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.
Highlights
The development of brain metastases is a growing public health problem affecting more than 100,000 patients in the United States every year [1], including 10–30% of breast cancer patients [2, 3]
To characterize the expression of heregulin (NRG1 gene) and HER3 (ERBB3 gene) in breast cancer cell line models, and select the most appropriate lines for functional experiments, we investigated the relative baseline mRNA expression levels of ERBB3 and NRG1 (α and β heregulin splice isoforms) in a large panel of breast cancer cell lines by quantitative reverse transcription-PCR
Other key features to note are that MDA-MB-361 and SKBr3 harbor ERBB2 www.impactjournals.com/oncotarget amplification, MDA-MB-361 was isolated from a breast cancer-derived metastatic brain tumor, and SKBr3 cells do not express estrogen receptor (ER-negative) [44]
Summary
The development of brain metastases is a growing public health problem affecting more than 100,000 patients in the United States every year [1], including 10–30% of breast cancer patients [2, 3]. HER2-targeted drug therapies delay the onset of brain metastases in these patients, and improve median survival after a diagnosis of metastatic brain relapse [7,8,9,10]. These observations indicate that HER2 plays a critical role in brain relapse. The www.impactjournals.com/oncotarget molecular mechanisms underpinning this relationship have not been investigated in detail
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