title: Extracellular matrix protein 1 regulates cell proliferation and trastuzumab resistance through activation of epidermal growth factor signaling.
abstract: BACKGROUND
  Extracellular matrix protein 1 (ECM1) is a secreted glycoprotein with putative functions in cell proliferation, angiogenesis and differentiation. Expression of ECM1 in several types of carcinoma suggests that it may promote tumor development. In this study, we investigated the role of ECM1 in oncogenic cell signaling in breast cancer, and potential mechanisms for its effects.
  
  
  METHODS
  In order to find out the functional role of ECM1, we used the recombinant human ECM1 and viral transduction systems which stably regulated the expression level of ECM1. We examined the effect of ECM1 on cell proliferation and cell signaling in vitro and in vivo. Moreover, tissues and sera of patients with breast cancer were used to confirm the effect of ECM1.
  
  
  RESULTS
  ECM1 protein was increased in trastuzumab-resistant (TR) cells, in association with trastuzumab resistance and cell proliferation. Through physical interaction with epidermal growth factor receptor (EGFR), ECM1 potentiated the phosphorylation of EGFR and extracellular signal-regulated kinase upon EGF treatment. Moreover, ECM1-induced galectin-3 cleavage through upregulation of matrix metalloproteinase 9 not only improved mucin 1 expression, but also increased EGFR and human epidermal growth factor receptor 3 protein stability as a secondary signaling.
  
  
  CONCLUSIONS
  ECM1 has important roles in both cancer development and trastuzumab resistance in breast cancer through activation of EGFR signaling.
authors.affiliation: Department of Life Science, Hanyang University, 222 Wangshimni-ro, Seoul, 133-791, Republic of Korea. realwooma@gmail.com.
authors.forename: Kyung-min
authors.initials: KM
authors.lastname: Lee
authors.affiliation: Department of Life Science, Hanyang University, 222 Wangshimni-ro, Seoul, 133-791, Republic of Korea. namkeesu@naver.com.
authors.forename: Keesoo
authors.initials: K
authors.lastname: Nam
authors.affiliation: Department of Life Science, Hanyang University, 222 Wangshimni-ro, Seoul, 133-791, Republic of Korea. lemonjoa1@hanmail.net.
authors.forename: Sunhwa
authors.initials: S
authors.lastname: Oh
authors.affiliation: Department of Life Science, Hanyang University, 222 Wangshimni-ro, Seoul, 133-791, Republic of Korea. entia2me@hanmail.net.
authors.forename: Juyeon
authors.initials: J
authors.lastname: Lim
authors.affiliation: Department of Life Science, Hanyang University, 222 Wangshimni-ro, Seoul, 133-791, Republic of Korea. ypilkim@hanyang.ac.kr.
authors.forename: Young-Pil
authors.initials: YP
authors.lastname: Kim
authors.affiliation: Department of Surgery, College of Medicine, University of Ulsan and Asan Medical Center, 88 Olympic 43-ro, Seoul, 138-736, Republic of Korea. jjjongwr@hanmail.net.
authors.forename: Jong Won
authors.initials: JW
authors.lastname: Lee
authors.affiliation: Department of Surgery, College of Medicine, University of Ulsan and Asan Medical Center, 88 Olympic 43-ro, Seoul, 138-736, Republic of Korea. lymbics@hanmail.net.
authors.forename: Jong-Han
authors.initials: JH
authors.lastname: Yu
authors.affiliation: Department of Surgery, College of Medicine, University of Ulsan and Asan Medical Center, 88 Olympic 43-ro, Seoul, 138-736, Republic of Korea. ahnsh@amc.seoul.kr.
authors.forename: Sei-Hyun
authors.initials: SH
authors.lastname: Ahn
authors.affiliation: Department of Oncology, College of Medicine, University of Ulsan and Asan Medical Center, 88 Olympic 43-ro, Seoul, 138-736, Republic of Korea. sbkim3@amc.seoul.kr.
authors.forename: Sung-Bae
authors.initials: SB
authors.lastname: Kim
authors.affiliation: Cancer Research Institute, Seoul National University College of Medicine, 101 Daehak-ro, Seoul, 110-744, Republic of Korea. dynoh@snu.ac.kr.
authors.forename: Dong-Young
authors.initials: DY
authors.lastname: Noh
authors.affiliation: NOVA Cell Technology, 77 Cheongam-ro, Pohang, 790-784, Republic of Korea. taehoon@novacelltech.com.
authors.forename: Taehoon
authors.initials: T
authors.lastname: Lee
authors.affiliation: Department of Life Science, Hanyang University, 222 Wangshimni-ro, Seoul, 133-791, Republic of Korea. incheol@hanyang.ac.kr.|Natural Science Institute, Hanyang University, 222 Wangshimni-ro, Seoul, 133-791, Republic of Korea. incheol@hanyang.ac.kr.
authors.forename: Incheol
authors.initials: I
authors.lastname: Shin
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics*; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D004815:Epidermal Growth Factor / Q000378:metabolism; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism; D016326:Extracellular Matrix Proteins / Q000235:genetics* / Q000378:metabolism; D005260:Female; D037502:Galectin 3 / Q000378:metabolism; D006801:Humans; D061986:MCF-7 Cells; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D008819:Mice, Nude; D018396:Mucin-1 / Q000378:metabolism; D009368:Neoplasm Transplantation; D012333:RNA, Messenger / Q000378:metabolism*; D020893:Receptor, ErbB-3 / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D000068878:Trastuzumab
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; C490607:ECM1 protein, human; D016326:Extracellular Matrix Proteins; D037502:Galectin 3; C060192:MUC1 protein, human; D018396:Mucin-1; D012333:RNA, Messenger; D004815:Epidermal Growth Factor; C512478:EGFR protein, human; C581292:ERBB3 protein, human; D066246:ErbB Receptors; D020893:Receptor, ErbB-3; C579270:MMP9 protein, human; D020780:Matrix Metalloproteinase 9; D000068878:Trastuzumab