PMID- 27717868 OWN - NLM STAT- MEDLINE DCOM- 20171225 LR - 20180131 IS - 1873-4596 (Electronic) IS - 0891-5849 (Linking) VI - 101 DP - 2016 Dec TI - Intermittent hypoxia confers pro-metastatic gene expression selectively through NF-kappaB in inflammatory breast cancer cells. PG - 129-142 LID - S0891-5849(16)30443-9 [pii] LID - 10.1016/j.freeradbiomed.2016.10.002 [doi] AB - Inflammatory breast cancer (IBC) is the most aggressive form of breast cancer. Treatment options are limited and the mechanisms underlying its aggressiveness are poorly understood. Intermittent hypoxia (IH) causes oxidative stress and is emerging as important regulator of tumor metastasis. Vessels in IBC tumors have been shown to be immature, which is a primary cause of IH. We therefore investigated the relevance of IH for the modulation of gene expression in IBC cells in order to assess IH as potential regulator of IBC aggressiveness. Gene array analysis of IBC cells following chronic IH (45-60 days) demonstrated increased expression of pro-metastatic genes of the extracellular matrix, such as tenascin-C (TNC; an essential factor of the metastatic niche) and matrix metalloproteinase 9 (MMP9), and of pro-inflammatory processes, such as cyclooxygenase-2 (COX-2). Investigating the oxidative stress-dependent regulation of TNC, we found a gradual sensitivity on mRNA and protein levels. Oxidative stress activated NF-E2-related factor 2 (Nrf2), c-Jun N-terminal kinase (JNK), c-Jun and nuclear factor kappaB (NF-kappaB), but TNC upregulation was only dependent on NF-kappaB activation. Pharmacological inhibition of inhibitor of NF-kappaB alpha (IkappaBalpha) phosphorylation as well as overexpression of IkappaBalpha prevented TNC, MMP9 and COX-2 induction, whereas the pro-inflammatory cytokine interleukin-1beta (IL-1beta) increased their expression levels. Analysis of the gene array data showed NF-kappaB binding sites for 64% of all upregulated genes, linking NF-kappaB with IH-dependent regulation of pro-metastatic gene expression in IBC cells. Our results provide a first link between intermittent hypoxia and pro-metastatic gene expression in IBC cells, revealing a putative novel mechanism for the high metastatic potential of IBC. CI - Copyright (c) 2016 Elsevier Inc. All rights reserved. FAU - Gutsche, Katrin AU - Gutsche K AD - Institute of Physiology, University of Zurich, 8057 Zurich, Switzerland; Zurich Center for Integrative Human Physiology (ZIHP), University of Zurich, 8057 Zurich, Switzerland; Department of Gynecology, University Hospital of Zurich, 8091 Zurich, Switzerland. FAU - Randi, Elisa B AU - Randi EB AD - Institute of Physiology, University of Zurich, 8057 Zurich, Switzerland; Zurich Center for Integrative Human Physiology (ZIHP), University of Zurich, 8057 Zurich, Switzerland. FAU - Blank, Volker AU - Blank V AD - Lady Davis Institute for Medical Research, Department of Medicine & Department of Physiology, McGill University, Montreal, Quebec, Canada H3T 1E2. FAU - Fink, Daniel AU - Fink D AD - Department of Gynecology, University Hospital of Zurich, 8091 Zurich, Switzerland. FAU - Wenger, Roland H AU - Wenger RH AD - Institute of Physiology, University of Zurich, 8057 Zurich, Switzerland; Zurich Center for Integrative Human Physiology (ZIHP), University of Zurich, 8057 Zurich, Switzerland. FAU - Leo, Cornelia AU - Leo C AD - Department Women and Children, Cantonal Hospital Baden, 5404 Baden, Switzerland. Electronic address: cornelia.leo@ksb.ch. FAU - Scholz, Carsten C AU - Scholz CC AD - Institute of Physiology, University of Zurich, 8057 Zurich, Switzerland. Electronic address: carsten.scholz@uzh.ch. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20161005 PL - United States TA - Free Radic Biol Med JT - Free radical biology & medicine JID - 8709159 RN - 0 (3-(4-methylphenylsulfonyl)-2-propenenitrile) RN - 0 (Anthracenes) RN - 0 (IL1B protein, human) RN - 0 (Interleukin-1beta) RN - 0 (NF-E2-Related Factor 2) RN - 0 (NF-kappa B) RN - 0 (NFE2L2 protein, human) RN - 0 (Nitriles) RN - 0 (Proto-Oncogene Proteins c-jun) RN - 0 (Sulfones) RN - 0 (Tenascin) RN - 139874-52-5 (NF-KappaB Inhibitor alpha) RN - 1TW30Y2766 (pyrazolanthrone) RN - EC 1.14.99.1 (Cyclooxygenase 2) RN - EC 1.14.99.1 (PTGS2 protein, human) RN - EC 2.7.11.24 (JNK Mitogen-Activated Protein Kinases) RN - EC 3.4.24.35 (MMP9 protein, human) RN - EC 3.4.24.35 (Matrix Metalloproteinase 9) RN - S88TT14065 (Oxygen) RN - WYQ7N0BPYC (Acetylcysteine) SB - IM MH - Acetylcysteine/pharmacology MH - Anthracenes/pharmacology MH - Cell Hypoxia MH - Cell Line, Tumor MH - Cyclooxygenase 2/genetics/metabolism MH - Epithelial Cells/*drug effects/metabolism/pathology MH - *Gene Expression Regulation, Neoplastic MH - Humans MH - Interleukin-1beta/pharmacology MH - JNK Mitogen-Activated Protein Kinases/antagonists & inhibitors/genetics/metabolism MH - Mammary Glands, Human/drug effects/metabolism/pathology MH - Matrix Metalloproteinase 9/*genetics/metabolism MH - NF-E2-Related Factor 2/genetics/metabolism MH - NF-KappaB Inhibitor alpha/genetics/metabolism MH - NF-kappa B/*genetics/metabolism MH - Neoplasm Metastasis MH - Nitriles/pharmacology MH - Oxidative Stress MH - Oxygen/*pharmacology MH - Phosphorylation/drug effects MH - Proto-Oncogene Proteins c-jun/antagonists & inhibitors/genetics/metabolism MH - Signal Transduction MH - Sulfones/pharmacology MH - Tenascin/*genetics/metabolism OTO - NOTNLM OT - Inflammatory breast cancer OT - Intermittent hypoxia OT - NF-kappaB OT - Oxidative stress OT - ROS OT - Reactive oxygen species OT - Tenascin-C EDAT- 2016/11/05 06:00 MHDA- 2017/12/26 06:00 CRDT- 2016/11/05 06:00 PHST- 2016/05/25 00:00 [received] PHST- 2016/09/14 00:00 [revised] PHST- 2016/10/02 00:00 [accepted] PHST- 2016/11/05 06:00 [pubmed] PHST- 2017/12/26 06:00 [medline] PHST- 2016/11/05 06:00 [entrez] AID - S0891-5849(16)30443-9 [pii] AID - 10.1016/j.freeradbiomed.2016.10.002 [doi] PST - ppublish SO - Free Radic Biol Med. 2016 Dec;101:129-142. doi: 10.1016/j.freeradbiomed.2016.10.002. Epub 2016 Oct 5.