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Interferon-Induced Transmembrane Protein 1 (IFITM1) Overexpression

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Interferon-Induced Transmembrane Protein 1 (IFITM1) Overexpression Ogony et al. Breast Cancer Research (2016) 18:25 DOI 10.1186/s13058-016-0683-7 RESEARCHARTICLE Open Access Interferon-induced transmembrane protein 1(IFITM1) overexpression enhances the aggressive phenotype of SUM149 inflammatory breast cancer cells in a signal transducer and activator of transcription 2 (STAT2)-dependent manner Joshua Ogony1, Hye Joung Choi1, Asona Lui1,2, Massimo Cristofanilli3 and Joan Lewis-Wambi1* Abstract Background: Inflammatory breast cancer (IBC) is a very aggressive and lethal subtype of breast cancer that accounts for about 4 % of all breast cancers diagnosed in the United States. Despite the efforts of several investigators to identify the molecular factors driving the aggressive phenotype of IBC, a great deal is still unknown about the molecular underpinnings of the disease. In the present study, we investigated the role of interferon-induced transmembrane protein 1 (IFITM1), a well-known interferon-stimulated gene (ISG), in promoting the aggressiveness of SUM149 IBC cells. Methods: Western blot and real-time polymerase chain reaction analyses were performed to assess the protein and messenger RNA (mRNA) levels of IFITM1 and other ISGs in three IBC cell lines: SUM149, MDA-IBC-3, and SUM190. IFITM1 expression and cellular localization were assessed by using immunofluorescence, while the tumorigenic potential was assessed by performing cell migration, invasion, and colony formation assays. Small interfering RNA and short hairpin RNA knockdowns, enzyme-linked immunosorbent assays, and luciferase assays were performed to determine the functional significance of IFITM1 and signal transducers and activators of transcription 1 and 2 (STAT1/2) in SUM149 cells. Results: We found that IFITM1 was constitutively overexpressed at the mRNA and protein levels in triple-negative SUM149 IBC cells, but that it was not expressed in SUM190 and MDA-IBC-3 IBC cells, and that suppression of IFITM1 or blockade of the IFNα signaling pathway significantly reduced the aggressive phenotype of SUM149 cells. Additionally, we found that knockdown of STAT2 abolished IFITM1 expression and IFITM1 promoter activity in SUM149 cells and that loss of STAT2 significantly inhibited the ability of SUM149 cells to proliferate, migrate, invade, and form 2-D colonies. Notably, we found that STAT2-mediated activation of IFITM1 was particularly dependent on the chromatin remodeler brahma-related gene 1 (BRG1), which was significantly elevated in SUM149 cells compared with SUM190 and MDA-IBC-3 cells. (Continued on next page) * Correspondence: [email protected] 1Department of Cancer Biology, University of Kansas Medical Center, Kansas City, KS, USA Full list of author information is available at the end of the article © 2016 Ogony et al. Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Ogony et al. Breast Cancer Research (2016) 18:25 Page 2 of 19 (Continued from previous page) Conclusions: These findings indicate that overexpression of IFITM1 enhances the aggressive phenotype of triple-negative SUM149 IBC cells and that this effect is dependent on STAT2/BRG1 interaction. Further studies are necessary to explore the potential of IFITM1 as a novel therapeutic target and prognostic marker for some subtypes of IBCs. Keywords: Inflammatory breast cancer, IFITM1, JAK/STAT signaling, Interferon-stimulated genes, BRG1 Background signaling, resulting in increased expression of ISGs, Inflammatory breast cancer (IBC) is one of the most ag- might play a role in tumorigenesis and contribute to gressive and lethal subtypes of human breast cancer, ac- poor patient prognosis [10–13]. Indeed, increased expres- counting for about 4 % of all breast cancer cases diagnosed sion of IFITM1, a well-known ISG, has been shown to in the United States. A recent study published by Fouad et correlate with disease progression, resistance to endocrine al. [1] showed that the 5-year overall survival for patients therapy and chemotherapy, and worse overall prognosis in diagnosed with stage IV IBC is significantly lower than that patients with gastrointestinal, colorectal, and breast can- of patients diagnosed with stage IV non-IBC, emphasizing cers [14, 15]. the lethality of IBC [2–5]. In the last decade, remarkable IFITM1 is a member of the IFITM protein family progress has been made toward genomic profiling of IBC, whose expression is strongly induced by type I IFNs leading to identification of molecular alterations commonly [16]. It was initially identified as a leukocyte antigen that found in these tumors. The most notable alterations that is part of a membrane complex involved in the transduc- have been reported include lack of estrogen and progester- tion of antiproliferative and homotypic cell adhesion sig- one receptors (ER−/PR−); overexpression of epidermal nals in lymphocytes [17]. Most recently, however, there growth factor receptor, ERBB2/human epidermal growth has been evidence to suggest that IFITM1 might also factor receptor 2 (HER2), E-cadherin, eIF4GI, chemokines, play a role in tumorigenesis. IFITM1 has been shown to and chemokine receptors; dysfunction of mucin 1; high be overexpressed in several types of cancers, including proliferation; tumor protein 53 mutations; and elevated colorectal, gastrointestinal, head and neck, and breast angiogenesis [6]. Despite these efforts, however, there is cancers, and its overexpression positively correlates with still a great deal that is not known about the biology of IBC tumor progression and increased invasiveness [14, 18–21]. or the factors that drive its aggressive phenotype. We hypothesized that hyperactivation of the IFNα sig- A recent study by the international IBC consortium naling pathway drives IFITM1 overexpression, which reported that the interferon alpha (IFNα) signaling path- enhances the aggressive phenotype of IBC cells. way was significantly upregulated in IBC [7]. Interferons In this study, we measured IFITM1 expression in three (IFNs) are cytokines that affect biological responses IBC cell lines—SUM149, SUM190, and MDA-IBC- through the Janus kinase/signal transducer and activator 3—and in a non-IBC breast cancer cell line, MCF-7. We of transcription (JAK-STAT) signaling pathway. This path- found that IFITM1 was highly expressed in SUM149 way involves IFNs, which, acting as ligands, bind their cor- cells, which are ER−/PR−/HER2−, but not expressed in responding receptors [interferon (alpha, beta and omega) HER2-overexpressing SUM190 and MDA-IBC-3 cells or receptor (IFNAR)/interferon gamma receptor], resulting ER+/PR+ MCF-7 cells. We also found that IFITM1 over- in the phosphorylation and activation of STAT1 and expression promoted—whereas its knockdown inhibi- STAT2 and subsequent transcription of interferon- ted—proliferation, migration, invasion, and tumorigenicity stimulated genes (ISGs), which include STAT1, STAT2, in SUM149 cells. Additionally, we determined that block- phospholipid scramblase 1 (PLSCR1), interferon-induced ade of IFNα signaling using a neutralizing antibody against transmembrane protein 1 (IFITM1), interferon-inducible its receptor, IFNAR1/2, or knockdown of STAT2 and the protein 27 (IFI27), interferon-induced protein with tetra- chromatin remodeling protein BRG1, dramatically re- tricopeptide repeats 1 (IFIT1), and many others [8]. The duced IFITM1 expression and the tumorigenic potential transcription of these ISGs requires the remodeling of of SUM149 cells. These findings suggest a critical role for their promoter regions to increase accessibility to tran- IFNα signaling and STAT2-mediated activation of IFITM1 scription factors. Brahma-related gene 1 (BRG1), which is in promoting the aggressiveness of triple-negative the adenosine triphosphate (ATP) subunit of the brahma- SUM149 IBC cells; however, additional studies need to be associated factor (BAF) complex, is responsible for the performed in other triple-negative inflammatory breast remodeling of the promoter region of many ISGs and cancer (TNIBC) cell lines as well as in IBC tumors to val- is recruited to its site of action by STAT2 [9]. Several idate the biological and clinical significance of these find- studies have suggested that altered type I IFNα/IFNβ ings in IBC. Ogony et al. Breast Cancer Research (2016) 18:25 Page 3 of 19 Methods were performed in 6-well plates as per the protocol pub- Reagents lished by Debeb et al. [22]. Briefly, the base layer was Ham’sF-12(1×)nutrientmixture(cataloguenumber made of 2 ml of medium containing 1 % FBS and 0.5 % 11765-054), RPMI 1640 medium (catalogue number agarose (A9539-100G; Sigma-Aldrich). A quantity of 5 × 11875-093), fetal bovine serum (FBS; catalogue number 104 cells was layered onto the base in 2 ml of medium 16000-044), antibiotic/antimycotic solution (containing containing 1 % FBS and 0.35 % agarose. The plates were 10,000 U/ml penicillin, 10 mg/ml streptomycin, and 25 μg/ briefly cooled at 4 °C so that agarose could solidify be- ml Fungizone®), minimum essential medium nonessential fore the growth medium was added, and the plates
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