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      Short-Term Microgravity Influences Cell Adhesion in Human Breast Cancer Cells

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          Abstract

          With the commercialization of spaceflight and the exploration of space, it is important to understand the changes occurring in human cells exposed to real microgravity (r-µ g) conditions. We examined the influence of r-µ g, simulated microgravity (s-µ g, incubator random positioning machine (iRPM)), hypergravity (hyper- g), and vibration (VIB) on triple-negative breast cancer (TNBC) cells (MDA-MB-231 cell line) with the aim to study early changes in the gene expression of factors associated with cell adhesion, apoptosis, nuclear factor “kappa-light-chain-enhancer” of activated B-cells (NF-κB) and mitogen-activated protein kinase (MAPK) signaling. We had the opportunity to attend a parabolic flight (PF) mission and to study changes in RNA transcription in the MDA-MB cells exposed to PF maneuvers (29th Deutsches Zentrum für Luft- und Raumfahrt (DLR) PF campaign). PF maneuvers induced an early up-regulation of ICAM1, CD44 and ERK1 mRNAs after the first parabola (P1) and a delayed upregulation of NFKB1, NFKBIA, NFKBIB, and FAK1 after the last parabola (P31). ICAM-1, VCAM-1 and CD44 protein levels were elevated, whereas the NF-κB subunit p-65 and annexin-A2 protein levels were reduced after the 31st parabola (P31). The PRKCA, RAF1, BAX mRNA were not changed and cleaved caspase-3 was not detectable in MDA-MB-231 cells exposed to PF maneuvers. Hyper- g-exposure of the cells elevated the expression of CD44 and NFKBIA mRNAs, iRPM-exposure downregulated ANXA2 and BAX, whereas VIB did not affect the TNBC cells. The early changes in ICAM-1 and VCAM-1 and the rapid decrease in the NF-κB subunit p-65 might be considered as fast-reacting, gravity-regulated and cell-protective mechanisms of TNBC cells exposed to altered gravity conditions. This data suggest a key role for the detected gravity-signaling elements in three-dimensional growth and metastasis.

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          Breast cancer intrinsic subtype classification, clinical use and future trends.

          Breast cancer is composed of multiple subtypes with distinct morphologies and clinical implications. The advent of microarrays has led to a new paradigm in deciphering breast cancer heterogeneity, based on which the intrinsic subtyping system using prognostic multigene classifiers was developed. Subtypes identified using different gene panels, though overlap to a great extent, do not completely converge, and the avail of new information and perspectives has led to the emergence of novel subtypes, which complicate our understanding towards breast tumor heterogeneity. This review explores and summarizes the existing intrinsic subtypes, patient clinical features and management, commercial signature panels, as well as various information used for tumor classification. Two trends are pointed out in the end on breast cancer subtyping, i.e., either diverging to more refined groups or converging to the major subtypes. This review improves our understandings towards breast cancer intrinsic classification, current status on clinical application, and future trends.
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            Targeting Apoptosis Pathways in Cancer Therapy

            Apoptosis, or programmed cell death, is a mechanism by which cells undergo death to control cell proliferation or in response to DNA damage. The understanding of apoptosis has provided the basis for novel targeted therapies that can induce death in cancer cells or sensitize them to established cytotoxic agents and radiation therapy. These novel agents include those targeting the extrinsic pathway such as tumor necrosis factor-related apoptosis-inducing ligand receptor 1, and those targeting the intrinsic Bcl-2 family pathway such as antisense bcl-2 oligonucleotides. Many pathways and proteins control the apoptosis machinery. Examples include p53, the nuclear factor kappa B, the phosphatidylinositol 3 kinase pathway, and the ubiquitin/proteosome pathway. These can be targeted by specific modulators such as bortezomib, and mammalian target of rapamycin inhibitors such as CCI-779 and RAD 001. Because these pathways may be preferentially altered in tumor cells, there is potential for a selective effect in tumors sparing normal tissue. This article reviews the current understanding of the apoptotic pathways, including the extrinsic (cytoplasmic) and intrinsic (mitochondrial) pathways, and the agents being developed to target these pathways.
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              Breast tumor cell lines from pleural effusions.

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                Author and article information

                Journal
                Int J Mol Sci
                Int J Mol Sci
                ijms
                International Journal of Molecular Sciences
                MDPI
                1422-0067
                15 November 2019
                November 2019
                : 20
                : 22
                : 5730
                Affiliations
                [1 ]Clinic for Plastic, Aesthetic and Hand Surgery, Otto von Guericke University Magdeburg, 39120 Magdeburg, Germany; mohamed.nassef@ 123456med.ovgu.de (M.Z.N.); daniela.melnik@ 123456med.ovgu.de (D.M.); marcus.krueger@ 123456med.ovgu.de (M.K.); markus.wehland@ 123456med.ovgu.de (M.W.); thomas.bauer@ 123456med.ovgu.de (T.J.B.); manfred.infanger@ 123456med.ovgu.de (M.I.)
                [2 ]Department of Biomedicine, Aarhus University, 8000 Aarhus C, Denmark; corydon@ 123456biomed.au.dk (T.J.C.);
                [3 ]Department of Ophthalmology, Aarhus University Hospital, 8200 Aarhus N, Denmark
                [4 ]Institute of Aerospace Medicine, Department of Gravitational Biology, German Aerospace Center, 51147 Cologne, Germany; christian.liemersdorf@ 123456dlr.de (C.L.); ruth.hemmersbach@ 123456dlr.de (R.H.)
                [5 ]Gravitational Biology and Translational Regenerative Medicine, Faculty of Medicine and Mechanical Engineering, Otto von Guericke University, 39120 Magdeburg, Germany
                Author notes
                [* ]Correspondence: sascha.kopp@ 123456med.ovgu.de (S.K.); dgg@ 123456biomed.au.dk (D.G.); Tel.: +49-391-6721267 (S.K.); +45-871-67693 (D.G.)
                Author information
                https://orcid.org/0000-0003-3588-6350
                https://orcid.org/0000-0003-1120-0246
                https://orcid.org/0000-0001-8407-5226
                Article
                ijms-20-05730
                10.3390/ijms20225730
                6887954
                31731625
                92da40ca-94dd-4a26-81b9-09a42e3aa7d4
                © 2019 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 11 October 2019
                : 12 November 2019
                Categories
                Article

                Molecular biology
                breast cancer cells,microgravity,hypergravity,cell adhesion,apoptosis,nf-κb
                Molecular biology
                breast cancer cells, microgravity, hypergravity, cell adhesion, apoptosis, nf-κb

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