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

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Item Type:Article
Title:Heregulin-HER3-HER2 signaling promotes matrix metalloproteinase-dependent blood-brain-barrier transendothelial migration of human breast cancer cell lines
Creators Name:Momeny, M. and Saunus, J.M. and Marturana, F. and McCart Reed, A.E. and Black, D. and Sala, G. and Iacobelli, S. and Holland, J.D. and Yu, D. and Da Silva, L. and Simpson, P.T. and Khanna, K.K. and Chenevix-Trench, G. and Lakhani, S.R.
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.
Keywords:Heregulin, HER2, HER3, Blood-Brain-Barrier, Matrix Metalloproteinase, Breast Cancer-Brain Metastases
Source:Oncotarget
ISSN:1949-2553
Publisher:Impact Journals (U.S.A.)
Volume:6
Number:6
Page Range:3932-3946
Date:19 February 2015
Official Publication:https://doi.org/10.18632/oncotarget.2846
PubMed:View item in PubMed

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