Heregulin-HER3-HER2 signaling promotes matrix metalloproteinase-dependent blood-brain-barrier transendothelial migration of human breast cancer cell lines

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// Majid Momeny 1 , Jodi M. Saunus 1, 2 , Flavia Marturana 1 , Amy E. McCart Reed 1, 2 , Debra Black 1, 2 , Gianluca Sala 3 , Stefano Iacobelli 3 , Jane D. Holland 4 , Dihua Yu 5 , Leonard Da Silva 1, 7 , Peter T. Simpson 1, 2, 7 , Kum Kum Khanna 2 , Georgia Chenevix-Trench 2 , Sunil R. Lakhani 1, 6, 7 1 University of Queensland, UQ Center for Clinical Research, Herston, QLD, Australia 2 QIMR Berghofer Medical Research Institute, Herston, QLD, Australia 3 Mediapharma s.r.l., Chieti, Italy 4 Department of Cancer Research, Max Delbruck Center for Molecular Medicine, Berlin, Germany 5 Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA 6 Pathology Queensland, The Royal Brisbane & Women’s Hospital, Herston, QLD Australia 7 The University of Queensland School of Medicine, Herston, QLD Australia Correspondence to: Sunil R. Lakhani, e-mail: s.lakhani@uq.edu.au Keywords: Heregulin, HER2, HER3, blood-brain-barrier, matrix metalloproteinase, breast cancer-brain metastases Received: July 23, 2014 Accepted: December 05, 2014 Published: February 19, 2015 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.

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