Heregulin-HER3-HER2 signaling promotes matrix metalloproteinase-dependent blood-brain-barrier transendothelial migration of human breast cancer cell lines
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Majid Momeny1, Jodi M. Saunus1,2, Flavia Marturana1, Amy E. McCart Reed1,2, Debra Black1,2, Gianluca Sala3, Stefano Iacobelli3, Jane D. Holland4, Dihua Yu5, Leonard Da Silva1,7, Peter T. Simpson1,2,7, Kum Kum Khanna2, Georgia Chenevix-Trench2, Sunil R. Lakhani1,6,7
1University of Queensland, UQ Center for Clinical Research, Herston, QLD, Australia
2QIMR Berghofer Medical Research Institute, Herston, QLD, Australia
3Mediapharma s.r.l., Chieti, Italy
4Department of Cancer Research, Max Delbruck Center for Molecular Medicine, Berlin, Germany
5Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
6Pathology Queensland, The Royal Brisbane & Women’s Hospital, Herston, QLD Australia
7The University of Queensland School of Medicine, Herston, QLD Australia
Sunil R. Lakhani, e-mail: [email protected]
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
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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