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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., Saunus, J.M., Marturana, F., McCart Reed, A.E., Black, D., Sala, G., Iacobelli, S., Holland, J.D., Yu, D., Da Silva, L., Simpson, P.T., Khanna, K.K., 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 |
| 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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