for biomarker discovery and validation.
Citation Format: Zhizhou Kuang, Ruochun Huang, Shuhong Luo, Yun-Ru Chen, Zhiqiang Lv, Zhuo Zhang, Ruo-Pan Huang. Quantitative screening of serum protein biomarkers by reversed phase protein serum arrays. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2005. doi:10.1158/1538-7445.AM2015-2005
Abstract 2013: SYNTHETIC LECTINS FOR THE DETERMINATION OF BREAST CANCER SUBTYPE
Authors: O'Connell Kathleen M. , Gatrone Erin E. , Veldkamp Anna A. , Lavigne John J. 
Published: August 2015

Abstract
Glycans represent promising biomarkers for cancer diagnostics. Aberrant glycosylation is known to occur in cancer cells and changes continue to occur as the disease progresses. This study sought to determine if glycan ‘fingerprints’ can distinguish between differing cell types associated with cancer; specifically for the early detection and subtyping of breast cancers. Synthetic Lectins (SLs) are small peptides functionalized with boronic acids that selectively bind to glycans. Different SLs, with differing peptide backbones, acting as an array can be used to study glycans and generate glycan ‘fingerprints’ of analytes.
An array of nine SLs, present on resin beads, were incubated with fluorescently labeled membrane proteins extracted from 1.) Breast cancer cell lines 2.) Matched normal and cancerous breast tissue from patients. Binding intensity information was obtained for each sample and analyzed statistically. Linear Discriminant Analysis was used to build two models, of breast cancer cell lines, based on a) metastatic potential and b) breast cancer subtype.
Leave one out analysis determined that the models could distinguish between healthy/cancerous non-metastatic/cancerous metastatic cells with 98% accuracy and between breast cancer subtypes with 99% accuracy. Classification accuracy based on metastatic potential was validated using clinical specimens. N = 3 matched normal and cancerous tissues were analyzed and classification accuracies of 97% were obtained.
We have developed an array, which distinguishes between healthy and cancerous cells as well as breast cancer subtypes with high accuracy. Work to expand validation to a larger group of patient samples as well as testing the array using patient serum is ongoing.
Citation Format: Kathleen M. O'Connell, Erin E. Gatrone, Anna A. Veldkamp, John J. Lavigne. SYNTHETIC LECTINS FOR THE DETERMINATION OF BREAST CANCER SUBTYPE. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2013. doi:10.1158/1538-7445.AM2015-2013