bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1075: Steroid receptor reprogramming of the chromatin landscape: crosstalk at the genomic level.
Authors: Miranda Tina B. , Voss Ty C. , Sung Myong-Hee , Baek Songjoon , John Sam , Hawkins Mary , Grontved Lars , Schiltz R. Louis , Hager Gordon L. 
Published: August 2014

Abstract
Crosstalk between the estrogen receptor (ER) and the glucocorticoid receptor (GR) plays an important role in controlling many cellular processes. Physiological interactions between ER and GR are not only important for the development of certain tissues, such as the uterus and bone, but also may play an important role in breast cancer. Recent studies have shown that the GR and ER status in breast cancer is a significant factor for determining the outcome of the disease. However, the mechanistic details defining the cellular interactions between ER and GR are poorly understood. Since the regulation of receptor binding to response elements controls the transcriptional output in response to hormones, it is logical to suspect that co-treatment of cells with corticosteroids and estradiol would have an effect on the genome-wide binding landscapes for GR and ER. Therefore, using chromatin immunoprecipitation followed by high-throughput sequencing we investigated the changes in genome-wide binding of ER and GR upon co-activation and revealed that there is global re-arrangement of steroid receptor binding. Furthermore, we unveiled a novel mechanism dictating the molecular interplay between ER and GR. Genome-wide sequencing of DnaseI hypersensitive sites upon induction of GR shows that GR facilitates selective access of ER to specific sites in the genome by maintaining an accessible configuration at these response elements. In addition, activation of ER can affect chromatin structure at novel GR binding sites, resulting in a new class of GR binding elements. Further studies show that at the sites where ER binding is facilitated by GR, binding to these newly accessible sites is not dependent on the direct binding of ER to its response element. Instead ER is brought to these sites through interactions with other factors, such as AP1. Overall, these studies define genome level interactions between ER and GR whereby the activation of multiple steroid receptors has a dramatic impact on controlling which regulatory elements are accessible to each receptor. The unveiling of this mechanism is important for understanding the molecular interplay between ER and GR in development and in cancer and may represent a general mechanism for crosstalk between receptors.
Citation Format: Tina B. Miranda, Ty C. Voss, Myong-Hee Sung, Songjoon Baek, Sam John, Mary Hawkins, Lars Grontved, R. Louis Schiltz, Gordon L. Hager. Steroid receptor reprogramming of the chromatin landscape: crosstalk at the genomic level. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1075. doi:10.1158/1538-7445.AM2013-1075
Abstract 1077: Dominant negative PI3-Kinase inhibits UV-induced squamous cell carcinoma in vivo.
Authors: Dickinson Sally E. , Olson Erik R. , Rusche Jadrian J. , Criswell P. Jane , Zhang Jack , Dong Zagong , Hu Chengcheng , Saboda Kathylynn , Alberts David S. , Bowden G. Timothy 
Published: August 2014

Abstract
Phosphoinositide-3 Kinase (PI3-Kinase) is an upstream regulator of cellular proliferation and anti-apoptotic signaling that has been implicated in cancer induction in many tissues, including skin. Pharmacological inhibition of PI3-Kinase is effective at inhibiting both chemical and UV-driven skin carcinogenesis. However, the specificity of these pharmacological inhibitors is often questioned. Therefore, specific genetic inhibition of PI3-Kinase in the epidermis needs to be carried out in mice. We report here on the generation of a new transgenic mouse which constitutively expresses the dominant negative mutant form of the regulatory subunit of the PI3-Kinase dimer, p85, in the epidermis under control of the keratin-5 promoter. These p85DN transgenic mice were derived on the SKH-1 hairless genetic background. A chronic UVB exposure experiment showed significant inhibition of both tumor size (p=0.0012) and tumor burden (p=0.0003) for mice carrying the transgene compared to wildtype littermates. The time to first tumor was also delayed in transgenic mice, but with only marginal significance (p=0.07). p85DN mice also showed significant inhibition of epidermal Activator Protein-1 (AP-1) transcription factor activity after acute UVB treatment (p=0.046). UVB induced activation of AP-1 in the epidermis has been shown to play a functional role in UVB mouse skin carcinogenesis. Further analysis of protein expression after acute treatment with UVB suggests that Akt signaling and COX-2 activation are both downregulated in p85DN transgenic mice. To our knowledge, this is the first report of genetic inhibition of PI3-Kinase in mouse skin carcinogenesis studies. Together, these data suggest a functional role of PI3-Kinase in UVB-induced squamous cell carcinoma and support the assertion that inhibition of this pathway is beneficial in chemoprevention of non-melanoma skin cancer. This work was supported in part by the following NIH grants: K07CA132956, K07CA132956-02S1, P01CA27502 and P30CA23074.
Citation Format: Sally E. Dickinson, Erik R. Olson, Jadrian J. Rusche, P. Jane Criswell, Jack Zhang, Zagong Dong, Chengcheng Hu, Kathylynn Saboda, David S. Alberts, G. Timothy Bowden. Dominant negative PI3-Kinase inhibits UV-induced squamous cell carcinoma in vivo. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1077. doi:10.1158/1538-7445.AM2013-1077
Abstract 1085: MYC inhibition is a potent therapy against glioma and induces mitotic crisis in cancer cells.
Authors: Annibali Daniela , Whitfield Jonathan R. , Favuzzi Emilia , Jauset Toni , serrano Erika , Folch Gerard , Cuartas Marta I. , Gonzalez Alba , Brown Swigart Lamorna , Nasi Sergio , Evan Gerard I. , Seoane Joan , Soucek Laura 
Published: August 2014

Abstract
Gliomas are the most common primary tumors affecting the adult human Central Nervous System (CNS). The most lethal is grade IV glioblastoma (GBM), which gives a median survival of only 15 months, but less severe grades also respond poorly to standard therapy. Myc is a bHLHZip transcription factor, causally implicated in most human tumors. In the past, we employed a dominant negative of Myc transactivation activity, termed Omomyc, and we showed that Myc inhibition is a potent strategy in cancer therapy, both in K-RasG12D-driven lung tumors and in T antigen-driven pancreatic β-cell insulinomas. Now, we make use of a mouse model of Ha-Ras driven glioma coupled with our Omomyc switchable model in order to assess Myc inhibition as a therapeutic strategy in glioma. Myc inhibition has a dramatic therapeutic impact in the animals, being able to both prevent formation and cause regression of tumors. We also tested neuroprogenitor cells derived from the same animal model as putative cells of origin of glioma. In this context, Myc inhibition reduced proliferation, increased death and impaired the self-renewal of Ha-Ras transformed neuroprogenitors. Similar results were obtained with human glioblastoma cell lines, which presented severe mitotic catastrophe as a consequence of Omomyc expression, revealing a new Achilles’ heel of glioblastoma. Finally, Myc inhibition was tested in orthotopic xenografts using patient-derived tumor samples and showed once again dramatic therapeutic impact, conferring a significant survival advantage to recipient animals. Conclusion: Myc inhibition is a potent therapeutic strategy in glioma and its effects include induction of mitotic crisis in tumor cells.
Citation Format: Daniela Annibali, Jonathan R. Whitfield, Emilia Favuzzi, Toni Jauset, Erika serrano, Gerard Folch, Marta I. Cuartas, Alba Gonzalez, Lamorna Brown Swigart, Sergio Nasi, Gerard I. Evan, Joan Seoane, Laura Soucek. MYC inhibition is a potent therapy against glioma and induces mitotic crisis in cancer cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1085. doi:10.1158/1538-7445.AM2013-1085
Abstract 1087: Differential oncogenicity of N-RAS mutations in melanoma.
Authors: Burd Christin , Jeck William R. , Fu Kailing , Clark Kelly S. , Xiong Jessie C. , Souroullas George P. , Sharpless Norman E. 
Published: August 2014

Abstract
In human cancer, N-RAS mutations resulting in constitutive, oncogenic signaling are predominately localized to codons 12, 13 or 61. Traditionally, activating RAS mutations have been considered oncogenically equivalent, yet recent studies suggest important clinical distinctions between colon cancers containing K-RAS codon 12 vs. codon 13 mutations. More than 20% of human melanomas harbor N-RAS mutations, the vast majority of which target codon 61, as opposed to N-RAS mutations of codon 12 or 13, which are common in other tumor types. To address this issue, we characterized syngeneic knock-in mouse models conditionally expressing either N-RasG12D or N-RasQ61R under the control of the endogenous locus. In primary melanocyte cultures, activation of either N-Ras allele reduced cellular proliferation even in the presence of concomitant p16INK4a deletion. Correspondingly, melanocyte-specific N-RasG12D expression combined with p16INK4a loss failed to efficiently promote melanoma formation in mice. In contrast, melanocyte-specific N-RasQ61R induction readily combined with p16INK4a loss to promote melanoma formation in vivo with short latency and high penetrance. These results provide a first murine model of melanoma featuring knock-in N-Ras mutationQ61R, and suggest that the preference for codon 61 mutations in human tumors is conserved in mice.
Citation Format: Christin Burd, William R. Jeck, Kailing Fu, Kelly S. Clark, Jessie C. Xiong, George P. Souroullas, Norman E. Sharpless. Differential oncogenicity of N-RAS mutations in melanoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1087. doi:10.1158/1538-7445.AM2013-1087
Abstract 1089: Spontaneous formation of sarcomas in Usp18 knockout mice.
Authors: Chinyengetere Fadzai , Giustini Andrew , Sekula David , Freemantle Sarah , Memoli Vincent A. , Hoopes Paul Jack , Dmitrovsky Ethan 
Published: August 2014

Abstract
Undifferentiated pleomorphic sarcoma (UPS) and leimyosarcoma are two of the most common adult soft tissue sarcomas. Their etiology is unknown hence the need for new models to elucidate the biology of these diseases. We report here a spontaneously occurring mouse model of sarcoma in Usp18 knockout mice. Usp18 is the deconjugase for isgylation. Isgylation is the ubiquitin-like protein modification in which ISG15 is conjugated to proteins. Usp18 removes ISG15 from the target proteins, thus reversing the functional consequences of ISG15 conjugation. Usp18 knockout mice on a C57Bl6 background developed neurological abnormalities and exhibited 100% mortality within 5 months. These mice were also hypersensitive to Type I IFN stimulation, which was attributed to an increased JAK-STAT signaling. We now report that Usp18 knockout mice in a FVB background developed subcutaneous tumors in the neck and trunk regions from ages ranging from 6 months to 16 months. Tumor formation to date shows a penetrance of 77%. Immunohistochemical analysis characterized the tumors as either UPSs or leimyosarcomas. About 30% of these tumors displayed stabilization of p53, a common event also seen in human sarcomas. We derived two cell lines (KHC-1, KHC-2) from the sarcomas of separate mice, and analyzed the levels of STAT family proteins in these cell lines. Stat3 was noted to be constitutively activated in these sarcoma cell lines. Persistent activation of Stat3 is seen in diverse human malignancies such as breast and head and neck cancers. To determine if restoring Usp18 activity reverses tumorigenicity in these cells, human USP18 was introduced retrovirally. Cells re-expressing USP18 versus empty vector showed a substantial decrease in anchorage independent growth in soft agar and also had reduced levels of activated Stat3 (pStat3). Furthermore, treatment of the parental cell lines with a Stat3 inhibitor, JSI-124, led to decreased cell growth, apoptosis and reduced levels of pStat3. In summary, Usp18 knockout mice spontaneously develop sarcomas, whose tumorigenicity can be partially reversed by reintroduction of Usp18. Thus, this new and tractable model should prove useful to elucidate the activity of Stat3 targeting and other agents to treat sarcomas.
Citation Format: Fadzai Chinyengetere, Andrew Giustini, David Sekula, Sarah Freemantle, Vincent A. Memoli, Paul Jack Hoopes, Ethan Dmitrovsky. Spontaneous formation of sarcomas in Usp18 knockout mice. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1089. doi:10.1158/1538-7445.AM2013-1089
Abstract 1090: NR2F1 coordinates a dormancy program by inducing low self-renewal capacity and a repressive chromatin state.
Authors: Sosa Maria S. , Estrada Yeriel , Parikh Falguni , Gutierrez Almudena Bosch , Zheng Yang , Bragado Paloma , Ekpin Esther , George Ajish , Farias Eduardo , Aguirre-ghiso Julio 
Published: August 2014

Abstract
Clinical studies have shown that solitary disseminated tumor cells (DTCs) in distant organs can be detected years after treatment of primary tumors. This has led to the notion that these solitary DTCs must enter a non-proliferative state or cellular dormancy. This may also hold true for residual tumor cells left behind in loco-regional sites after surgery. Unfortunately, the mechanisms regulating the timing of dormancy and the awakening of DTCs to fuel recurrences are unknown. Similarly, tools to stably induce dormancy of residual disease are unavailable. Here we show that transient differentiation signals propagated by treatment (3-4 days) with retinoic acid (atRA) along with the DNA demethylating agent 5-Aza-C reprogrammed malignant cells into dormancy for remarkably long periods of time (weeks). This reprogramming was associated with upregulation of the orphan nuclear receptor NR2F1/COUP-TF1 and other genes included in a gene signature previously linked to dormancy and late metastasis in breast patients. Importantly, the reprogramming was dependent on NR2F1, which is also silenced in breast and HNSCC tumors, cell lines and mouse cancer models. NR2F1-induced dormancy was associated with a global repressive chromatin state characterized by a H3K27-/K9-me3high/H3K4-me3/H3K27aclow profile. In both breast and HNSCC models NR2F1 blocked self-renewal extinguishing tumor initiating cell subpopulations. Tracking label retaining H2B-GFP cells, gain and loss of function studies showed that NR2F1-induced quiescence occurs via upregulation of SOX9, RARβ and CDK inhibitors. Importantly, inducible shRNAmir-mediated knock down of NR2F1 revealed that it mediates dormancy of occult loco-regional, spleen and lung DTCs, but not of dormant bone marrow DTCs. We conclude that the ability of NR2F1 to limit self-renewal and promote quiescence is key to dormancy induction. Manipulation of such mechanisms via epigenetic and differentiation therapies might represent a strategy to generate induced dormant cancer cells (iDCs) and maintain or eliminate asymptomatic residual disease.
Citation Format: Maria S. Sosa, Yeriel Estrada, Falguni Parikh, Almudena Bosch Gutierrez, Yang Zheng, Paloma Bragado, Esther Ekpin, Ajish George, Eduardo Farias, Julio Aguirre-ghiso. NR2F1 coordinates a dormancy program by inducing low self-renewal capacity and a repressive chromatin state. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1090. doi:10.1158/1538-7445.AM2013-1090
Abstract 1097: Transient mechanical stimulation can enhance cancer cell invasion.
Authors: Orzakar Snehal , Beningo Karen A. 
Published: August 2014

Abstract
Formation of secondary tumors by metastasis is a leading cause of death in cancer patients. During metastasis cells separate from the primary tumor, invade the stroma, travel through blood and lymph and colonize tissues distant from the primary mass. Several biochemical factors have been identified which are able to drive this metastatic cascade. However information of the role of mechanical factors in cancer metastasis has primarily focused on the effect of compliance, overshadowing other mechanical factors that might facilitate the metastatic progression. For example, contractile cells produce short term stress on extracellular matrix fibers during extensive remodeling of the stroma, such variable and transient force would easily propagate through the fibers providing communication between cells. To simulate this type of stress, we developed an in vitro invasion assay where cancer cells are subjected to tugging or pulling forces, similar in randomness and magnitudes to those produced by contractile cells in the tumor microenvironment, without interference of any secreted factors that could be provided by the stromal cells. We discovered a significant difference in the extent of invasion by cancer cells that were mechanically stimulated in this manner verses non- stimulated cell culture environments. This response requires the presence of fibronectin in the extracellular matrix. The objective of our current study is to understand the mechanotransduction pathway leading to enhanced invasion. We speculated that in response to mechanical forces in the stroma, tumor cells will show an altered expression of genes involved in mechanosensing. We performed expression profiling of several genes related to cell migration, adhesion and tumor metastasis by real-time PCR analysis. Given a 24 hour assay period, six genes were confirmed to be differentially expressed between mechanically stimulated and non-stimulated conditions. Of particular interest was the down-regulation of a fibronectin specific integrin subunit in response to the mechanical stimulation that enhanced invasion. Over-expression of this gene resulted in a significant decrease in enhanced invasion, supporting its role in sensing the mechanical stimulus. We speculate that mechanical stimulation during cancer cell invasion results in integrin cross-talk leading to the downregulation of specific integrins, while enriching others within the invadopodia.
Citation Format: Snehal Orzakar, Karen A. Beningo. Transient mechanical stimulation can enhance cancer cell invasion. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1097. doi:10.1158/1538-7445.AM2013-1097
Abstract 1098: Mechano-molecular imaging of the role of COX-2 in cell traction force.
Authors: Yoon A Rum , Stasinopoulos Ioannis , An Steven , Bhujwalla Zaver M. 
Published: August 2014

Abstract
The cytoplasmic enzyme cyclooxygenase (COX)-2 and its secondary lipid byproducts are critical determinants of cancer cell invasion and metastasis. Poorly differentiated MDA-MB-231 human breast cancer cells stably expressing COX-2 shRNA exhibit marked attenuation in their ability to secrete secondary lipid mediator products of the COX reaction, as well as invade and degrade reconstituted extracellular matrix in vitro. COX-2-silenced cells inoculated in vivo show significant reduction of tumor growth and extrapulmonary colonization than their parental counterpart. Based on compelling evidence for the positive correlation between cancer invasion and cell traction force, here we interrogated the mechanistic role for COX-2 in mediating this physical force and imaged the spatiotemporal distribution of contractile stress arising at the interface between each adherent cell and its substrate. Over a physiological range of substrate stiffness, COX-2-silenced MDA-MB-231 cells exhibited a smaller spreading area and a lower cell traction force than their highly metastatic, parental counterpart. Strikingly, unlike COX-2-silenced cells, COX-2-high parental MDA-MB-231 cells showed progressive increases in cell spreading area and traction force with increasing substrate rigidity. Cell spreading and traction force in COX-2-silenced cells were restored with an exogenous addition of COX-2-derived PGE2, however. COX-2-high MDA-MB-231 cells also showed increases in the expression of mechanosensitive integrin β1, and not β3, with increasing substrate rigidity. Consistent with these physical attributes, COX-2-silenced cells expressed a 4.6-fold reduction of the transcript coding for RhoJ, a member of the family of Rho GTPases, and displayed a slower remodeling dynamics of the cytoskeleton (CSK). To our knowledge this is the first report linking the expression of COX-2 with increased cell traction force and CSK remodeling in a highly metastatic human breast cancer.
Citation Format: A Rum Yoon, Ioannis Stasinopoulos, Steven An, Zaver M. Bhujwalla. Mechano-molecular imaging of the role of COX-2 in cell traction force. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1098. doi:10.1158/1538-7445.AM2013-1098
Abstract 1100: Dynamic multicellular mechanics controlling protrusion in 3D.
Authors: Fessenden Timothy , Gardel Margaret L. 
Published: August 2014

Abstract
Despite much effort, the transition from benign to malignant breast cancer remains poorly understood, resulting in overtreatment of women with in situ lesions. A growing appreciation for the role of cell mechanics in driving cell behavior has prompted interest in how mechanical interactions might control tumor growth and progression. How these parameters impact the transition from benign to malignant breast cancer remains unclear.
Mechanical interactions among cells via adherens junctions, and between cells and the ECM via focal adhesions, can each exert dominant effects on cell behavior. Cell motility and invasion require force interactions by harnessing cytoskeletal dynamics, which permit shape changes and generate and transmit forces. Tension maintained across the actin cortex mechanically restricts protrusions, and may be transmitted across multiple cells via adherens junctions. Thus epithelial cells form mechanically integrated tissues that may be responsive to changes in cortical tension over great distances. However, the regulatory role of cortical tension in restricting cells from protruding is unclear. Overall, we lack detailed morphologic and mechanical models of cell protrusion and invasion out of 3D collectives.
Using MDCK cell exposure to HGF as a model for rupture of epithelial integrity and protrusion, we have demonstrated the morphologic parameters that permit protrusion of a cell from its surrounding epithelium. Combined with work from our lab on force interactions between cells via adherens junctions, as well as mechanical interactions between a cell and its substrate, we may extrapolate detailed force interactions that underlie the observed cell shape and motility parameters that permit protrusion.
Citation Format: Timothy Fessenden, Margaret L. Gardel. Dynamic multicellular mechanics controlling protrusion in 3D. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1100. doi:10.1158/1538-7445.AM2013-1100