Validation of Valosin-Containing Protein (VCP) as a Therapeutic Target for Triple Negative Breast Cancer

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Analysis of phosphatases in ER-negative breast cancers identifies DUSP4 as a critical regulator of growth and invasion.

Estrogen receptor (ER)-negative cancers have a poor prognosis, and few targeted therapies are available for their treatment. Our previous analyses have identified potential kinase targets critical for the growth of ER-negative, progesterone receptor (PR)-negative and HER2-negative, or "triple-negative" breast cancer (TNBC). Because phosphatases regulate the function of kinase signaling pathways, in this study, we investigated whether phosphatases are also differentially expressed in ER-negative compared to those in ER-positive breast cancers. We compared RNA expression in 98 human breast cancers (56 ER-positive and 42 ER-negative) to identify phosphatases differentially expressed in ER-negative compared to those in ER-positive breast cancers. We then examined the effects of one selected phosphatase, dual specificity phosphatase 4 (DUSP4), on proliferation, cell growth, migration and invasion, and on signaling pathways using protein microarray analyses of 172 proteins, including phosphoproteins. We identified 48 phosphatase genes are significantly differentially expressed in ER-negative compared to those in ER-positive breast tumors. We discovered that 31 phosphatases were more highly expressed, while 11 were underexpressed specifically in ER-negative breast cancers. The DUSP4 gene is underexpressed in ER-negative breast cancer and is deleted in approximately 50 % of breast cancers. Induced DUSP4 expression suppresses both in vitro and in vivo growths of breast cancer cells. Our studies show that induced DUSP4 expression blocks the cell cycle at the G1/S checkpoint; inhibits ERK1/2, p38, JNK1, RB, and NFkB p65 phosphorylation; and inhibits invasiveness of TNBC cells. These results suggest that that DUSP4 is a critical regulator of the growth and invasion of triple-negative breast cancer cells

Investigation of thermal and magnetic properties of defects in a spin-gap compound NaV2O5

The specific heat, magnetic susceptibility and ESR signals of a Na-deficient vanadate Na_xV_2O_5 (x=1.00 - 0.90) were studied in the temperature range 0.07 - 10 K, well below the transition point to a spin-gap state. The contribution of defects provided by sodium vacancies to the specific heat was observed. It has a low temperature part which does not tend to zero till at least 0.3 K and a high temperature power-like tail appears above 2 K. Such dependence may correspond to the existence of local modes and correlations between defects in V-O layers. The magnetic measurements and ESR data reveal S=1/2 degrees of freedom for the defects, with their effective number increasing in temperature and under magnetic field. The latter results in the nonsaturating magnetization at low temperature. No long-range magnetic ordering in the system of defects was found. A model for the defects based on electron jumps near vacancies is proposed to explain the observed effects. The concept of a frustrated two-dimensional correlated magnet induced by the defects is considered to be responsible for the absence of magnetic ordering.Comment: 6 pages, 8 figure

Functional consequence of the MET-T1010I polymorphism in breast cancer.

Major breast cancer predisposition genes, only account for approximately 30% of high-risk breast cancer families and only explain 15% of breast cancer familial relative risk. The HGF growth factor receptor MET is potentially functionally altered due to an uncommon germline single nucleotide polymorphism (SNP), MET-T1010I, in many cancer lineages including breast cancer where the MET-T1010I SNP is present in 2% of patients with metastatic breast cancer. Expression of MET-T1010I in the context of mammary epithelium increases colony formation, cell migration and invasion in-vitro and tumor growth and invasion in-vivo. A selective effect of MET-T1010I as compared to wild type MET on cell invasion both in-vitro and in-vivo suggests that the MET-T1010I SNP may alter tumor pathophysiology and should be considered as a potential biomarker when implementing MET targeted clinical trials

Tissue Effects in a Randomized Controlled Trial of Short-term Finasteride in Early Prostate Cancer.

BackgroundIn the Prostate Cancer Prevention Trial, finasteride selectively suppressed low-grade prostate cancer and significantly reduced the incidence of prostate cancer in men treated with finasteride compared with placebo. However, an apparent increase in high-grade disease was also observed among men randomized to finasteride. We aimed to determine why and hypothesized that there is a grade-dependent response to finasteride.MethodsFrom 2007 to 2012, we randomized dynamically by intranet-accessible software 183 men with localized prostate cancer to receive 5mg finasteride or placebo daily in a double-blind study during the 4-6weeks preceding prostatectomy. As the primary end point, the expression of a predefined molecular signature (ERβ, UBE2C, SRD5A2, and VEGF) differentiating high- and low-grade tumors in Gleason grade (GG) 3 areas of finasteride-exposed tumors from those in GG3 areas of placebo-exposed tumors, adjusted for Gleason score (GS) at prostatectomy, was compared. We also determined androgen receptor (AR) levels, Ki-67, and cleaved caspase 3 to evaluate the effects of finasteride on the expression of its downstream target, cell proliferation, and apoptosis, respectively. The expression of these markers was also compared across grades between and within treatment groups. Logistic regression was used to assess the expression of markers.FindingsWe found that the predetermined molecular signature did not distinguish GG3 from GG4 areas in the placebo group. However, AR expression was significantly lower in the GG4 areas of the finasteride group than in those of the placebo group. Within the finasteride group, AR expression was also lower in GG4 than in GG3 areas, but not significantly. Expression of cleaved caspase 3 was significantly increased in both GG3 and GG4 areas in the finasteride group compared to the placebo group, although it was lower in GG4 than in GG3 areas in both groups.InterpretationWe showed that finasteride's effect on apoptosis and AR expression is tumor grade dependent after short-term intervention. This may explain finasteride's selective suppression of low-grade tumors observed in the PCPT

Multiple Front Propagation Into Unstable States

The dynamics of transient patterns formed by front propagation in extended nonequilibrium systems is considered. Under certain circumstances, the state left behind a front propagating into an unstable homogeneous state can be an unstable periodic pattern. It is found by a numerical solution of a model of the Fr\'eedericksz transition in nematic liquid crystals that the mechanism of decay of such periodic unstable states is the propagation of a second front which replaces the unstable pattern by a another unstable periodic state with larger wavelength. The speed of this second front and the periodicity of the new state are analytically calculated with a generalization of the marginal stability formalism suited to the study of front propagation into periodic unstable states. PACS: 47.20.Ky, 03.40.Kf, 47.54.+rComment: 12 page

The Close AGN Reference Survey (CARS) A massive multi-phase outflow impacting the edge-on galaxy HE 1353-1917

Open Access article, published by EDP Sciences, under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Open Access funding provided by Max Planck Society.Context. Galaxy-wide outflows driven by star formation and/or an active galactic nucleus (AGN) are thought to play a crucial rule in the evolution of galaxies and the metal enrichment of the inter-galactic medium. Direct measurements of these processes are still scarce and new observations are needed to reveal the nature of outflows in the majority of the galaxy population. Aims. We combine extensive, spatially-resolved, multi-wavelength observations, taken as part of the Close AGN Reference Survey (CARS), for the edge-on disc galaxy HE 1353-1917 in order to characterise the impact of the AGN on its host galaxy via outflows and radiation. Methods. Multi-color broad-band photometry was combined with spatially-resolved optical, near-infrared (NIR) and sub-mm and radio observations taken with the Multi-Unit Spectroscopy Explorer (MUSE), the Near-infrared Integral Field Spectrometer (NIFS), the Atacama Large Millimeter Array (ALMA), and the Karl G. Jansky Very Large Array (VLA) to map the physical properties and kinematics of the multi-phase interstellar medium. Results. We detect a biconical extended narrow-line region ionised by the luminous AGN orientated nearly parallel to the galaxy disc, extending out to at least 25 kpc. The extra-planar gas originates from galactic fountains initiated by star formation processes in the disc, rather than an AGN outflow, as shown by the kinematics and the metallicity of the gas. Nevertheless, a fast, multi-phase, AGN-driven outflow with speeds up to 1000 km s(-1) is detected close to the nucleus at 1 kpc distance. A radio jet, in connection with the AGN radiation field, is likely responsible for driving the outflow as confirmed by the energetics and the spatial alignment of the jet and multi-phase outflow. Evidence for negative AGN feedback suppressing the star formation rate (SFR) is mild and restricted to the central kpc. But while any SFR suppression must have happened recently, the outflow has the potential to greatly impact the future evolution of the galaxy disc due to its geometrical orientation. Conclusions.. Our observations reveal that low-power radio jets can play a major role in driving fast, multi-phase, galaxy-scale outflows even in radio-quiet AGN. Since the outflow energetics for HE 1353-1917 are consistent with literature, scaling relation of AGN-driven outflows the contribution of radio jets as the driving mechanisms still needs to be systematically explored.© B. Husemann et al. 2019We thank the referee for providing very valuable comments, which significantly improved the quality of the manuscript. MK acknowledges support from DLR grant 50OR1802. GRT acknowledges support from the NASA through Einstein Postdoctoral Fellowship Award Number PF-150128, issued by the Chandra X-ray Observatory Center, which is operated by the Smithsonian Astrophysical Observatory for and on behalf of NASA under contract NAS8-03060. MG is supported by the Lyman Spitzer Jr. Fellowship (Princeton University) and by NASA Chandra grants GO7-18121X/GO8-19104X. SMC acknowledges support from the Australian Research Council (DP190102714). We thank Alex Markowitz for helpful discussions on the RGS data in the context of warm absorbers. The work of SAB, CPO and MS was supported by a generous grant from the Natural Sciences and Engineering Research Council of Canada. Based on observations collected at the European Organization for Astronomical Research in the Southern Hemisphere under ESO programme 095. B-0015(A). Based on observations obtained at the Gemini Observatory, which is operated by the Association of Universities for Research in Astronomy, Inc., under a cooperative agreement with the NSF on behalf of the Gemini partnership: the National Science Foundation (United States), National Research Council (Canada), CONICYT (Chile), Ministerio de Ciencia, Tecnologia e Innovacion Productiva (Argentina), Ministerio da Ciencia, Tecnologia e Inovacao (Brazil), and Korea Astronomy and Space Science Institute (Republic of Korea). Based on observations obtained at the Southern Astrophysical Research (SOAR) telescope, which is a joint project of the Ministerio da Ciencia, Tecnologia, Inovacoes e Comunicacoes (MCTIC) do Brasil, the U.S. National Optical Astronomy Observatory (NOAO), the University of North Carolina at Chapel Hill (UNC), and Michigan State University (MSU). Based on observations collected at the German-Spanish Astronomical Center, Calar Alto, jointly operated by the Max-Planck-Institut fur Astronomie Heidelberg and the Instituto de Astrofiica de Andaluci (CSIC). This paper makes use of the following ALMA data: ADS/JAO.ALMA#2016.1.00952. S. ALMA is a partnership of ESO (representing its member states), NSF (USA) and NINS (Japan), together with NRC (Canada), MOST and ASIAA (Taiwan), and KASI (Republic of Korea), in cooperation with the Republic of Chile. The Joint ALMA Observatory is operated by ESO, AUI/NRAO and NAOJ. This work is based on observations obtained with XMM-Newton, an ESA science mission with instruments and contributions directly funded by ESA Member States and NASA. The VLA is operated by the National Radio Astronomy Observatory, a facility of the National Science Foundation operated under cooperative agreement by Associated Universities, Inc. Herschel is an ESA space observatory with science instruments provided by European-led Principal Investigator consortia and with important participation from NASA. This publication makes use of data products from the Wide-field Infrared Survey Explorer, which is a joint project of the University of California, Los Angeles, and the Jet Propulsion Laboratory/California Institute of Technology, funded by the National Aeronautics and Space Administration. This research has made use of the NASA/IPAC Infrared Science Archive, which is operated by the Jet Propulsion Laboratory, California Institute of Technology, under contract with the National Aeronautics and Space Administration. The Pan-STARRS1 Surveys (PS1) and the PS1 public science archive have been made possible through contributions by the Institute for Astronomy, the University of Hawaii, the Pan-STARRS Project Office, the Max-Planck Society and its participating institutes, the Max Planck Institute for Astronomy, Heidelberg and the Max Planck Institute for Extraterrestrial Physics, Garching, The Johns Hopkins University, Durham University, the University of Edinburgh, the Queen's University Belfast, the Harvard-Smithsonian Center for Astrophysics, the Las Cumbres Observatory Global Telescope Network Incorporated, the National Central University of Taiwan, the Space Telescope Science Institute, the National Aeronautics and Space Administration under Grant No. NNX08AR22G issued through the Planetary Science Division of the NASA Science Mission Directorate, the National Science Foundation Grant No. AST-1238877, the University of Maryland, Eotvos Lorand University (ELTE), the Los Alamos National Laboratory, and the Gordon and Betty Moore Foundation. This work is based in part on observations made with the Galaxy Evolution Explorer (GALEX). GALEX is a NASA Small Explorer, whose mission was developed in cooperation with the Centre National d'Etudes Spatiales (CNES) of France and the Korean Ministry of Science and Technology. GALEX is operated for NASA by the California Institute of Technology under NASA contract NAS5-98034

Cancer-Preventive Rexinoid Modulates Neutral Lipid Contents of Mammary Epithelial Cells through a Peroxisome Proliferator- Activated Receptor ␥-Dependent Mechanism

ABSTRACT Synthetic rexinoids effectively suppress both estrogen receptor-positive and estrogen receptor-negative mammary tumors in animal models, which makes them prime candidates for a novel class of cancer-preventive agents. When used in combination with chemotherapy for non-small-cell lung cancer, the rexinoid bexarotene was most effective for patients who developed hypertriglyceridemia as a side effect. Although serum triglycerides originate from the liver, the effect of bexarotene on lipogenesis in breast epithelial cells is not known. Gene expression studies with normal mammary epithelial cells indicated that rexinoids modulate lipid metabolism, particularly enzymes involved in triglyceride synthesis. High-content analysis revealed dose-dependent accumulation of neutral lipids within adipocyte differentiation-related protein-associated cytoplasmic lipid droplets after long-term bexarotene treatment. Bexarotene also induced mRNA and protein levels for peroxisome proliferator-activated receptor (PPAR) ␥, whereas selective knockdown of PPAR␥ attenuated the induction of both lipid droplets and adipocyte differentiation-related protein. Pharmacological activation of PPAR␥, but not PPAR␣ or retinoic acid receptors, effectively induced lipid accumulation. Furthermore, the combination of the PPAR␥ agonist rosiglitazone with bexarotene synergistically suppressed the growth of human mammary epithelial cells and revealed a strong, nonlinear, inverse correlation of cell growth with lipid droplet accumulation in the cell population. These findings indicate that rexinoids activate a lipogenic program in mammary epithelial cells through a retinoid X receptor/PPAR␥-mediated mechanism. It is noteworthy that combining low doses of bexarotene with the PPAR␥ agonist rosiglitazone provides effective growth suppression of mammary epithelial cells, potentially dissociating systemic adverse effects associated with standard bexarotene treatment from the antiproliferative effects on mammary epithelium

The Inter-organizational Business Case in ES Implementations: Exploring the Impact of Coordination Structures and Their Properties

Developing the business case (BC) for an inter-organizational network is a major challenge. Factors like competition and differences in semantics between actors influence the stakeholders’ willingness to share information necessary for the BC development. In this paper we develop an exploratory framework showing the effect that coordination structure and project scope have on the development of a shared BC. We defined several coordination properties, such as competition, decision making location and decision power that mitigate this effect. We applied the framework in a case study where a BC is developed for an inter-organizational network. Our findings show that current BC development methods need to be re-stated and complemented by extra tools and interventions to support stakeholders in the inter-organizational specific setting

Risk indicators of elder mistreatment in the community

This study examined risk indicators of chronic verbal aggression, physical aggression, and financial mistreatment in a population-based sample of 1,797 independently living elderly in Amsterdam, The Netherlands. Included were socio-demographic characteristics, physical and psychological health, and functional capacity. The data were collected using standardized interviews that took place in the homes of the respondents. The results showed that chronic verbal aggression was associated with an elder living with a partner or other(s) and in poor or bad health. Physical aggression was associated with an elder living with a partner or other(s) and having depressive symptoms. Finally, financial mistreatment was associated with being male, living alone, being partially dependent in instrumental activities of daily living and having depressive symptoms. The results indicate that the risk indicators of victims of financial mistreatment differ from those of chronic verbal aggression and physical aggression, suggesting that financial mistreatment may occur more often as a single form of abuse whereas verbal and physical aggression may more frequently occur together