Heregulin-HER3-HER2 signaling promotes matrix metalloproteinase-dependent blood-brain-barrier transendothelial migration of human breast cancer cell lines
| Autor: | Kum Kum Khanna, Flavia Marturana, Georgia Chenevix-Trench, Jodi M. Saunus, Gianluca Sala, Leonard Da Silva, Dihua Yu, Amy E. McCart Reed, Peter T. Simpson, Majid Momeny, Sunil R. Lakhani, Stefano Iacobelli, Jane D. Holland, Debra Black |
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| Rok vydání: | 2014 |
| Předmět: |
medicine.medical_specialty
matrix metalloproteinase Receptor ErbB-3 Receptor ErbB-2 Neuregulin-1 Breast Neoplasms Matrix metalloproteinase Biology Blood–brain barrier blood-brain-barrier Cathepsin B Cyclin D1 Cell Movement HER3 Internal medicine Cell Line Tumor HER2 medicine Humans skin and connective tissue diseases neoplasms Matrigel Heregulin Brain Endothelial Cells breast cancer-brain metastases Endocrinology medicine.anatomical_structure Oncology Matrix Metalloproteinase 9 SKBR3 Blood-Brain Barrier Cancer research MCF-7 Cells Neuregulin Matrix Metalloproteinase 2 Female Signal transduction Signal Transduction Research Paper |
| Zdroj: | Oncotarget |
| ISSN: | 1949-2553 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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