bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1999: Regulation of the oncogenic, invasion-promoting transcription factor myeloid zinc finger-1 (MZF1) in breast cancer by microRNAs
Authors: Kallunki Tuula , Tvingsholm Siri A. , Bundgaard Clemmensen Knut K. , Brix Ditte M. , Rafn Bo , Moreira José , Frankel Lisa , Lund Anders , Louhimo Riku , Hautaniemi Sampsa , Gromova Irina , Jäättelä Marja 
Published: July 2016

Abstract
INTRODUCTION: Myeloid Zinc Finger 1 (MZF1) is a transcription factor that is normally involved in myeloid differentiation. MZF1 can also be found in epithelial cancers, where it functions as an invasion and metastasis promoting oncogene. MZF1 is a central node of the invasive signaling network activated by HER2/ErbB2 in breast cancer, where MZF1 mobilizes and activates lysosomes and increases the expression of cysteine cathepsin B to promote invasion and metastasis. Thus, maintaining the sufficient expression level of MZF1 is important for the invasive signaling of breast cancer cells.
RESULTS AND EXPERIMETAL PROCHEDURES: Here we show that MZF1 is essential for the invasion of breast cancer cells in 3-dimensional cultures. We also describe a possible mechanism that regulates MZF1 levels in breast cancer. By using available micro-RNA (miRNA) binding site prediction programs (www.microrna.org/), specific microRNA mimics, corresponding miRNA inhibitors e.g. locked nucleic acids, luciferase reporter assays, immunofluorescense, quantitative PCR and 3-dimensional invasion assays we show that some breast cancer specific miRNAs can regulate MZF1 RNA and protein levels and revert the malignant and invasive cellular phenotype of breast cancer cells by altering the invasion promoting functions of lysosomes. These results are supported by the analysis of breast cancer patient data from the cancer genome atlas (http://cancergenome.nih.gov) showing that MZF1 expression correlates negatively with the expression of the identified miRNAs, when using data collected from over 600 primary breast cancer tumors.
SUMMARY: This study shows that MZF1 is an oncogene whose sufficient expression levels are central for breast cancer cell invasion and whose specific miRNA-mediated downregulation can inhibit breast cancer malignancy by modifying the expression of its lysosomal target genes.
CONCLUSION: Cancer-associated upregulation of MZF1 increases the breast cancer malignancy. Thus finding ways to downregulate MZF1 expression or inhibit its activity can be beneficial for breast cancer therapy.
Citation Format: Tuula Kallunki, Siri A. Tvingsholm, Knut K. Bundgaard Clemmensen, Ditte M. Brix, Bo Rafn, José Moreira, Lisa Frankel, Anders Lund, Riku Louhimo, Sampsa Hautaniemi, Irina Gromova, Marja Jäättelä. Regulation of the oncogenic, invasion-promoting transcription factor myeloid zinc finger-1 (MZF1) in breast cancer by microRNAs. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1999.
Abstract 2005: Global binding pattern of the Wilms’ tumor gene 1 (WT1) +17AA -KTS isoform in leukemic cells
Authors: Ullmark Tove , Järvstråt Linnea , Montano Giorgia , Jernmark-Nilsson Helena , Sandén Carl , Nilsson Björn , Vidovic Karina , Gullberg Urban 
Published: July 2016

Abstract
The aim of this study was to investigate the global DNA-binding pattern of Wilms’ tumor gene 1 (WT1) in leukemic cells. Clinical and preclinical data indicate the zinc finger transcription factor WT1 as an oncogene, but the full target gene repertoire of WT1 in leukemic cells has not been previously characterized. The -KTS isoforms (excluding the three amino acid (KTS) insert between zinc finger three and four) are considered as the most efficient DNA-binders. Among these, the 17AA isoform (including 17 amino acids encoded by exon 5) is the most abundant one. To specifically analyze the DNA-binding of WT1(+17AA/-KTS) in leukemic cells, we generated a K562 clone that stably expressed BIO-tagged WT1(+17AA/-KTS), as well as the biotinylating enzyme Bir A. From the cells chromatin immunoprecipitation (ChIP) by streptavidin capture was performed followed by sequencing with a minimum of 50 million reads per sample. After alignment to the genome and peak calling, peaks were characterized and compared to available K562 tracks in the ENCODE database. We found that 45% of identified WT1(+17AA/-KTS) peaks are in the proximity of transcription start sites (promoter area, first exon or first intron) of target genes, whereas only 11% of randomized peaks were found here. Within the peaks we show strong enrichment for three different previously published WT1-binding motifs. Comparison to ENCODE tracks showed that WT1(+17AA/-KTS) peaks are in close proximity to binding sites of other transcription factors, to histone marks for actively transcribed genes, and to binding sites of chromatin modifiers. Considering peaks within promoters and gene bodies only (for safe assignment to a target gene), Gene Ontology (GO) analysis revealed enrichment of GO groups important for proliferation, cell death, embryonic development, and cell motility. In conclusion, WT1(+17AA/-KTS) binds close to transcription start sites in areas of active transcription. The target genes implicated in proliferation, cell death, cell signaling and motility adds to the growing evidence of WT1 as an effector gene in leukemia.
Citation Format: Tove Ullmark, Linnea Järvstråt, Giorgia Montano, Helena Jernmark-Nilsson, Carl Sandén, Björn Nilsson, Karina Vidovic, Urban Gullberg. Global binding pattern of the Wilms’ tumor gene 1 (WT1) +17AA -KTS isoform in leukemic cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2005.
Abstract 2007: Transcriptional regulatory program controlled by the oncogenic transcription factor LMO1 in neuroblastoma
Authors: Sanda Takaomi , Akahanse Koshi , Abraham Brian J. , Weichert Nina , Durbin Adam , Anders Lars , Tan Shi Hao , Yam Alice Wei Yee , Lawton Lee N. , Young Richard A. , Maris John M. , Look A Thomas 
Published: July 2016

Abstract
Neuroblastoma is an embryonal tumor of the peripheral sympathetic nervous system, accounting for 15% of all childhood cancer deaths. Both overexpression of the transcription factor LMO1 and the polymorphisms within this gene locus are associated with the susceptibility to neuroblastoma, but the oncogenic roles of LMO1 in neuroblastoma pathogenesis have not been elucidated. The roles of LMO1 in T-cell acute lymphoblastic leukemia (T-ALL) are better understood, and these suggest that some of its effects may be similar between the two malignancies. Here we identify the transcriptional regulatory program controlled by LMO1 in neuroblastoma and T-ALL cells. Knockdown of LMO1 induces apoptotic cell death in both tumor types. ChIP-seq and microarray analyses demonstrate that LMO1 frequently co-occupies its target genes with GATA3 and regulates gene expression in a tissue-specific manner. LMO1 positively regulates genes involved in neuronal development, tumor invasion and metastasis in neuroblastoma cells, whereas it regulates genes involved in lymphopoiesis and immune function in T-ALL cells. Gene set enrichment analysis reveals that many genes bound by LMO1 and GATA3 are significantly downregulated upon MYCN knockdown in the MYCN-amplified neuroblastoma cells. Importantly, LMO1 binds at the CDK6 gene locus, which is associated with a super-enhancer both in neuroblastoma and T-ALL cells. The mRNA expression of CDK6 is positively correlated with LMO1 expression in primary neuroblastoma samples. Knockdown of LMO1 downregulates CDK6 protein expression, whereas overexpression of LMO1 upregulates CDK6 expression. CDK6 knockdown induces apoptosis both in neuroblastoma and T-ALL cells. Our results indicate that CDK6 is a critical downstream target that is directly activated by LMO1 and is required for cell survival in neuroblastoma and T-ALL cells.
Citation Format: Takaomi Sanda, Koshi Akahanse, Brian J. Abraham, Nina Weichert, Adam Durbin, Lars Anders, Shi Hao Tan, Alice Wei Yee Yam, Lee N. Lawton, Richard A. Young, John M. Maris, A Thomas Look. Transcriptional regulatory program controlled by the oncogenic transcription factor LMO1 in neuroblastoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2007.
Abstract 2019: SOX2 silencing upregulates CDKN1A and suppresses growth of lung squamous cell carcinoma
Authors: Fukazawa Takuya , Yamatsuji Tomokoki , Takaoka Munenori , Yokota Etsuko , Haisa Minoru , Ishida Naomasa , Yoshida Masakazu , Miyake Noriko , Takigawa Nagio , Maeda Yutaka , Naomoto Yoshio 
Published: July 2016

Abstract
SOX2 is a master pluripotency controller that was recently identified as a novel major oncogene, recurrently amplified and activated in lung squamous cell carcinoma (lung SCC). Then, transcriptional downstream targets of SOX2 have been actively investigated; however, such targets are often cell line specific. Here, in order to identify highly consensus SOX2 downstream genes in lung SCC cells, we used RNA-seq data from 178 lung SCC specimens (containing tumor and tumor-associated cells) and analyzed the correlation between SOX2 and previously-reported SOX2-controlled genes in lung SCC. In addition, we used another RNA-seq dataset from 105 non-small cell lung cancer cell lines (NSCLC; including lung SCC cells) and again analyzed the correlation between SOX2 and the reported SOX2-controlled genes in the NSCLC cell lines (no tumor-associated cells). We combined the two analyses and identified genes commonly correlated with SOX2 in both datasets. Among the 99 genes reported as SOX2 downstream and/or correlated genes, we found 4 negatively-correlated (e.g., CDKN1A) and 11 positively-correlated genes with SOX2. We used biological studies to demonstrate that CDKN1A was suppressed by SOX2 in lung SCC cells. G1 cell cycle arrest induced by SOX2 siRNA was rescued by CDKN1A siRNA. These results indicate that the tumorigenic effect of SOX2 in lung SCC cells is mediated in part by suppression of CDKN1A.
Citation Format: Takuya Fukazawa, Tomokoki Yamatsuji, Munenori Takaoka, Etsuko Yokota, Minoru Haisa, Naomasa Ishida, Masakazu Yoshida, Noriko Miyake, Nagio Takigawa, Yutaka Maeda, Yoshio Naomoto. SOX2 silencing upregulates CDKN1A and suppresses growth of lung squamous cell carcinoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2019.
Abstract 2022: Twist1 regulates UVB-induced epidermal cell proliferation in non-melanoma skin cancer
Authors: Srivastava Jaya , Rho Okkyung , DiGiovanni. John 
Published: July 2016

Abstract
Nonmelanoma skin cancer (NMSC) is the most common cancer and consists of basal cell carcinoma (BCC) and squamous cell carcinoma (SCC). SCC metastases account for up to 20% of all deaths from skin cancer. The major risk factor for the development of NMSC is solar ultraviolet radiation (UV). UVA and UVB both function as initiators and promoters in carcinogenesis and possess immunosuppressive activity. Given the prevalence of this disease, there remains a pressing need for the development of novel prevention and treatment strategies for NMSC.
In a recent study (Srivastava et al. 2015. Mol. Carcinog. doi:10.1002/mc.22335), we evaluated the effect of Twist1, a transcription factor that is known to play a role in tumor progression, during epithelial carcinogenesis. Using the two-stage chemical carcinogenesis model, we identified that BK5.Cre x Twist1flox/flox mice, which have a keratinocyte-specific Twist1 knockout (Twist1 KO), developed significantly reduced numbers of papillomas (70% reduction) and SCCs (75% reduction) as well as delayed tumor latency compared to wild-type (WT) mice. Twist1 KO mice also exhibited significantly reduced epidermal proliferation in response to chemical promotion that correlated with reduced levels of cell cycle regulators and increased levels of p53 and p21.
In further studies, we have begun analyzing the effects of UVB irradiation in Twist1 KO mice. Specifically, Twist1 KO mice exhibited heightened sensitivity to UVB-induced apoptosis and decreased epidermal proliferation as compared to similarly exposed WT mice. In addition, the accumulation of mast cells in the skin was significantly decreased in Twist1 KO mice as compared to WT mice. Further preliminary experiments showed that the protein expression levels of c-Myc, phospho-p65 (S536) and phospho-p50 (S337) decreased following UVB irradiation whereas levels of the cell cycle inhibitors p21 and p27 exhibited an increased expression in Twist1 KO mice as compared to WT mice. Further experiments have suggested that Twist1 may play a pivotal role in the proliferation/migration of bulge region keratinocyte stem cells (KSCs) following exposure to UVB. These and other results from ongoing experiments will be presented. Collectively, these findings suggest that Twist1 may have a novel role in UVB-induced epithelial carcinogenesis by regulating proliferation and migration of keratinocytes and KSCs. Research supported by CPRIT RP150346, CPRIT RP140108, and NIH T32 ES007247.
Citation Format: Jaya Srivastava, Okkyung Rho, John DiGiovanni. Twist1 regulates UVB-induced epidermal cell proliferation in non-melanoma skin cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2022.
Abstract 2024: BP1 homeoprotein induces tumor cell growth and estrogen-independent tumorigenesis in mice
Authors: Fu Sidney W. , Kirolikar Saurabh , Ginsburg Erika , Schwartz Arnold , Simmens Samuel , Berg Patricia E. 
Published: July 2016

Abstract
BACKGROUND. BP1 is a member of the homeobox gene family of transcription factors. Our recent studies have shown that BP1 overexpression increases cell survival, aggressiveness and metastasis in breast cancer cells. BP1 protein is expressed in 80% of invasive ductal breast tumors, including 100% of ER negative (ER-) tumors and 73% of ER positive (ER+) tumors. Therefore we hypothesize that BP1 may regulate ER in breast cancer. A mouse model was developed to test the regulatory effects of BP1 in ER expression. MATERIALS AND METHODS. MCF-7 breast cancer cells transfected with BP1 or vector control were njected into the fat pads of nude mice. Regulation of ER by BP1 was studied using ChIP assays; EMSA assays were used to test binding of BP1 to ER DNA. Tamoxifen assays were used to evaluate the effects of BP1 overexpression on tamoxifen resistance. RESULTS. MCF-7 cells overexpressing BP1 or control cells containing an empty vector were injected into nude mice. Approximately half of the estrogen-supplemented mice developed tumors. Although MCF-7 cells require exogenous estrogen to form tumors in nude mice, approximately 20% of the mice implanted with cells overexpressing BP1 were able to form tumors in the absence of added estrogen. To understand the molecular mechanisms of this observation, we carried out in vitro experiments. Our data suggest that BP1 regulates ER both directly and indirectly: (1) Direct: ChIP assays and EMSA assays showed that BP1 binds to the first intron of the ER alpha gene and transcriptionally activates it, leading to increased ER protein. (2) Indirect: regulation of ER also occurs indirectly by BP1 upregulation of p300, an activator of ER, and also by repression of BRCA1 by BP1; BRCA1 destabilizes ER protein. Furthermore, MCF-7 cells overexpressing BP1 are more resistant to growth in 3uM tamoxifen compared with empty vector containing cells. CONCLUSIONS. BP1 overexpression in MCF-7 cells injected into mice not only increases tumor size but also promotes estrogen-independent tumorigenesis, and leads to resistance to tamoxifen. Therefore, BP1 could serve as a novel therapeutic target for ER+ breast cancer.
Citation Format: Sidney W. Fu, Saurabh Kirolikar, Erika Ginsburg, Arnold Schwartz, Samuel Simmens, Patricia E. Berg. BP1 homeoprotein induces tumor cell growth and estrogen-independent tumorigenesis in mice. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2024.
Abstract 2026: DEC1 negatively regulates AMPK activity via LKB1
Authors: Sato Fuyuki , Muragaki Yasuteru 
Published: July 2016

Abstract
Basic helix-loop-helix (bHLH) transcription factor DEC1 (bHLHE40/Stra13/Sharp2) is one of the clock genes that show a circadian rhythm in various tissues. AMP-activated protein kinase (AMPK) activity plays important roles in metabolism and in cell death induced by glucose depletion. Recent reports have shown that AMPK activity exhibited a circadian rhythm. However, how the circadian rhythm of AMPK activity is regulated is not known. The aim of this study is the direct correlation between DEC1 expression and AMPK activity. DEC1 protein and AMPK activity showed a circadian rhythm in the mouse liver with different peak levels. A medium change and serum shock led to rhythmic patterns of DEC1 protein and AMPK activity levels in WI-38 cells, and their peak levels occurred at different times. However, changing the medium did not induce circadian rhythms of DEC1 protein or AMPK activity levels in MCF-7 and U2OS cells, in which the intensities of these levels had inversely correlated patterns. Knocking down DEC1 expression increased AMPK activity, whereas DEC1 overexpression decreased it. DEC1 bound to the E-box of the LKB1 promoter, decreasing the LKB1 activity and total protein levels. In addition, knocking down DEC1 expression inhibited cell death under the condition of glucose depletion, increasing the activity of both AMPK and LKB1. Taken together, our results showed that the levels of DEC1 protein and AMPK activity were affected even long after the medium change and that the rhythmic patterns of these levels were inversely correlated. We concluded that DEC1 negatively regulated AMPK activity via LKB1.
Citation Format: Fuyuki Sato, Yasuteru Muragaki. DEC1 negatively regulates AMPK activity via LKB1. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2026.
Abstract 205: Analysis of resistance to RTK inhibitors using a novel RTK multiplex assay
Authors: Chen Lu , Saporita Anthony J. , Lie Wen-Rong , Maheshwari Reeti , Schluter Melissa , Mistry Jehangir , Hwang Joseph 
Published: July 2016

Abstract
A novel multiplex immunoassay was developed for examining acquired resistance to Receptor Tyrosine Kinase (RTK) inhibitors. RTKs are transmembrane proteins which act as receptors for growth factors, neurotrophic factors and other extracellular signaling molecules. These cell-surface kinases are activated by extracellular ligands leading to receptor dimerization and tyrosine phosphorylation at specific residues in the cytoplasmic tails to initiate RTK-mediated signal transduction. Of the &gt;500 known protein kinases in the human genome there are approximately 60 RTKs. They are central components of cell signaling networks and play crucial roles in normal physiological processes and disease processes ranging from diabetes to cancer. Many RTKs, such as EGFR, HER2, c-Kit, PDGFR and VEGFR, have been used as targets for drug development and RTK-targeted therapies have illustrated the utility of these treatments for selected cancers. However, in many cases, compensatory RTK signaling enables cancer cells to acquire resistance to RTK inhibitors that selectively target a single RTK. For example, some EGFR and HER2 inhibitors have led to resistance and are associated with increased expression of IGF1R. In order to understand the mechanisms of resistance to RTK inhibitors, we have developed a bead-based multiplex immunoassay capable of simultaneously detecting phosphorylation of 18 different RTKs. First we demonstrate detection of RTK phosphorylation in response to growth factor stimulation using various cell lines. Next we examined the specificity of two inhibitors targeting EGFR and HER2. These inhibitors specifically reduced growth factor-stimulated phosphorylation of EGFR and HER2, without inhibiting the activation of other RTKs. Although we did not observe compensatory activation of other RTKs in response to the two EGFR and HER2 inhibitors we tested, this study demonstrates the feasibility of using this novel 18-plex RTK panel for examining the mechanism of resistance to single RTK inhibitors. In summary, the RTK multiplex panel allowed for simultaneous detection of multiple tyrosine phosphorylated RTKs in a specific, sensitive, and reproducible manner.
Citation Format: Lu Chen, Anthony J. Saporita, Wen-Rong Lie, Reeti Maheshwari, Melissa Schluter, Jehangir Mistry, Joseph Hwang. Analysis of resistance to RTK inhibitors using a novel RTK multiplex assay. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 205.
Abstract 2053: Effects of thymoquinone encapsulation on its uptake, delivery and anticancer activity in breast cancer cells
Authors: Fakhoury Isabelle , Saad Walid , Bou Hadir Kamal , Schneider-Stock Regine , Gali-Muhtasib Hala 
Published: July 2016

Abstract
Introduction: Thymoquinone (TQ) is a promising anticancer molecule which suffers from limited bioavailability. Drug encapsulation is commonly used to overcome low drug solubility, bioavailability as well as nonspecific targeting. For this project, we synthesized different TQ nanoparticles (TQ-NPs), characterized their properties, uptake and delivery mechanisms, and assessed their anticancer potential in a panel of breast cancer cells.
Methods: The different TQ-NPs were prepared using Flash nanoprecipitation. Dynamic light scattering and scanning electron microscope were used for the characterization of the size, morphology and stability of the NPs. The anticancer effect was assessed by MTT. We subsequently formulated fluorescent TQ-NPs and evaluated their uptake and subcellular intake mechanism by both fluorometry and confocal microscopy.
Results: We were successful at formulating four different stable TQ-NPs that had an average diameter size between 45-130 nm. All TQ-NPs had also high entrapment efficiency and loading content. In vitro, TQ-NPs enhanced the antitumor activity of the drug in both MCF-7 and MDA-MB-231 cells, when compared to free TQ with no significant cytotoxicity of the blank NPs. Fluorescent TQ-NPs uptake was further found to be both time and concentration dependent. Finally, using inhibitors of endocytosis we determined that the endocytosis of TQ-NPs is caveolin mediated. This was also confirmed by examining the subcellular localization of TQ-NPs. The nanoparticle formulations colocalized with both caveolin and transferrin but not with lamp-1 and EEA-1 proteins.
Conclusion: Altogether, our results describe a new approach for the enhancement of TQ anticancer activity and provide insights on the uptake dynamics specific to our formulation.
Citation Format: Isabelle Fakhoury, Walid Saad, Kamal Bou Hadir, Regine Schneider-Stock, Hala Gali-Muhtasib. Effects of thymoquinone encapsulation on its uptake, delivery and anticancer activity in breast cancer cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2053.