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: Majid Momeny, Jodi M Saunus, Flavia Marturana, Amy E McCart Reed, Debra Black, Gianluca Sala, Stefano Iacobelli, Jane D Holland, Dihua Yu, Leonard Da Silva, Peter T Simpson, Kum Kum Khanna, Georgia Chenevix-Trench, Sunil R Lakhani
• Journal: Oncotarget (Oncotarget) Vol. 6 Issue 6 Pg. 3932-46 (Feb 28 2015) ISSN: 1949-2553 [Electronic] United States
• PMID: 25668816 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• NRG1 protein, human
• Neuregulin-1
• ERBB2 protein, human
• ERBB3 protein, human
• Receptor, ErbB-2
• Receptor, ErbB-3
• Matrix Metalloproteinase 2
• Matrix Metalloproteinase 9

Topics

• Blood-Brain Barrier (enzymology, metabolism, pathology)
• Brain (blood supply)
• Breast Neoplasms (enzymology, genetics, metabolism, pathology)
• Cell Line, Tumor
• Cell Movement (physiology)
• Endothelial Cells (metabolism)
• Female
• Humans
• MCF-7 Cells
• Matrix Metalloproteinase 2 (metabolism)
• Matrix Metalloproteinase 9 (metabolism)
• Neuregulin-1 (metabolism)
• Receptor, ErbB-2 (metabolism)
• Receptor, ErbB-3 (metabolism)
• Signal Transduction