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

Momeny, Majid, Saunus, Jodi M., Marturana, Flavia, McCart Reed, Amy E., Black, Debra, Sala, Gianluca, Iacobelli, Stefano, Holland, Jane D., Yu, Dihua, Da Silva, Leonard, Simpson, Peter T., Khanna, Kum Kum, Chenevix-Trench, Georgia and Lakhani, Sunil R. (2015) Heregulin-HER3-HER2 signaling promotes matrix metalloproteinase-dependent blood-brain-barrier transendothelial migration of human breast cancer cell lines. Oncotarget, 6 6: 3932-3946.

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Author Momeny, Majid
Saunus, Jodi M.
Marturana, Flavia
McCart Reed, Amy E.
Black, Debra
Sala, Gianluca
Iacobelli, Stefano
Holland, Jane D.
Yu, Dihua
Da Silva, Leonard
Simpson, Peter T.
Khanna, Kum Kum
Chenevix-Trench, Georgia
Lakhani, Sunil R.
Title Heregulin-HER3-HER2 signaling promotes matrix metalloproteinase-dependent blood-brain-barrier transendothelial migration of human breast cancer cell lines
Journal name Oncotarget   Check publisher's open access policy
ISSN 1949-2553
Publication date 2015-02-28
Sub-type Article (original research)
Open Access Status File (Author Post-print)
Volume 6
Issue 6
Start page 3932
End page 3946
Total pages 15
Place of publication Albany, NY, United States
Publisher Impact Journals
Collection year 2016
Language eng
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 tumorderived) 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 HerceptinĀ® 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.
Keyword Blood-brain-barrier
Breast cancer-brain metastases
HER2
HER3
Heregulin
Matrix metalloproteinase
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

 
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Created: Wed, 25 Mar 2015, 16:51:28 EST by Peter Simpson on behalf of UQ Centre for Clinical Research