title: Heregulin-HER3-HER2 signaling promotes matrix metalloproteinase-dependent blood-brain-barrier transendothelial migration of human breast cancer cell lines.
abstract: HER2-positive breast tumors are associated with a high risk of brain relapse. HER3 is thought to be an indispensible signaling substrate for HER2 (encoded by ERBB2) and is induced in breast cancer-brain metastases, though the molecular mechanisms by which this oncogenic dimer promotes the development of brain metastases are still elusive. We studied the effects of the HER3-HER2 ligand, heregulin (neuregulin-1, broadly expressed in the brain), on luminal breast cancer cell lines in vitro. Treatment of SKBr3 (ERBB2-amplified), MDA-MB-361 (ERBB2-amplified, metastatic brain tumor-derived) and MCF7 (HER2-positive, not ERBB2-amplified) cells with exogenous heregulin increased proliferation and adhesive potential, concomitant with induction of cyclin D1 and ICAM-1, and suppression of p27. All three cell lines invaded through matrigel toward a heregulin chemotactic signal in transwell experiments, associated with activation of extracellular cathepsin B and matrix metalloproteinase-9 (MMP-9). Moreover, heregulin induced breast cancer cell transmigration across a tight barrier of primary human brain microvascular endothelia. This was dependent on the activity of HER2, HER3 and MMPs, and was completely abrogated by combination HER2-HER3 blockade using Herceptin® and the humanized HER3 monoclonal antibody, EV20. Collectively these data suggest mechanisms by which the HER3-HER2 dimer promotes development of metastatic tumors in the heregulin-rich brain microenvironment.
authors: University of Queensland, UQ Center for Clinical Research, Herston, QLD, Australia.
authors: Majid
authors: M
authors: Momeny
authors: University of Queensland, UQ Center for Clinical Research, Herston, QLD, Australia.|QIMR Berghofer Medical Research Institute, Herston, QLD, Australia.
authors: Jodi M
authors: JM
authors: Saunus
authors: University of Queensland, UQ Center for Clinical Research, Herston, QLD, Australia.
authors: Flavia
authors: F
authors: Marturana
authors: University of Queensland, UQ Center for Clinical Research, Herston, QLD, Australia.|QIMR Berghofer Medical Research Institute, Herston, QLD, Australia.
authors: Amy E
authors: AE
authors: McCart Reed
authors: University of Queensland, UQ Center for Clinical Research, Herston, QLD, Australia.|QIMR Berghofer Medical Research Institute, Herston, QLD, Australia.
authors: Debra
authors: D
authors: Black
authors: Mediapharma s.r.l., Chieti, Italy.
authors: Gianluca
authors: G
authors: Sala
authors: Mediapharma s.r.l., Chieti, Italy.
authors: Stefano
authors: S
authors: Iacobelli
authors: Department of Cancer Research, Max Delbruck Center for Molecular Medicine, Berlin, Germany.
authors: Jane D
authors: JD
authors: Holland
authors: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors: Dihua
authors: D
authors: Yu
authors: University of Queensland, UQ Center for Clinical Research, Herston, QLD, Australia.|The University of Queensland School of Medicine, Herston, QLD, Australia.
authors: Leonard
authors: L
authors: Da Silva
authors: University of Queensland, UQ Center for Clinical Research, Herston, QLD, Australia.|QIMR Berghofer Medical Research Institute, Herston, QLD, Australia.|The University of Queensland School of Medicine, Herston, QLD, Australia.
authors: Peter T
authors: PT
authors: Simpson
authors: QIMR Berghofer Medical Research Institute, Herston, QLD, Australia.
authors: Kum Kum
authors: KK
authors: Khanna
authors: QIMR Berghofer Medical Research Institute, Herston, QLD, Australia.
authors: Georgia
authors: G
authors: Chenevix-Trench
authors: University of Queensland, UQ Center for Clinical Research, Herston, QLD, Australia.|Pathology Queensland, The Royal Brisbane & Women's Hospital, Herston, QLD, Australia.|The University of Queensland School of Medicine, Herston, QLD, Australia.
authors: Sunil R
authors: SR
authors: Lakhani
mesh_terms: D001812:Blood-Brain Barrier / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D001921:Brain / Q000098:blood supply; D001943:Breast Neoplasms / Q000201:enzymology / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology; D042783:Endothelial Cells / Q000378:metabolism; D005260:Female; D006801:Humans; D061986:MCF-7 Cells; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D020890:Neuregulin-1 / Q000378:metabolism*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D020893:Receptor, ErbB-3 / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D020890:Neuregulin-1; D018719:Erb-b2 Receptor Tyrosine Kinases; D020893:Receptor, ErbB-3; C094131:NRG1 protein, human; C508053:ERBB2 protein, human; C581292:ERBB3 protein, human